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CORK Bibliography: Immune System

113 citations. January 2003 to present

Prepared: March 2009

Armentia A. Adverse reactions to wine: Think outside the bottle. (review). Current Opinion in Allergy and Clinical Immunology 8(3): 266-269, 2008. (9 refs.)

Purpose of review: Wine contains chemical and biological contaminants. Symptoms such as facial flushing, asthma and oral allergic swelling and burning (oral syndrome) have been attributed to these contaminants and food additives. Their clinical implications should be known. Recent findings: Recent studies have reported a high prevalence of hypersensitivity symptoms after intake of alcoholic drinks in the general population. Red wine was the most common beverage implicated. Wine contains many contaminants. Some of them come from Hymenoptera insects that fall into the wine when grapes are collected and pressed. We have found patients with allergic symptoms related to wine consumption who are sensitized to Hymenoptera venom without previous stings. The aim of this study is to assess the potential importance of their sensitization to Hymenoptera antigens as the cause of their symptoms and also to comment on other recent studies on wine hypersensitivity. Summary: We found patients with allergic symptoms related to wine consumption who are sensitized to Hymenoptera venoms. Challenges were negative with sulfites, other additives and aging wines, but positive with young wines. Sera from all the patients detected Hymenoptera. venom antigens. We report the first cases of sensitization to venom antigens by the oral route.

Breitmeier D; Becker N; Weilbach C; Albrecht K; Scheinichen D; sdPanning B et al. Ethanol-induced malfunction of neutrophils respiratory burst on patients suffering from alcohol dependence. Alcoholism: Clinical and Experimental Research 32(10): 1708-1713, 2008. (32 refs.)

Background: Polymorphonuclear, neutrophil granulocytes (PMN) play a major role in the control of infections, and people who abuse alcohol are susceptible to infections. Resistance against infections ensues intracellularly following initial phagocytosis of microorganisms with the oxygen-dependent respiratory burst, the key enzyme of which is the respiratory burst oxidase, whereby oxygen radicals are produced for microbial destruction. To date there is insufficient information available in connection with the process of impaired defence against infection in patients suffering from alcohol dependence. Therefore, our investigation was carried out to determine the influence of alcohol exposition on the formation of oxygen radicals and the respiratory burst. Methods: 4.5 ml of whole blood was taken from 10 healthy adults and 10 patients suffering from alcohol dependence. An additional 3.5 ml of whole blood was taken from the alcoholic patients for determination of the blood alcohol concentration. The respiratory burst of PMN was tested using the Four-Colour-Continuous Flow Cytometer. Each experimental procedure consisted of 4 test samples [negative controls, Escherichia coli, FMLP-supplement (N-formyl-l-methionyl-l-leucyl-l-phenylalanin), PMA-supplement (phorbol-12-myristate-13-acetate)]. Differing concentrations of ethanol were also introduced to each of the tests performed (0.20 to 4.00 g/l). Results: Ethanol revealed a marked decrease of burst activity in those patients suffering from alcoholism with increased alcohol concentration. A dependence between the burst activity and the ethanol concentration was seen to be statistically significant. This effect was only evident after stimulation with E. coli and FMLP in those patients with alcohol dependence. Conclusion: The results presented in this study show an impairment in the function of PMN in those patients addicted to alcohol due to the decrease in burst activity. In view of the results of the different stimuli, the second-messenger effects were not evident. A clarification of this phenomenon could well be assumed as an allosteric receptor effect on the burst oxidase, namely, a direct effect on the phagocytosis interaction between circulating granulocytes and causative organisms.

Buttari B; Profumo E; Mancinelli R; Incani UC; Tosti ME; Attilia ML et al. Chronic and acute alcohol exposure prevents monocyte-deried dendritic cells from differentiating and maturing. International Journal of Immunopathology and Pharmacology 21(4): 929-939, 2008. (30 refs.)

Increasing evidence suggests that alcohol abuse may be linked to adverse immunomodulatory effects on immune responses. Our study was undertaken to clarify the immunological consequences of chronic and acute alcohol exposure on differentiation and maturation of human dendritic cells (DCs). Using immunochemical and cytofluorimetric analysis we determined the phenotype and functions of monocyte-derived DCs from alcoholics and healthy subjects and analyzed their ability to respond to lipopolysaccharide (LPS) in the presence or absence of ethanol (EtOH) exposure. Our results showed that alcoholics' monocytes differentiated to immature DCs with altered phenotype and functions (alciDCs). Alc-iDCs showed fewer CD1a(+) cells, weaker CD86 expression and higher HLA-DR expression associated with lower endocytosis and allostimulatory functions than iDCs from healthy subjects (control-iDCs). Despite these impairments, alc-iDCs produced TNF-alpha and IL-6 in large amounts. LPS stimulation failed to induce full phenotypical and functional alc-iDC maturation. In vitro acute EtOH exposure also prevented alc-iDCs and control-iDCs from maturing in response to LPS. T-cell priming experiments showed that EtOH treatment prevented LPS-stimulated control-iDCs from priming and polarizing naive allogeneic T cells into Th1 cells, thus favouring a predominant Th2 environment. Collectively, our results provide evidence that chronic and acute alcohol exposure prevents DCs from differentiating and maturing in response to a microbial stimulus.

Chao C; Jacobson LP; Tashkin D; Martinez-Maza O; Roth MD; Margolick JB et al. Recreational drug use and T lymphocyte subpopulations in HIV-uninfected and HIV-infected men. Drug and Alcohol Dependence 94(1/3): 165-171, 2008. (38 refs.)

The effects of recreational drugs on CD4 and CD8 T cells in humans are not well understood. We conducted a longitudinal analysis of men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study (MACS) to define associations between self-reported use of marijuana, cocaine, poppers and amphetamines, and CD4 and CD8 T cell parameters in both HIV-uninfected and HIV-infected MSM. For the HIV-infected MSM, we used clinical and laboratory data collected semiannually before 1996 to avoid potential effects of antiretroviral treatment. A regression model that allowed random intercepts and slopes as well as autoregressive covariance structure for within subject errors was used. Potential confounders adjusted for included length of follow-up, demographics, tobacco smoking, alcohol use, risky sexual behaviors, history of sexually transmitted infections, and antiviral therapy. We found no clinically meaningful associations between use of marijuana, cocaine, poppers, or amphetamines and CD4 and CD8 T cell counts, percentages, or rates of change in either HIV-uninfected or -infected men. The regression coefficients were of minimum magnitude despite some reaching statistical significance. No threshold effect was detected for frequent (at least weekly) or continuous substance use in the previous year. These results indicate that use of these substances does not adversely affect the numbers and percentages of circulating CD4 or CD8 T cells in either HIV-uninfected or -infected MSM.

Durvasula RS. Alcohol use and neuropsychological performance in persons with HIV/AIDS. (review). International Journal on Disability and Human Development 6(4): 417-429, 2007. (56 refs.)

Both human immunodeficiency virus (HIV) and alcohol use contribute to neuropsychological (NP) impairment, and a relatively large proportion of HIV seropositive individuals have histories of heavy alcohol use. Evidence from neuropathological, and both structural and functional neuroimaging studies have supported the direct central nervous system effects of both HIV and alcohol. HIV preferentially affects frontal regions of the brain as well as subcortical structures including the basal ganglia, while alcohol has been shown to result in cortical atrophy and cerebellar and frontal damage. These central nervous system changes are clinically manifested through psychomotor slowing, memory impairments, slowed reaction time, and executive dysfunction in persons with HIV. Alcohol use and abuse are associated with similar deficits as well as dysfunction in domains including visuoperception. While some studies have observed a synergistic effect between alcohol and HIV on NP performance, particularly reaction time, this has not been consistent. Whether HIV and alcohol exert purely independent, additive or interactive NP effects remains unresolved, and this may in part be due to methodological issues inherent in the measurement of alcohol use, comorbidities such as substance use, and other co-factors, such as socioeconomic status and neurologic history. The picture of NP decline due to HIV continues to evolve in the era of highly active antiretroviral therapy (HAART), and it is still unclear whether such changes will mitigate the impact of alcohol on NP functioning in persons with HIV.

Goral J; Karavitis J; Kovacs EJ. Exposure-dependent effects of ethanol on the innate immune system. (review). Alcohol 42(4): 237-247, 2008. (138 refs.)

Extensive evidence indicates that ethanol (alcohol) has immunomodulatory properties. Many of its effects on innate immune response are dose dependent, with acute or moderate use associated with attenuated inflammatory responses, and heavy ethanol consumption linked with augmentation of inflammation. Ethanol may modify innate immunity via functional alterations of the cells of the innate immune system. Mounting evidence indicates that ethanol can diversely affect antigen recognition and intracellular signaling events, which include activation of mitogen activated protein kinases, and NF kappa B, mediated by Toll-like receptors, leading to altered inflammatory responses. The mechanism(s) underlying these changes may involve dose-dependent effects of ethanol on the fluidity of cell membrane, resulting in interference with the timely assembly or disassembly of lipid rafts. Ethanol could also modify cell activation by specific interactions with cell membrane molecules.

HuangFu WC; Liu JH; Harty RN; Fuchs SY. Cigarette smoking products suppress anti-viral effects of Type I interferon via phosphorylation-dependent downregulation of its receptor. FEBS Letters 582(21-22): 3206-3210, 2008. (20 refs.)

While negative effect of smoking on the resistance to viral infections was known, the underlying mechanisms remained unclear. Here we report that products of cigarette smoking compromise the cellular anti-viral defenses by inhibiting the signaling induced by Type I interferon (IFN). Cigarette smoking condensate (but not pure nicotine) stimulated specific serine phosphorylation-dependent ubiquitination and degradation of the IFNAR1 subunit of the Type I IFN receptor leading to attenuation of IFN signaling and decreased resistance to viral infection. This resistance was restored in cells where phosphorylation-dependent degradation of IFNAR1 is abolished. We conclude that smoking compromises cellular anti-viral defenses via degradation of Type I IFN receptor and discuss the significance of this mechanism for efficacy of IFN-based therapies.

Linneberg A; Berg ND; Gonzalez-Quintela A; Elverling J. Prevalence of self-reported hypersensitiviy symptoms following intake of alcoholic drinks. Clinical & Experimental Allergy 37(1): 141-151, 2008. (57 refs.)

Background: Although hypersensitivity symptoms following alcoholic drink consumption are common in asthmatics, the prevalence of such symptoms in the general population is not known. Objective: To assess the prevalence of hypersensitivity symptoms following alcoholic drink consumption in an adult Northern European general population and the association of these symptoms with the prevalence of allergic rhinitis (AR) and asthma. Methods: In 2006, a postal questionnaire was sent to a random sample of 18–69-year-olds living in Copenhagen, the capital of Denmark. The response rate was 70.7% (4242/6000). Results: The prevalence of alcohol-induced symptoms from the upper airways, lower airways, and skin was 7.6% [95% confidence interval (CI): 6.8–8.4%], 3.2% (95% CI: 2.7–3.8%), and 7.2% (95% CI: 6.4–8.9%), respectively. A total of 13.9% (95% CI: 12.9–15.0%) had ever experienced alcohol-induced symptoms from at least one of the three regions (upper airways, lower airways, or skin), and 9.9% (95% CI: 9.0–10.8%) had experienced symptoms in the last 12 months. All types of beverages were commonly reported as triggers of hypersensitivity symptoms, red wine being the most common. Alcohol-induced hypersensitivity symptoms from the upper and lower airways were significantly more prevalent in persons with AR and asthma (odds ratios between 3.0 and 8.1, P-value <0.001 for all associations). Conclusions:In this Northern European general population, self-reported hypersensitivity symptoms following the intake of alcoholic drinks are common. These symptoms were markedly more prevalent in persons with AR and asthma. The underlying mechanisms and the clinical significance of these symptoms remain to be elucidated.

Ness KJ; Fan J; Wilke WW; Coleman RA; Cook RT; Schlueter AJ. Chronic ethanol consumption decreases murine langerhans cell numbers and delays migration of langerhans cells as well as dermal dendritic cells. Alcoholism: Clinical and Experimental Research 32(4): 657-668, 2008. (42 refs.)

Background: Chronic alcoholics experience increased incidence and severity of infections, the mechanism of which is incompletely understood. Dendritic cells (DC) migrate from peripheral locations to lymph nodes (LN) to initiate adaptive immunity against infection. Little is known about how chronic alcohol exposure affects skin DC numbers or migration. Methods: Mice received 20% EtOH in the drinking water for up to 35 weeks. Baseline Langerhans cell (LC) and dermal DC (dDC) numbers were enumerated by immunofluorescence (IF). LC repopulation after inflammation was determined following congenic bone marrow (BM) transplant and ultraviolet (UV) irradiation. Net LC loss from epidermis was determined by IF following TNF-alpha or CpG stimulation. LC and dDC migration into LN was assessed by flow cytometry following epicutaneous FITC administration. Results: Chronic EtOH consumption caused a baseline reduction in LC but not dDC numbers. The deficit was not corrected following transplantation with non-EtOH-exposed BM and UV irradiation, supporting the hypothesis that the defect is intrinsic to the skin environment rather than LC precursors. Net loss of LC from epidermis following inflammation was greatly reduced in EtOH-fed mice versus controls. Ethanol consumption for at least 4 weeks led to delayed LC migration into LN, and consumption for at least 8 weeks led to delayed dDC migration into LN following epicutaneous FITC application. Conclusions: Chronic EtOH consumption causes decreased density of epidermal LC, which likely results in decreased epidermal immunosurveillance. It also results in altered migratory responsiveness and delayed LC and dDC migration into LN, which likely delays activation of adaptive immunity. Decreased LC density at baseline appears to be the result of an alteration in the skin environment rather than an intrinsic LC defect. These findings provide novel mechanisms to at least partially explain why chronic alcoholics are more susceptible to infections, especially those following skin penetration.

Prescott SL. Effects of early cigarette smoke exposure on early immune development and respiratory disease. Paediatric Respiratory Reviews 9(1): 3-10, 2008. (85 refs.)

Exposure to tobacco constituents during early development remains a common but avoidable toxic exposure, which has been clearly linked with decreased lung growth and subsequent wheezing illness. There is also now emerging evidence that tobacco smoke can influence early immune function. This includes alterations in cytokine production by the fetoplacental unit, as detected ex vivo in cord blood, as well as in patterns of fetal mononuclear cell responses in vitro. Recent studies also suggest that the newborns of smoking mothers have altered signalling through Toll-like receptors (TLRs) that are essential for innate microbial responses. This may be implicated in the increased predisposition to infection in exposed infants. TLR-mediated innate response pathways are also believed to be important in promoting regulatory pathways that inhibit allergic immune responses. However, although a number of studies have documented associations between early cigarette smoke exposure and subsequent allergic disease, this remains controversial. This review explores the consequences of smoking on these important aspects of early development, including potential mechanisms, interactions with predisposing asthma genes and a potential role in epigenetic regulation. Although parental smoking may not be the primary factor in the changing prevalence of asthma and respiratory disease, we propose that it is an important contributor, with significant potential to interact with other genetic factors and environmental risk factors to influence disease propensity.

Reece AS. Clinical implications of addiction related immunosuppression. Journal of Infection 56(6): 437-445, 2008. (62 refs.)

Objectives: Despite increasing evidence suggesting that drug addicts have compromised immunity, vigorous discussion continues. One way to examine this clinically is to compare the rates of infections presenting to a clinic which sees both non-substance dependent (N-SUD) and opiate addicted (SUD) patients. Methods: A survey was conducted amongst our patients of all infectious presentations. Results: Four-hundred and thirty SLID and 116 N-SUD patients of similar ages (mean +/- SD 30.81 +/- 7.77 years vs. 32.91 +/- 14.41 respectively) were reviewed. SUD had fewer acute infections (120/430, 28% vs. 51/116 44%, OR = 0.60 95% Cl 0.40-0.84, P = 0.0034) but their severity was greater (P < 0.00001). The pattern of infections was also different with respiratory infections predominating in N-SUD (32/50 infections, 64%; seasonally invariant) vs. dental (74/114, 64%) and skin infections (18/114, 16%) in SUD. SLID had significantly more dental infections (74/430 patients 21% vs. 3/116 3%, P = 0.0001). In multivariate analysis, group membership was the only variable which explained the variance of "Infection". Chronic hepatitis C (60% vs. 1%, P < 0.00001) was more frequent in the SUD but there was no difference in hepatitis B or HIV. Conclusion: These data are consistent with clinical immunosuppression in SUD and may reflect immunostimulation and immunosenescence.

Sacerdote P; Franchi S; Gerra G; Leccese V; Panerai AE; Somaini L. Buprenorphine and methadone maintenance treatment of heroin addicts preserves immune function. Brain, Behavior and Immunity 22(4): 606-613, 2008. (69 refs.)

Opiate addiction influences many physiological functions including immune responses. The objective of this study was to investigate the immune system function in heroin addicted patients submitted to methadone or buprenorphine maintenance treatment compared to untreated heroin addicts and healthy controls. Four groups were studied: group A included nine heroin addicted subjects, who were still injecting heroin; groups B and C were composed of 12 patients previously addicted to heroin, being treated with methadone (mean dosage 58 +/- 12.7 mg/day) or buprenorphine (mean dose 9.3 +/- 2.3 mg/day) since at least 6 months; group D was composed of 15 sex and age matched healthy controls. Lymphoproliferation and peripheral mononuclear cell cultures production of the Th1 cytokines IL-2 and IFN-gamma, the Th2 cytokine IL-4, and of the pro-inflammatory cytokine TNF-alpha were evaluated in all the patients and controls. PHA-lymphoproliferation was lower in untreated heroin addicts than in controls, while it was normal in methadone and buprenorphine treated patients. An altered Th1/Th2 balance, characterized by reduced IL-4, IFN-gamma and TNF-alpha but normal IL-2 levels, was present in untreated heroin addicted subjects, while the Th1/Th2 balance was well conserved in the methadone and buprenorphine groups. These findings suggest that the immune system abnormalities in heroin addicted patients can be restored to almost normal values by controlled treatment with methadone and buprenorphine.

Spies CD; Lanzke N; Schlichting U; Muehlbauer S; Pipolo C; von Mettenheim M et al. Effects of ethanol on cytokine production after surgery in a murine model of gram-negative pneumonia. Alcoholism: Clinical and Experimental Research 32(2): 331-338, 2008. (40 refs.)

Background: Both alcohol abuse and surgery have been shown to impair immune function. The frequency of postoperative infectious complications is 2- to 5-fold increased in long-term alcoholic patients, leading to prolonged hospital stay. Following surgery, an increase in interleukin (IL)-6 has been shown to be associated with increased tissue injury and interleukin 1-(IL-10) is known to represent an anti-inflammatory signal. The purpose of this study was to test the hypothesis that several days of excess alcohol consumption results in more pronounced immunosuppression. We assume that alcoholic animals show increased levels of IL-10 in response to infection and increased IL-6 due to a more pronounced lung pathology. Methods: Thirty-two female Balb/c mice were pretreated with ethanol (EtOH) at a dose of (3.8 mg/g body weight) or saline (NaCl) for 8 days. At day 8 of the experiment all mice underwent a median laparotomy. Two days postsurgery mice were either applicated 10(4) CFU Klebsiella pneumoniae or received sham-infection with saline. A total number of 4 groups (EtOH/K. pneumoniae; NaCl/K. pneumoniae; EtOH/Sham-infection, NaCl/Sham-infection) was investigated and a clinical score evaluated. Twenty-four hours later mice were killed; lung, spleen, and liver were excised for protein isolation and histological assessment. IL-6 and IL-10 levels were detected by ELISA. Results: Alcohol-exposed mice exhibited a worsened clinical appearance. The histological assessment demonstrated a distinct deterioration of the pulmonary structure in alcohol-treated animals. In the lung, IL-6 and IL-10 was significantly increased in alcohol-exposed infected mice compared to saline-treated infected mice. The clinical score correlated significantly with IL-6 (r = 0.71; p < 0.01) and IL-10 levels (r = 0.64; p < 0.01) in the lung. Conclusions: Ethanol treatment in this surgical model led to a more severe pulmonary infection with K. pneumoniae which was associated with more tissue destruction and increased levels of IL-6 and IL-10 and a worsened clinical score.

Szabo G; Mandrekar P. A recent perspective on alcohol, immunity, and host defense. (review). Alcoholism: Clinical and Experimental Research 33(2): 220-232, 2009. (161 refs.)

Background: Multiple line of clinical and experimental evidence demonstrates that both acute, moderate, and chronic, excessive alcohol use result in various abnormalities in the functions of the immune system. Methods: Medline and Pubmed databases were used to identify published reports with particular interest in the period of 2000-2008 in the subject of alcohol use, infection, inflammation, innate, and adaptive immunity. Results: This review article summarizes recent findings relevant to acute or chronic alcohol use-induced immunomodulation and its consequences on host defense against microbial pathogens and tissue injury. Studies with in vivo and in vitro alcohol administration are both discussed. The effects of alcohol on lung infections, trauma and burn injury, liver, pancreas, and cardiovascular diseases are evaluated with respect to the role of immune cells. Specific changes in innate immune response and abnormalities in adaptive immunity caused by alcohol intake are detailed. Conclusion: Altered inflammatory cell and adaptive immune responses after alcohol consumption result in increased incidence and poor outcome of infections and other organ-specific immune-mediated effects.

Tebow G; Sherrill DL; Lohman IC; Stern DA; Wright AL; Martinez FD et al. Effects of parental smoking on interferon gamma production in children. Pediatrics 121(6): e1563-e1569, 2008. (27 refs.)

OBJECTIVES. Environmental tobacco smoke is associated with several negative health outcomes in children, including an increased susceptibility to infections. One of the postulated mechanisms for these effects is the impairment of the immune system function and/ or development. Yet, it remains unknown whether cumulative exposure to parental smoking is associated with altered immune responses in childhood and whether these effects are independent of in utero exposure to maternal smoking. In a population-based birth cohort, we sought to determine the relation of parental smoking, as assessed prospectively since pregnancy, to the child's interferon gamma and interleukin 4 production at 11 years of age. PATIENTS AND METHODS. We used data on 512 children and their parents from the Tucson Children's Respiratory Study cohort. Information on maternal and paternal smoking was collected prospectively by questionnaire, and pack-years for mother, father, and both parents combined were assessed prospectively between the prenatal period and year 11. At age 11 years, children's interferon gamma and interleukin 4 production from mitogen-stimulated peripheral blood mononuclear cells was measured. RESULTS. Children of parents who smoked between the prenatal period and year 11 were more likely to be in lower quartiles of interferon gamma production than children of nonsmoking parents. In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with interferon gamma production in the child. These dose-response relationships with interferon gamma remained significant for both paternal and parental pack-years among children of mothers who did not smoke during pregnancy, suggesting the existence of specific postnatal effects of environmental tobacco smoke exposure. In contrast, no significant effects of parental smoking were found on interleukin 4 production. CONCLUSIONS. Interferon gamma responses of school-aged children are impacted by parental smoking.

Valley H. Allergic and asthmatic reactions to alcoholic drinks: A significant problem in the community. Clinical & Experimental Allergy 38(1): 1-3, 2008. (22 refs.)

The effects of alcoholic drink consumption on health are complex. Adding to the complexity is the fact that some health effects have been specifically attributed to alcohol itself (ethanol), while others are thought to be due to one or more of the large number of non-alcohol components that give these drinks their unique flavour and character. Similar challenges are apparent in considering the relationship between alcoholic drinks and allergic disease. Alcohol is a potent immunomodulatory drug, and there is some evidence that consumption of alcoholic drinks may play a role in the development of allergic disease itself. Those with underlying allergic disease or asthma, may find that alcoholic drinks can trigger symptoms. Alcohol itself is responsible, causing a classical facial flushing response (along with a number of other symptoms, including bronchoconstriction) within 30 min of consumption in up to 50% of subjects of Asian ethnicity, due to genetic variation in the enzyme aldehyde dehydrogenase. Sensitivities to the non-alcohol components of alcoholic drinks have been observed; many individuals report sensitivities only to particular types of drink and can tolerate others. Data from the United Kingdom in the early 1980s first highlighted the extent of self-reported allergic and asthmatic responses to alcoholic drinks. A subsequent Australian community-based survey of asthmatic patients, over 40% of repondents reported allergic or allergic-like symptoms following alcoholic drink consumption, with 33.1% specifically reporting asthmatic responses Despite these interesting findings, the weakness of these previous surveys was that they were conducted in highly selected populations of asthmatics, and therefore did not provide an estimate of the true prevalence of alcoholic drink sensitivities in the community. The study by Linneberg et al. in this issue of provides insights into the true prevalence of these sensitivities. While prevalences were lower, drink sensitivities were still surprisingly high, with 13.9% of community respondents reporting adverse reactions in the upper airways, lower airways or skin. Among the asthmatic subjects surveyed in this study, 17.5% reported the triggering of upper airway symptoms and 12.9% reported lower airway symptoms, supporting the notion that sensitivities to alcoholic drinks are a significant problem among the broader asthmatic community.

Wang J; Barke RA; Ma J; Charboneau R; Roy S. Opiate abuse, innate immunity, and bacterial infectious diseases. (review). Archivum Immunologiae et Therapiae Experimentalis 56(5): 299-309, 2008. (93 refs.)

The first line of defense against invading bacteria is provided by the innate immune system. Morphine and other opiates can immediately disrupt the body's first line of defense against harmful external bacteria. Opiate, for example morphine, abuse degrades physical and physiologic barriers, and modulates phagocytic cells (macrophages, neutrophils) and, nonspecific cytotoxic T cells (gamma delta T), natural killer cells, and dendritic cells, that are functionally important for carrying out a rapid immune reaction to invading pathogens. In vitro studies with innate immune cells from experimental animals and humans and in vivo studies with animal models have shown that opiate abuse impairs innate immunity and is responsible for increased susceptibility to bacterial infection. However, to better understand the complex interactions between opiates, innate immunity, and bacterial infection and develop novel approaches to treat and even prevent bacterial infection in the opiate-abuse population, there is an urgent need to fill the numerous gaps in our understanding of the cellular and molecular mechanisms by which opiate abuse increases susceptibility to bacterial infection.

Wang J; Pan HF; Ye DQ; Su H; Li XP. Moderate alcohol drinking might be protective for systemic lupus erythematosus: a systematic review and meta-analysis. (review). Clinical Rheumatology 27(12): 1557-1563, 2008. (25 refs.)

Conflicting evidence for the effect of moderate alcohol drinking on the development of systemic lupus erythematosus (SLE) existed at present. In the current study, we performed an extensive search of relevant studies and performed a meta-analysis to obtain a more precise estimate. Thirty-eight studies were identified from electronic databases and chosen for detailed review, then six articles from six case-control studies with one cohort study were included in our meta-analyses. Meta-analyses were divided into two subgroups in which patients in the study of Washio et al. treated for less than 5 years (subgroup A) or less than 10 years (subgroup B) were involved, respectively. The odds ratio (OR) of moderate alcohol drinking in the meta-analyses of subgroup B for the development of SLE was significantly decreased (OR 0.723, 95% confidence interval (95% CI) 0.547-0.954), while moderate alcohol drinking in the meta-analysis of subgroup A did not demonstrate a decreased risk of SLE (OR 0.780, 95% CI 0.491-1.240). Meta-analyses of six case-control studies in the two subgroups both demonstrated that moderate alcohol drinking had a protective effect on the development of SLE. Taken together, our results show that moderate alcohol drinking might be protective for SLE.

Waszkiewicz N; Szajda SD; Jankowska A; Zwierz P; Czernikiewicz A; Szulc A et al. The effect of acute ethanol intoxication on salivary proteins of innate and adaptive immunity. Alcoholism: Clinical and Experimental Research 32(4): 652-656, 2008. (48 refs.)

Background: Human salivary proteins: peroxidase, lysozyme, lactoferrin, and IgA, participate in the protection of oral tissues, as well as upper digestive and respiratory tracts, against a number of microbial pathogens. In the current study, we investigated the effect of acute consumption of a large dose of ethanol on representative human salivary proteins of the innate and adaptive immune systems. Methods: Eight healthy male volunteers drank an average of 2.0 g (1.4 to 2.5 g/kg) body weight of ethanol, in the form of vodka, in the 6-hour period. Samples of resting whole saliva were collected 12 hours before, then 36 and 108 hours after, the alcohol consumption. The levels of total protein, immunoglobulin A, lysozyme and lactoferrin as well as peroxidase activity were determined in saliva. Results: At 36 hours after alcohol consumption, salivary protein and lysozyme concentrations as well as peroxidase activity were significantly decreased (p = 0.002, p = 0.043, and p = 0.003, respectively), in comparison to the values obtained at 12 hours before drinking. Between 36 and 108 hours after alcohol consumption, the salivary protein and lysozyme concentrations, as well as peroxidase activity showed a tendency to increase, although at 108 hours after the drinking session, the concentration of protein and peroxidase activity were still significantly lower than before drinking. There was no significant change in the level of lactoferrin, after the drinking session. The salivary concentration of IgA tended to increase at 36 hours after alcohol consumption, and at 108 hours it was significantly higher (p = 0.028), when compared to IgA concentration in the saliva collected before drinking (from 8% to 26% and 32% of total protein content, respectively). Conclusion: Our report is the first to show that acute ingestion of relatively large, yet tolerable dose of alcohol, significantly disturbs salivary antimicrobial defense system. Reduced lysozyme level and decreased peroxidase activity may contribute to increased susceptibility to infections, when acute alcohol intake coincides with exposure to pathogens.

Ye L; Peng JS; Wang X; Wang YJ; Luo GX; Ho WZ. Methamphetamine enhances hepatitis C virus replication in human hepatocytes. Journal of Viral Hepatitis 15(4): 261-270, 2008. (49 refs.)

Very little is known about the interactions between hepatitis C virus (HCV) and methamphetamine, which is a highly abused psychostimulant and a known risk factor for human immunodeficiency virus (HIV)/HCV infection. This study examined whether methamphetamine has the ability to inhibit innate immunity in the host cells, facilitating HCV replication in human hepatocytes. Methamphetamine inhibited intracellular interferon alpha expression in human hepatocytes, which was associated with the increase in HCV replication. In addition, methamphetamine also compromised the anti-HCV effect of recombinant interferon alpha. Further investigation of mechanism(s) responsible for the methamphetamine action revealed that methamphetamine was able to inhibit the expression of the signal transducer and activator of transcription 1, a key modulator in interferon-mediated immune and biological responses. Methamphetamine also down-regulated the expression of interferon regulatory factor-5, a crucial transcriptional factor that activates the interferon pathway. These in vitro findings that methamphetamine compromises interferon alpha-mediated innate immunity against HCV infection indicate that methamphetamine may have a cofactor role in the immunopathogenesis of HCV disease.

Al-Ghamdi HS; Anil S. Serum antibody levels in smoker and non-smoker Saudi subjects with chronic periodontitis. Journal of Periodontology 78(6): 1043-1050, 2007. (73 refs.)

Background: Cigarette smoking is a significant risk factor for the initiation and progression of periodontal disease. Studies have shown altered serum and gingival crevicular fluid inflammatory cytokine profiles, immune cell function, and altered proteolytic regulation in smokers. The observations are not consistent, and to date, there is no clear mechanism to explain how smoking may affect periodontal disease. Hence, the present study was undertaken to assess the alterations of serum immunoglobulin levels in smokers with periodontitis and its potential role as a risk indicator of the disease process. Methods: In this study, 30 patients who smoked and 30 patients who did not smoke with chronic periodontitis and 30 healthy subjects were enrolled. Serum immunoglobulin (Ig) G, IgA, and IgM levels were estimated with immunoturbidimetric assay. The IgG subclass (IgG1, IgG2, IgG3, and IgG4) levels were performed using single radial immunodiffusion assay. Results: Levels of serum IgG and IgA were significantly lower in smokers compared to non-smokers and healthy controls (P < 0.001). Although IgM levels were low in smokers, it was not significant. Of the four subclasses of IgG studied, the IgG2 was found to be significantly lower among smokers with periodontitis. Conclusions: Current observations indicate that cigarette smoking may be associated with the suppression of B-cell function and immunoglobulin production. The alteration of antibody levels further explains the potential mechanism by which smoking exacerbates periodontal disease. Further studies at the molecular level may highlight the specific mechanism by which tobacco can interact with cells of the immune system and its impact on periodontal disease process.

Ashcroft RE; Franey C. Further ethical and social issues in using a cocaine vaccine: Response to Hall and Carter. Journal of Medical Ethics 30(4): 341-343, 2004. (19 refs.)

Evaluation of the potential of a cocaine vaccine requires a detailed understanding of the intended and unintended social consequences of its use. Prospective technology assessment is always difficult, but in the case of treatment and prevention of cocaine addiction we need to understand not only the neuroscience and pharmacology of cocaine addiction, but also social attitudes to drug use and addiction, the social context of drug use, and the factors which make drug use a rational strategy for an addict and make treatment seeking or relapse more or less likely. By considering different scenarios related to differing levels of effectiveness of the vaccine, the authors argue that vaccination will be at best a useful adjunct to existing methods of treatment, rather than a substitute for them.

Besson H; Brennan P; Becker N; Nieters A; De Sanjose S; Font R et al. Tobacco smoking, alcohol drinking and non-Hodgkin's lymphoma: A European multicenter case-control study (Epilymph). International Journal of Cancer 119(4): 901-908, 2006. (60 refs.)

To study the role of tobacco smoking and alcohol drinking in the etiology of non-Hodgkin's lymphoma (NHL), we conducted a multicenter case-control study in Spain, France, Germany, Italy, Ireland and Czech Republic between 1998 and 2004, which included 1,742 cases of NHL and 2,465 controls matched on age, sex and recruitment area. Tobacco smoking was not associated with the risk of NHL overall or with risk of specific histological subtypes. Similarly, there was no association between alcohol drinking and the risk of NHL overall or across histological subtypes. However. a protective effect of alcohol drinking was observed among men (OR = 0.76, 95% CI = 0.62-0.93) and in non-Mediterranean countries (OR = 0.73, 95% CI = 0.61-0.86). There was no evidence of interaction between alcohol drinking and tobacco smoking in NHL etiology. The results of this large-scale European study did not support an association between tobacco and NHL and suggested a protective effect of alcohol on development of NHL for men and in non-Mediterranean countries.

Besson H; Renaudier P; Merrill RM; Coiffier B; Sebban C; Fabry J et al. Smoking and non-Hodgkin's lymphoma: A case-control study in the Rhone-Alpes region of France. Cancer Causes and Control 14(4): 381-389, 2003. (39 refs.)

Objective: To study the relation between smoking and non-Hodgkin's lymphoma (NHL), in the Rhone-Alpes region of France. Methods: We conducted a hospital-based case-control study that included 180 cases of NHL and 360 age-, gender-matched hospital controls. Matched univariable and multivariable logistic regression models were used for analysis. Results: For the whole study population as well as for men, smoking does not elevate the risk of NHL. However, the risk of NHL is higher for women who currently smoke compared to women who have never smoked (odds ratio [OR] = 2.40, 95% confidence interval [95% CI] = 1.19-4.84). Among ever smokers, the OR of NHL is 5.04 (95% CI = 1.40-18.12) for women who have smoked for more than 30 years compared with those who have never smoked. Similarly, women who started to smoke before the age of 20 years compared with women who have never smoked are at greater risk of developing NHL (OR = 2.40, 95% CI = 0.99-5.85). In the total population (women and men), smoking may be associated with one histologic subtype, follicular NHL with an adjusted OR for the current smokers compared to subjects having never smoked of 3.20, 95% CI = 0.79-12.97. Conclusions: In spite of the small number of subjects in the subgroups, a relation is observed between smoking and NHL among women, but not men, and in the total population a relation is suggested between smoking and follicular NHL.

Brown LAS; Cook RT; Jerrells TR; Kolls JK; Nagy LE; Szabo G et al. Acute and chronic alcohol abuse modulate immunity. Alcoholism: Clinical and Experimental Research 30(9): 1624-1631, 2006. (43 refs.)

This article represents the proceedings of the Alcohol and Immunology Research Interest Group (AIRIG) meeting, a satellite workshop held at the 37th Annual Meeting of the Society for Leukocyte Biology. The meeting was sponsored by the AIRIG and the National Institute on Alcohol Abuse and Alcoholism. The presentations were as follows: (1) Effects of Ethanol on Immune Response to Hepatitis C Virus by Jack R. Wands, (2) Alcohol and Alveolar Macrophage Dysfunction: The Role of Chronic Oxidant Stress by Lou Ann S. Brown, (3) T Cell Responses to Listeria monocytogenes in Mice on a Chronic Ethanol Exposure Protocol by Robert T. Cook, (4) Mechanisms of Acute and Chronic Alcohol Consumption on Severity of Viral Infections by the Liver and Pancreas by Thomas R. Jerrells, (5) Acute and Chronic Effects on Macrophage Ectodomain Shedding: Implications for Lung Host Defenses by Jay K. Kolls, (6) Increased Susceptibility to Pseudomonas Infection of Burn-Injured Mice Given Alcohol Before Injury by Elizabeth J. Kovacs, (7) Regulation of Tumor Necrosis Factor alpha Expression in Macrophages by Chronic Ethanol by Laura E. Nagy, and (8) Hepatitis C Virus Infection and Alcohol Use by Gyongyi Szabo. Meeting coorganizers were Elizabeth J. Kovacs, Lou Ann S. Brown, Thomas R. Jerrells, and Robert T. Cook.

Brown LAS; Harris FL; Ping XD; Gauthier TW. Chronic ethanol ingestion and the risk of acute lung injury: A role for glutathione availability? Alcohol 33(3): 191-197, 2004. (38 refs.)

Although pulmonary function is not altered, a history of alcohol abuse is an independent outcome variable in the development of acute respiratory distress syndrome. In the absence of cirrhosis, alcohol abuse decreased glutathione, the key antioxidant lining the alveolar space, by 80% and is associated with alveolar barrier leak. Neither the glutathione pool nor barrier leak was corrected by abstinence for 1 week. This aberrant glutathione homeostasis may contribute to enhanced alveolar permeability, thereby increasing susceptibility to the development of acute respiratory distress syndrome. In a rat model, chronic ingestion of ethanol decreased pulmonary glutathione concentration, increased alveolar barrier permeability, and increased the risk of acute lung injury. In alveolar type II cells, chronic ingestion of ethanol altered cellular functions such as decreased surfactant processing, decreased barrier integrity, and increased sensitivity to cytotoxin-induced apoptosis in vitro and in vivo. In alveolar macrophages, chronic ingestion of ethanol decreased phagocytosis of microorganisms and decreased cell viability, events that would increase the risk of pneumonia. A central role for glutathione availability was demonstrated by the normalization of cellular function and viability of type II cells and macrophages as well as decreased sensitivity to endotoxemia-induced acute lung injury when glutathione precursors were added to the ethanol diet. These results support the suggestion that chronic ingestion of ethanol increased the risk of acute lung injury not through ethanol per se but through the chronic oxidative stress that resulted from ethanol-induced glutathione depletion. Because chronic oxidative stress alters cellular functions and viability, the lung becomes more susceptible when a second hit such as sepsis occurs.

Budney AJ; Moore BA; Vandrey R. Health consequences of marijuana use. IN: Brick J, ed. Handbook of the Medical Consequences of Alcohol and Drug Abuse. Binghamton, NY: Haworth Press, 2004. pp. 171-218. (272 refs.)

There is rather limited research on the chronic effects of marijuana use in terms of health. This chapter provides a review of the existing literature, with particular attention to the respiratory system, immune system, cardiovascular system, endocrine, as well as its impact on reproductive function. There is also attention to the psychological and psychiatric effects of marijuana on psychomotor function, attention, memory, academic performance, driving ability, and motivation. It also touches upon the current discussion of medical use of marijuana.

Carlsson S; Midthjell K; Grill V. Smoking is associated with an increased risk of type 2 diabetes but a decreased risk of autoimmune diabetes in adults: An 11-year follow-up of incidence of diabetes in the Nord-Trondelag study. Diabetologia 47(11): 1953-1956, 2004. (9 refs.)

Aims/hypothesis. We compared the association between smoking habits and later occurrence of type 2 diabetes on the one hand and between smoking and diabetes with autoimmunity on the other hand. Methods. We used data from a prospective study of 11-year cumulative incidence of diabetes in the Nord-Trondelag Health Survey. Results. Confirming previous reports, heavy smoking (greater than or equal to20 cigarettes per day) carried an increased relative risk (RR) of type 2 diabetes (n=738, RR=1.64, 95% Cl: 1.12-2.39). In contrast, smoking reduced the risk of latent autoimmune diabetes in adults (LADA) and of traditional type 1 diabetes (LADA n=81, RR=0.25, 95% CI: 0.11-0.60; type 1 diabetes, n=18, RR=0.17, 95% Cl: 0.04-0.73). Conclusions/interpretations. The results indicate that nicotine influences autoimmune processes in human diabetes.

Carrera MRA; Kaufmann GF; Mee JM; Meijler MM; Koob GF; Janda KD. Treating cocaine addiction with viruses. Proceedings of the National Academy of Sciences 101(28): 10416-10421, 2004. (45 refs.)

Cocaine addiction continues to be a major health and social problem in the United States and other countries. Currently used pharmacological agents for treating cocaine abuse have proved inadequate, leaving few treatment options. An alternative is to use protein-based therapeutics that can eliminate the load of cocaine, thereby attenuating its effects. This approach is especially attractive because the therapeutic agents exert no pharmacodynamic action of their own and therefore have little potential for side effects. The effectiveness of these agents, however, is limited by their inability to act directly within the CNS. Bacteriophage have the capacity to penetrate the CNS when administered intranasally. Here, a method is presented for engineering filamentous bacteriophage to display cocaine-binding proteins on its surface that sequester cocaine in the brain. These antibody-displaying constructs were examined by using a locomotor activity rodent model to assess the ability of the phage-displayed proteins to block the psychoactive effects of cocaine. Results presented demonstrate a strategy in the continuing efforts to find effective treatments for cocaine addiction and suggest the application of this protein-based treatment for other drug abuse syndromes.

Choudhry MA; Rana SN; Kavanaugh MJ; Kovacs EJ; Gamelli RL; Sayeed MM. Impaired intestinal immunity and barrier function: A cause for enhanced bacterial translocation in alcohol intoxication and burn injury. Alcohol 33(3): 199-208, 2004. (121 refs.)

Alcohol intoxication is being recognized increasingly as the major factor in pathogenesis after burn injury. Findings from multiple studies support the suggestion that, in comparison with burn-injured patients who sustained injury in the absence of alcohol intoxication, burn-injured patients who sustained injury under the influence of alcohol exhibit higher rates of infection and are more likely to die. Thus, infection becomes the primary cause of death in burn-injured patients. Because the intestine is considered to be a major source of bacteria, studies in experimental animals have been designed to examine whether alcohol intoxication before burn injury enhances bacterial translocation from the intestine. Results of these studies have shown a several-fold increase in bacterial translocation from the intestine in the group of animals receiving combined insult of alcohol intoxication and burn injury compared with findings for the groups receiving either insult alone. Alcohol intoxication and burn injury independent of each other have also been shown to cause an increase in bacterial translocation. The gastrointestinal tract normally maintains a physical mucosal and immunologic barrier that provides an effective defense in keeping bacteria within the intestinal lumen. However, in injury conditions these defense mechanisms are impaired. Intestinal bacteria consequently gain access to extraintestinal sites. Intestine-derived bacteria are implicated in causing systemic infection and in subsequent multiple organ dysfunction in both immunocompromised patients and patients with injury, such as burn and trauma. In this article, we discuss three potential mechanisms that are likely to contribute to the increase in bacterial translocation in alcohol intoxication and burn injury: (1) increase in bacterial growth in the intestine, (2) physical disruption of mucosal barrier of the intestine, and (3) suppression of the immune defense in the intestine.

Cristiani SA; Pukay-Martin ND; Bornstein RA. Marijuana use and cognitive function in HIV-infected people. Journal of Neuropsychiatry and Clinical Neurosciences 16(3): 330-335, 2004. (27 refs.)

The effect of marijuana use on cognitive function is controversial. Although marijuana use is common in HIV-infected individuals for recreational and medicinal purposes, there have been no studies of the impact of marijuana on cognitive function in these subjects. Marijuana also has known immunologic effects, which increases the relevance in HIV-infected patients. We examined the interaction of HIV disease-stage and marijuana use in 282 subjects, stratified by disease stage and frequency of marijuana use. After controlling for the effects of depression, anxiety, and alcohol use, a significant interaction was observed on an overall measure of cognitive impairment. The effect of marijuana use was greatest in subjects with symptomatic HIV infection. Further inspection suggested that this effect was due primarily to performance on memory tasks. These data suggest that although there is minimal impact of marijuana on uninfected individuals or those at early stages of HIV infection, there is a synergistic effect of HIV and marijuana use in patients with advanced HIV disease. This is consistent with other data suggesting that the subtle effects of some conditions may become more manifest in the setting of immunocompromise

Croxford JL; Yamamura T. Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases? (review). Journal of Neuroimmunology 166(1-2): 3-18, 2005. (186 refs.)

Since the discovery of the cannabinoid receptors and their endogenous ligands, significant advances have been made in studying the physiological function of the endocannabinoid system. The presence of cannabinoid receptors on cells of the immune system and anecdotal and historical evidence suggesting that cannabis use has potent immuno-modulatory effects, has led to research directed at understanding the function and role of these receptors within the context of immunological cellular function. Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory effects of cannabis in humans, and animal and in vitro studies of immune cells such as T cells and macrophages have also provided important evidence. Cannabinoids can modulate both the function and secretion of cytokines from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease. This review article will highlight recent research on cannabinoids and how they interact with the immune system and also their potential use as therapeutic agents for a number of inflammatory disorders.

De Bie J; Robaeys G; Buntinx F. Hepatitis C, interferon alpha and psychiatric co-morbidity in intravenous drug users (IVDU): Guidelines for clinical practice. Acta Gastro-enterologica Belgica 68(1): 68-80, 2005. (97 refs.)

The evidence regarding the co-morbidity of chronic hepatitis C, psychiatric illness and intravenous drug abuse is reviewed from the literature. Also the occurrence and the treatment of psychiatric side effects during treatment with interferon in patients with a history of drug abuse are reviewed. There is insufficient evidence for a specific hepatitis C induced depression or fatigue, but a direct link between hepatitis C and cerebral dysfunction is not excluded. Immune system activation rather than drug use may explain cerebral symptoms. In HCV positive substance users anxiety and depression are more prevalent than in HCV negative substance users. During treatment with regular or pegylated (PEG) interferon depression is a frequent side effect (ca 30%) and occurs independently from pre-existing psychiatric disorders or drug abuse. A history of drug abuse per se does not increase the risk of depression as a side effect of interferon treatment. It is extremely important to monitor symptoms of depression in the early weeks of treatment and to start antidepressant treatment as early as possible. Antidepressants should be continued throughout the interferon treatment period. There are insufficient data to assess these situations in which preventive antidepressant treatment should be started before interferon treatment. Clinical judgment can, however, lead to preventive antidepressant treatment, even at subclinical levels of depression. A cut off score of > 10 on the Beck Depression Inventory before interferon treatment is associated with a higher risk of depression during treatment. Both selective serotonin reuptake inhibitors and other classes of antidepressants can be used.

Dewey WL, ed. Problems of Drug Dependence, 2003: Proceedings of the 65th Annual Scientific Meeting. NIDA Research Monograph 184. Rockville MD: National Institute on Drug Abuse, 2004. (Chapter refs.)

This volume represents the proceedings of The 65th Annual Scientific Meeting of The College on Problems of Drug Dependence. The report includes presented papers, poster sessions, and oral communications. There are reports of seventeen symposia that focus on the following topics: understanding the pathway from use to addiction; immunotherapies for substance abuse; drug reward in humans, the role of dopamine; sex differences in the addicted brain, neuroimaging studies of cocaine and alcohol-dependent men and women; current knowledge about exposure to buprenorphine during pregnancy and lactation; vocational rehabilitation models of substance users; controversies in the pharmacology and toxicology of substituted amphetamines; conceptions of drug dependence, theories, science and policy; changing proteins; changing brain; nicotine, addiction and immunomodulation; neuro-aids, and the role of recreational drugs; effectiveness of adolescent substance abuse treatment; abuse potential.

Dhillon NK; Williams R; Peng F; Tsai YJ; Dhillon S; Nicolay B et al. Cocaine-mediated enhancement of virus replication in macrophages: Implications for human immunodeficiency virus-associated dementia. Journal of Neurovirology 13(6): 483-495, 2007. (58 refs.)

Injection drug use has been recognized as a major risk factor for acquired immunodeficiency syndrome (AIDS) from the outset of the epidemic. Cocaine, one of the most widely abused drugs in the United States, can both impair the functions of macrophages and CD4(+) lymphocytes and also activate human immunodeficiency virus (HIV)-1 expression in these cells. Because the brain is the target organ for both cocaine and HIV, the objective of the present study was to explore the effects of cocaine on virus replication in macrophages, the target cells for the virus in the central nervous system (CNS). Cocaine markedly enhanced virus production in simian human immunodeficiency virus (SHIV)-infected monocyte-derived macrophages (MDMs) and in U1 cells, a chronically infected promonocytic cell line as monitored by enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry. Cocaine treatment also resulted in the activation of nuclear factor (NF)-kappa B and transcriptional activation of the HIV-LTR (long terminal repeat) gag-GFP (green fluorescent protein). Analyses of chemokines in cocaine-treated macrophages by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Luminex assays suggested increased expression of interleukin (IL)-10, a cytokine that is known to promote HIV replication in MDMs. In addition to enhancing IL-10 expression, cocaine also caused an up-regulation of the macrophage activation marker, human leukocyte antigen (HLA)-DR, in MDMs. The synergistic effect of cocaine on virus replication and its enhancement of host activation markers suggest that cocaine functions at multiple pathways to accelerate HIV-associated dementia (HAD).

Dolan KA. Quitter's aid. Forbes 174(2): 180, 2004

A new approach to nicotine addiction is emerging: an experimental vaccine to block the nicotine from entering the brain to deliver its pleasurable rush. Nicotine floats around the blood like any other foreign antigen, but its molecules are small enough both to slip past the blood-brain barrier and elude the immune system's policing antibody cells. A nicotine vaccine would work like other vaccines, provoking the body into producing targeted antibodies that, in this case, latch onto molecules so they're too big to enter the brain. Several companies are pursuing nicotine vaccines. One NicVax vaccine is being studied. Preliminary quitting rates are due out later this year from its study of 63 smokers who were injected with the vaccine. Efforts date to 1996, when the company came up with a workable vaccine for Staphylococcus aureus, a leading cause of infection in hospitals. Staph molecules are good at eluding the immune system because they're disguised by an abundant coat of sugars. Fattom's solution was to link the sugars to a larger carrier protein, in this case an inactivated bacteria called Pseudomonas. The immune system spots the combination and produces antibodies that then bind to the staph molecules in the body, preventing infection. it was thought the same process would work on other elusive molecules, such as nicotine. Early-stage human trials completed in 2002 have shown that nicotine antibodies are still at measurable levels in the blood for 7 to 14 days after one shot. Side effects such as soreness and redness at the injection point clear up in a few days.

Douglas SD; Camarca M; Xu JH; Durako S; Murphy D; Moscicki B et al. The relationships between substance abuse, psychosocial variables, and natural killer cell enumeration and function in HIV-infected and high-risk uninfected adolescents. AIDS Research and Human Retroviruses 19(5): 399-408, 2003. (45 refs.)

This report examines the relationship between substance use, psychosocial stressors, and natural killer (NK) cell enumeration and function in HIV-infected and high-risk uninfected adolescents. We studied the association of demographic characteristics; self-report measures of alcohol, tobacco, and marijuana use; and self-report measures of psychosocial stressors (depressive symptoms, anxiety) with three immune outcomes: NK (CD3(-)CD16(+)CD56(+)) absolute counts, lytic units per peripheral blood mononuclear cells (PBMCs), and lytic units per NK cell. In addition, we determined the association of HIV disease stage, antiretroviral therapy (ART), CD4(+) T-cell count, and viral load with these outcomes in the subset of HIV-infected adolescents. Methods: This cross-sectional analysis reports on data collected during a longitudinal observational study of adolescents (the REACH Study). A cross-sectional analysis was performed with data from the first visit for each subject that met criteria for concurrent (within 3 days) assessment of NK number and function, substance use, and psychosocial data. The data set represented 501 subjects. Analyses were performed separately for the HIV-seropositive and seronegative adolescents. In the HIV-seronegative population, there were no significant predictors of NK cell count and only female gender was significantly associated with CD3(-)CD16(+)CD56(+) NK lytic units per PBMC. Analysis of the HIV-seronegative cohort also showed that black race was significantly associated with higher lytic units per NK cell. Results: In HIV-seropositive adolescents, we observed an association of female gender with lower NK cell number and lytic units per PBMC, but not with lytic units per NK cells. Current use of one or two antiretroviral drugs was predictive of lower NK numbers. This drug effect was also noted in the functional assay per PBMC but not per NK cell. Increasing worry scores and no marijuana use over the past 3 months were associated with lower functional NK measures per PBMC in HIV-seropositive youth. Laboratory-confirmed recent marijuana use was highly predictive of increased lytic activity calculated per NK cell. These effects were not observed in similar analyses of data from HIV-seronegative adolescents. Depressive symptoms, assessed with an epidemiologic screening tool, were not found to be predictive of NK cell number or function in either the HIV-seronegative or the HIV-seropositive subset. These findings document associations between substance abuse, psychosocial variables, and NK numbers and function in adolescents.

Duryee MJ; Willis MS; Freeman TL; Kuszynski CA; Tuma DJ; Klassen LW et al. Mechanisms of alcohol liver damage: Aldehydes, scavenger receptors, and autoimmunity. (review). Frontiers in Bioscience 9(Supplement S): 3145-3155, 2004. (112 refs.)

While most of the investigations into the causative events in the development of alcoholic liver disease (ALD) have been focused on multiple factors, increasing interest has centered around the possible role of immune mechanisms in the pathogenesis and perpetuation of ALD. This is because many of the clinical features of ALD suggest that immune effector mechanisms may be contributing to liver tissue damage, as evidenced by the detection of circulating autoantibodies, and the presence of CD4+ and CD8+ lymphoid cells in the livers of patients with ALD. One mechanism that has been associated with the development of autoimmune responses is the modification (haptenation or adduction) of liver proteins with aldehydes or other products of oxidative stress. This is because it has been shown that these adducted proteins can induce specific immune responses, to the adduct, the adduct plus protein (conformational antigens), as well as the unmodified parts of the protein. More importantly, it is possible to demonstrate that adducted self-proteins can induce reactivity to the normal self-protein and thereby induce autoimmune responses. Therefore, it is the purpose of this manuscript to outline the mechanism(s) by which these modified self proteins can induce autoimmune reactivity, and thus play a role in the development and/or progression of ALD.

EL-Gohary M; Eid MA. Effect of cannabinoid ingestion (in the form of bhang) on the immune system of high school and university students. Human and Experimental Toxicology 23(3): 149-156, 2004. (37 refs.)

The discovery of cannabinoid receptors in the immune system and a family of endogenous ligands of these receptors provides a basis for understanding the cellular and molecular mechanisms of cannabis-induced immunotoxicity. The present study was conducted on 90 nonsmoker males of high school and university students living in Tanta city of matched age and socioeconomic lifestyle. They were divided into a control group (30 males) and a bhang user group (60 males), which used bhang by eating its sweet juice after boiling with a little water and drying in an oven, 'fola'. The bhang group was divided equally into two subgroups: subgroup 1 used bhang for 6-24 months (average 199 +/- 1.2) and subgroup 2 used bhang for 24-36 months (average 31 +/- 1.7). The immunotoxic effects of using bhang appeared in the form of a significant decrease in serum immunoglobulins (IgG and IgM), and C3 and C4 complement protein concentrations (P < 0.05). In addition, our results demonstrated a significant decrease in the absolute number of functionally different subsets of peripheral blood mononuclear lymphocytes, T and B lymphocytes and natural killer (NK) cells in bhang users as compared to controls (P < 0.05). Moreover, the fatty acid amide hydrolase (FAAH) showed significant decrease in bhang users as compared to controls and in subgroup 2 as compared to subgroup 1 (P < 0.05), indicating that the decrease in FAAH protein level is closely related to the duration of bhang use. Positive correlations were found between FAAH level and the absolute number of mononuclear cells (T, B lymphocytes and NK cells) among bhang user subgroups. The present study is the first study to report on the effect of bhang on complement proteins and immunoglobulins in humans. Our study revealed that bhang-induced immunotoxicity could be attributed to decrease in FAAH protein.

Fingerhood MI. Co-morbid medical disorders. IN: Strain EC; Stitzer ML, eds. The Treatment of Opioid Dependence. Baltimore: Johns Hopkins University Press, 2006. pp. 398-420. (65 refs.)

This chapter focuses on the provision of medical care to individuals receiving opioid agonist medications. It considers the issues related to health maintenance, and the multiple medical complications. Among those with a history of intravenous use, there are special concerns related to the route of administration -- including viruses from needle sharing as well as the soft tissue infections from injecting technique. These problems are not restricted to those involved with opiates, but also common in cocaine users. The chapter begins with an overview of basic primary care, with attention to medical history and physical exam. It then turns of matters related to prescribing, pain management, and drug interactions with methadone, that may have an impact on blood levels or alter methadone's effects. Also specifically addressed are skin and soft tissue infections, HIV/AIDS, sexually transmitted disease, hepatitis, as well as cardiac, pulmonary, renal, neurological, and immunologic complications, and for women concerns related to domestic violence.

Floto RA; Smith KGC. The vagus nerve, macrophages, and nicotine. (editorial). Lancet 361(9363): 1069-1070, 2003. (15 refs.)

Frank J; Witte K; Schrodl W; Schutt C. Chronic alcoholism causes deleterious conditioning of innate immunity. Alcohol and Alcoholism 39(5): 386-392, 2004. (60 refs.)

Aims: To examine the immune consequences of chronic alcoholism in man, in relation to the known association between alcoholism and raised incidence and severity of infections. Methods: In 36 alcoholics without liver disease, at the point of commencing withdrawal from alcohol, the following measures of immune competence were measured: the immunophenotypes of cells, acute phase proteins, the endotoxin-neutralizing capacity (ENC) of the serum, titers of anti-lipopolysaccharide (LPS) antibodies, and ex vivo cytokine inducibility in T cells and monocytes (TNFalpha, IL1beta, IL1RA, IL4, IL6, IL8, IL10 and IL12). The results were compared to those from healthy volunteers (day controls). Measures were repeated after 8-13 days of abstinence. Results: LPS-binding protein (LBP) and soluble CD14 (sCD14) were significantly increased in patients' sera at the outset of withdrawal, whereas reduced titers of anti-LPS IgG (P = 0.012) and a reduced ENC (P = 0.001) were measured. Only ENC rapidly returned to normal values after withdrawal therapy. Cytokine induction with phorbol ester showed no significant alterations in patients' T cells. Patients' monocytes, however, responded to LPS stimulation with enhanced IL1beta-, but reduced TNFalpha- and IL12-production (P = 0.004, P = 0.0042 and P = 0.001, respectively). While IL1- and TNFalpha-responses normalized after the withdrawal period, impairment of the IL12 response persisted throughout the observation period of 2 weeks. Conclusions: Alcoholism results in a prolonged LPS-mediated hypoinflammatory conditioning of the innate but not the adaptive immune system, which is not reversed immediately after withdrawal. This alcohol-induced status of the immune system predisposes to infections and sepsis by blunting initial response to the pathogens.

Friedman H; Pross S; Klein TW. Addictive drugs and their relationship with infectious diseases. (review). FEMS Immunology and Medical Microbiology 47(3): 330-342, 2006. (120 refs.)

The use of drugs of abuse, both recreationally and medicinally, may be related to serious public health concerns. There is a relationship between addictive drugs of abuse such as alcohol and nicotine in cigarette smoke, as well as illegal drugs such as opiates, cocaine and marijuana, and increased susceptibility to infections. The nature and mechanisms of immunomodulation induced by such drugs of abuse are described in this review. The effects of opiates and marijuana, using animal models as well as in vitro studies with immune cells from experimental animals and humans, have shown that immunomodulation induced by these drugs is mainly receptor-mediated, either directly by interaction with specific receptors on immune cells or indirectly by reaction with similar receptors on cells of the nervous system. Similar studies also show that cocaine and nicotine have marked immunomodulatory effects, which are mainly receptor-mediated. Both cocaine, an illegal drug, and nicotine, a widely used legal addictive component of cigarettes, are markedly immunomodulatory and increase susceptibility to infection. The nature and mechanism of immunomodulation induced by alcohol, the most widely used addictive substance of abuse, are similar but immunomodulatory effects, although not receptor-mediated. The many research studies on the effects of these drugs on immunity and increased susceptibility to infectious diseases, including AIDS, are providing a better understanding of the complex interactions between immunity, infections and substance abuse.

Gallus S; Giordano L; Altieri A; Talamini R; La Vecchia C. Cigarette smoking and risk of Hodgkin's disease. European Journal of Cancer Prevention 13(2): 143-144, 2004. (11 refs.)

The role of cigarette smoking on the risk of Hodgkin's disease remains controversial. To provide further information on the issue, we analysed data of a case-control study from northern Italy. The cases were 158 patients with incident histologically confirmed Hodgkin's disease, and the controls were 316 patients, frequency-matched to the cases by age, sex and study centre, and admitted to the same network of hospitals for acute, non-neoplastic, non-alcohol- or non-tobacco-related conditions. Compared with those who had never smoked, the multivariate odds ratio was 0.54 for former and 0.85 for current smokers. No trend in risk was found for either the number of cigarettes smoked or the duration of consumption. None of the estimates, or the corresponding trends in risk, was statistically significant Our results are consistent with those of several studies indicating no direct association between cigarette smoking and risk of Hodgkin's disease.

Gamble L; Mason CM; Nelson S. The effects of alcohol on immunity and bacterial infection in the lung. (review). Medecine et Maladies Infectieuses 36(2): 72-77, 2006. (39 refs.)

When faced with invading pathogens that can lead to infection, patients must mount an effective and appropriate immune response. Altered immune function in patients who abuse alcohol has long been described in the medical literature. The alcohol-consuming host is particularly prone to infections in the lung, including bacterial pneumonia and tuberculosis. Over the last several decades, there has been increased interest in the immune mechanisms that underlie the increased risk of infection observed in this population. This article will review the basic immunology involved in the host response to an infection and then describe how alcohol disrupts many of these immune mechanisms. It will further provide an overview of lung infections which have been linked to alcohol abuse, and finally, it will address the evolving therapeutic approaches of the immune system that are being advanced to assist in caring for immuno suppressed hosts.

Gauthier TW; Manar MH; Brown LAS. Is maternal alcohol use a risk factor for early-onset sepsis in premature newborns? Alcohol 33(2): 139-145, 2004. (55 refs.)

Because chronic alcohol abuse alters immune defenses and increases infection in adults, we tested the hypothesis that maternal alcohol use during pregnancy would increase the risk of sepsis in very low birth weight (VLBW) premature newborns. We performed a case-controlled analysis of VLBW newborns born at Grady Memorial Hospital (Atlanta, GA). Alcohol exposure, as the predictive variable, was assessed by maternal self-report. The outcome variables were early-onset and multiple late-onset sepsis. Univariate analysis with Fisher exact test and multivariate analysis with the use of binary logistic regression were performed. Early-onset sepsis was 15-fold higher in the alcohol-exposed group (n = 20) compared with findings for the matched control group (n = 168) [alcohol-exposed group, 10%, vs. control group, 0.6%: odds ratio (OR) 6.8 (95% confidence interval [CI], 2.7-17.1), P ² .05]. Early-onset sepsis in the alcohol + cocaine-exposed group (n = 64) did not differ from findings for the control group. The prevalence of multiple late-onset sepsis did not differ among the exposure groups. Logistic regression analysis, controlling for chorioamnionitis and premature prolonged rupture of membranes, demonstrated an independent, increased risk of early-onset sepsis with alcohol exposure [OR 16 (95% CI, 1.2-210), P ² .05]. We conclude that alcohol exposure significantly increased the risk of early-onset sepsis in this group of VLBW newborns. The effects of maternal alcohol abuse during pregnancy on the risk of infection in the VLBW newborn require further analysis.

Ghaussy NO; Sibbitt WL; Bankhurst AD; Qualls CR. Cigarette smoking and disease activity in systemic lupus erythematosus. Journal of Rheumatology 30(6): 1215-1221, 2003. (62 refs.)

Objective. To investigate the effect of cigarette smoking on disease activity and cumulative organ damage in systemic lupus erythematosus (SLE). Methods. Extensive clinical and demographic variables, including current and previous cigarette smoking, were collected from 111 SLE patients using a detailed interview-administered questionnaire. Disease activity was estimated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Cumulative organ damage was measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR). Smoking status was correlated with disease activity and cumulative organ damage, while statistically adjusting for the individual effects of potentially confounding demographic and clinical variables using analysis of variance followed by Fisher's least significant difference method. Results. Current smokers demonstrated significantly higher (p < 0.001) SLEDAI scores (15.6 +/- 7.8) than ex-smokers (9.63 +/- 6.00), and never smokers (9.03 +/- 5.75). This association remained significant (p = 0.001) after adjusting for all covariates, including ethnicity, education level, income level, alcohol use, age of onset of SLE, current age, mean duration of SLE, marital status, and hydroxychloroquine therapy. Current smokers also demonstrated significantly (p = 0.003) higher scores for both the neurological and non-neurological components of SLEDAI There was no significant difference in the SLICC/ACR scores across the various smoking groups, although there was a trend for more severe disease in current smokers. Conclusion. Cigarette smoking is associated with increased disease activity in SLE. These data further establish the association of SLE with cigarette smoking, and suggest that individuals with SLE should avoid all exposure to tobacco products.

Goforth HW; Lupash DP; Brown ME; Tan J; Fernandez F. Role of alcohol and substances of abuse in the immunomodulation of human immunodeficiency virus disease: A review. Addictive Disorders and Their Treatment 3(4): 174-182, 2004. (45 refs.)

A significant body of evidence links the continued spread of infection with human immunodeficiency virus (HIV) with substance abuse. Some studies have shown changes in behavior which leave individuals at risk for acquiring and spreading HIV infection. Moreover, alcohol and illicit drugs are known to have a direct and toxic effect on the immune system, increase susceptibility to opportunistic infections, inadequate response to antiretroviral therapies, and exacerbate or uncover cognitive inefficiency. This review focuses on the emerging data of the immunomodulatory and toxic effects of alcohol and illicit drugs as well as nicotine. The use of these agents presents a special challenge because of the deleterious effects on HIV-related disease and its progression to fully developed AIDS. There is an urgent need to recognize and incorporate this knowledge into collaborative care between medicine, infectious disease, addiction medicine and mental health professionals to inform treatment and management decisions.

Gonzalez-Quintela A; Vidal C; Gude F. Alcohol, IgE and allergy. (review). Addiction Biology 9(3/4): 195-204, 2004. (91 refs.)

Alcoholic drinks are involved in a variety of hypersensitivity reactions. These include flushing syndrome, anaphylactoid reactions (urticaria/angioedema and even shock), as well as the triggering of asthma, food allergy or exercise-induced anaphylaxis in susceptible subjects. In addition, there is increasing evidence that alcohol intake may play a role as a promoter of the development of immunoglobulin-E (IgE)-mediated hypersensitivity to different allergens. It seems clear that alcohol intake (alcohol abuse and even moderate alcohol consumption) is associated with increased total serum IgE levels. Similarly, alcohol intake may be associated with allergic (IgE-mediated) sensitization to environmental allergens. The clinical significance of these facts is probably moderate. The mechanisms by which alcohol can influence IgE responses are not entirely known, but further developments in this area could increase the understanding of both allergic diseases and alcohol-induced alterations in the immune system.

Gorelick DA; Gardner EL; Xi ZX. Agents in development for the management of cocaine abuse. (review). Drugs 64(14): 1547-1573, 2004. (252 refs.)

Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence. Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site. The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial. Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methylphenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-p-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity. Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D-1 receptor agonist; BP 897 is a D-3 receptor partial agonist. A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a 'cocaine vaccine' found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation.

Goto Y; O'Malley C; Fanning NF; Wang J; Redmond HP; Shorten GD. Benzodiazepines inhibit the rate of neutrophil apoptosis. Irish Journal of Medical Science 172(4): 191-194, 2003. (24 refs.)

Background Benzodiazepines, which are commonly administered perioperatively, can depress immune function. Neutrophil apoptosis plays a central role in the regulation of inflammation. This is particularly important during and after surgery. Aim To examine the effects of benzodiazepines (midazolam and diazepam) on neutrophil apoptosis. Methods: Venous blood samples were withdrawn from patients scheduled to undergo elective surgery, (a) immediately prior to, and 10 minutes after administration of midazolam 0.2mg/kg intravenously (n=11) and (b) immediately prior to, and 60 minutes after administration of diazepam 10mg po (n=10). Neutrophil apoptosis was measured by Annexin VFITC after 1 and 12 hours in culture.Results The percentage of apoptotic cells was significantly less after midazolam at 12% (11.9) hours in culture compared to pre-midazolam 29.7% (13.3) (p<0.05). After diazepam, the rates of neutrophil apoptosis were also significantly less after 12 hours in culture (p<0.05). Conclusion: Administration of benzodiazepines in clinically relevant doses inhibits neutrophil apoptosis. In the perioperative period, this may influence the inflammatory response to surgery.

Hall W; Carter L. Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence. Journal of Medical Ethics 30(4): 337-340, 2004. (35 refs.)

A "cocaine vaccine'' is a promising immunotherapeutic approach to treating cocaine dependence which induces the immune system to form antibodies that prevent cocaine from crossing the blood brain barrier to act on receptor sites in the brain. Studies in rats show that cocaine antibodies block cocaine from reaching the brain and prevent the reinstatement of cocaine self administration. A successful phase 1 trial of a human cocaine vaccine has been reported. The most promising application of a cocaine vaccine is to prevent relapse to dependence in abstinent users who voluntarily enter treatment. Any use of a vaccine to treat cocaine addicts under legal coercion raises major ethical issues. If this is done at all, it should be carefully trialled first, and only after considerable clinical experience has been obtained in using the vaccine to treat voluntary patients. There will need to be an informed community debate about what role, if any, a cocaine vaccine may have as a way of preventing cocaine addiction in children and adolescents.

Halpern JH; Sholar MB; Glowacki J; Mello NK; Mendelson JH; Siegel AJ. Diminished interleukin-6 response to proinflammatory challenge in men and women after intravenous cocaine administration. Journal of Clinical Endocrinology and Metabolism 88(3): 1188-1193, 2003. (47 refs.)

Cocaine abuse is associated with increased rates of infections, including human immunodeficiency virus, and cocaine has immunomodulatory effects in experimental animal and cellular models. When challenged by antigens, tissues release cytokine polypeptides that signal a complex balance of cellular and humoral immune responses. Placement of indwelling venous catheters also leads to surrounding tissue inflammation, mediated partially by local production and release of the proinflammatory cytokine, IL-6. Thus, catheter placement provides a model for examination of cocaine's immunological effects. Thirty healthy men and women with a history of cocaine use participated in this study of neuroendocrine and immunological responses to iv injection of 0.4 mg/kg cocaine or saline placebo. After injection, blood samples were collected from the antecubital vein of the opposite arm via anindwelling venous catheter at 2,4,8,12,16,20,30,40,60,80,120, 180, and 240 min. Cocaine, ACTH, cortisol, and dehydroepiandrosterone concentrations peaked at 8, 12, 40, and 20 min, respectively. Stimulation of IL-6 at 240 min was markedly reduced in subjects receiving cocaine compared with subjects receiving placebo (3.85 +/- 0.49 vs. 11.64 +/- 2.21 pg/ml; P = 0.0019, by two-tailed t test). Gender and menstrual cycle phase did not significantly influence most endocrine or IL-6 measures, although the small number of subjects limits the power of these comparisons. Because cocaine stimulates the hypothalamic-pituitary-adrenal axis, IL-6 suppression may be a consequence of corticosteroid release. Cocaine-induced suppression of proinflammatory IL-6 may mediate impaired host defenses to infections.

Hancox RJ; Welch D; Poulton R; Taylor DR; McLachlan CR; Greene JM et al. Cigarette smoking and allergic sensitization: A 32-year population-based cohort study. Journal of Allergy and Clinical Immunology 121(1): 38-42, 2008. (33 refs.)

Background: Cigarette smoke has immunosuppressant effects, but its effect on allergic sensitization is unclear. Objective: To investigate associations between parental and personal smoking and skin prick tests (SPTs) for atopy in a population-based birth cohort of 1037 participants followed to adulthood. Methods: Parental history of atopic disease, parental smoking, and personal smoking were obtained at multiple assessments between birth and age 32 years. Atopy was assessed by SPTs for 11 common inhaled allergens at ages 13 and 32 years. Results: Children of atopic parents were less likely to have positive SPTs at age 13 years if either parent smoked (odds ratio, 0.55; P =.009). This association was not significant after adjusting for breast-feeding history, number of siblings, and childhood socioeconomic status. Subjects with atopic parents were also less likely to develop positive results to SPTs between ages 13 and 32 years if they smoked themselves (odds ratio, 0.18; P <.001). This reduction in risk remained significant after adjusting for multiple potential confounding factors. Neither parental nor personal smoking was significantly associated with allergic sensitization among subjects whose parents did not have a history of atopic disease. Few of those with positive SPT results at age 13 years had negative tests at age 32 years, and there was no evidence that this was influenced by smoking. Conclusion: Personal and parental smoking is associated with a reduced risk of allergic sensitization in people with a family history of atopy.

Harwood HJ; Myers TG, eds. New Treatments for Addiction: Behavioural, Ethical, Legal and Social Questions. Washington DC: National Academies Press, 2004. (Chapter refs.)

In developing this report the National Academy of Science assembled leading addiction researchers and policy analysts to anticipate the behavioural, ethical, legal and social questions that will arise if promising new immunological treatments (drug vaccines) and depot forms of opioid antagonists are approved for the treatment of addiction to nicotine and illicit drugs. The book includes a 53-page overview of the consensus statement and the accompanying, commissioned background papers. The report begins by describing the immunological rationale of drug vaccines (Pentel). Drug vaccines induce the immune system to form antibodies that bind to the drug (e.g. nicotine) by combining a protein molecule with the drug to provoke an immune response. The antibodydrug complex binds to the drug to form molecules that are too large to cross the bloodbrain barrier, thereby intercepting the drug in the bloodstream before it can act on receptor sites in the brain. Animal studies have provided evidence for the feasibility of using vaccines to block drug effects and interrupt self-administration. Human trials are under way for cocaine and nicotine vaccines so the current volume is a very timely one. Among the range of issues addressed are -- the regulatory and economic challenges in getting drug vaccines approved by the FDA (Kosten & Kranzler); lessons from past failures to introduce new pharmacotherapies into the specialist addiction treatment system (Wood & McNicholas) or the primary health-care setting in the United States (Thomas and McCarty); legal issues raised by the use of vaccines and depot drugs under legal coercion within the criminal justice system (Ridgely et al.) and the probable 'off label' use of vaccines by parents eager to prevent their children and adolescents from becoming addicted to drugs (Miller & Klanica); ethical issues raised by researching and using drug vaccines (Murray); and the probable costs and benefits of drug vaccines (Kleiman). MacCoun makes some plausible projections about the unanticipated consequences of using drug vaccines to treat addiction, which include: addicts using other drugs or larger doses to overcome the immune blockade, thereby increasing overdose risk; risk compensation if addiction comes to be seen as an easily treated minor inconvenience; increased crime to fund more expensive drug use; and a possible arms race between vaccine makers and black market entrepreneurs.

Hasman A; Holm S. Nicotine conjugate vaccine: Is there a right to a smoking future? Journal of Medical Ethics 30(4): 344-345, 2004. (7 refs.)

Tobacco consumption is believed to be one of the world's greatest preventable health problems. According to the World Health Organisation, 1.1 billion people worldwide are addicted to nicotine with tobacco causing an estimated four million premature deaths every year. The development of a nicotine conjugate vaccine suggests that immunisation may hold promise as a future therapeutic and preventive strategy for tobacco smoking and nicotine addiction. Allowing parents to immunise their children against smoking could be an infringement of children's right to an open future, however, and is not ethically unproblematic.

Helliwell RJA; Chamley LW; Blake-Palmer K; Mitchell MD; Wu J; Kearn CS. Characterization of the endocannabinoid system in early human pregnancy. Journal of Clinical Endocrinology and Metabolism 89(10): 5168 -5174, 2004. (26 refs.)

In recent years, it has been demonstrated that high circulating levels of the endogenous cannabinoid anandamide, resulting from low expression of its metabolizing enzyme fatty acid amide hydrolase (FAAH), may contribute to spontaneous miscarriage and poor outcome in women undergoing in vitro fertilization. The site of action of this compound, however, has not been determined. In this study, we examined the distribution of the cannabinoid receptors, CB1 and CB2, and the endocannabinoid-metabolizing enzyme FAAH in first trimester human placenta. Here, we show that FAAH is expressed throughout the human first trimester placenta, in extravillous trophoblast columns, villous cytotrophoblasts, syncytiotrophoblasts, and macrophages. Furthermore, FAAH mRNA levels appear to be regulated during gestation, with levels peaking at 11 wk before declining again. The immune system-associated cannabinoid CB2 receptors were localized only to placental macrophages. Interestingly, the cannabinoid receptor CB1 was not identified in first trimester placenta despite having previously been shown to be present in placental tissues at term. These findings suggest that the placenta may form a barrier preventing maternal-fetal transfer of anandamide and/or modulate local levels of anandamide by regulation of FAAH expression with gestation.

Horrigan LA; Kelly JP; Connor TJ. Immunomodulatory effects of caffeine: Friend or foe? (review). Pharmacology & Therapeutics 111(3): 877-892, 2006. (135 refs.)

Caffeine is a member of the methylxanthine family of drugs, and is the most widely consumed behaviourally active substance in the western world. This article is focused on the impact of caffeine on immune function. In this regard, a number of in vitro and in vivo studies have demonstrated that caffeine modulates both innate and adaptive immune responses. For instance studies indicate that caffeine and its major metabolite paraxanthine suppress neutrophil and monocyte chemotaxis, and also suppress production of the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha from human blood. Caffeine has also been reported to suppress human lymphocyte function as indicated by reduced T-cell proliferation and impaired production of Th-1(interleukin [IL]-2 and interferon [IFN]-gamma), Th-2 (IL-4, IL-5) and Th-3 (IL-10) cytokines. Studies also indicate that caffeine suppresses antibody production. The evidence suggests that at least some of the immunomodulatory actions of caffeine are mediated via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE), and consequential increase in intracellular cAMP concentrations. Overall, these studies indicate that caffeine, like other members of the methylxanthine family, is largely anti-inflammatory in nature, and based on the pharmacokinetics of caffeine, we suggest that many of its immunomodulatory effects occur at concentrations that are relevant to normal human consumption. Finally, the potential of caffeine-induced immunomodulation to significantly impact upon health and well-being are discussed.

Imhof A; Koenig W. Alcohol inflammation and coronary heart disease. (review). Addiction Biology 8(3): 271-277, 2003. (66 refs.)

This overview summarizes the experimental and epidemiological evidence linking alcohol consumption and the immune system. It focuses on findings supporting the notion that moderate alcohol consumption exerts anti-inflammatory effects which may explain, at least in part, the reduced risk of coronary heart disease morbidity and mortality in these subjects. Alcohol consumption has been shown consistently to be associated with all-cause mortality in a F- or U-shaped manner. This is due primarily to reduced risk of coronary heart disease (CHD) mortality among moderate consumers of alcohol compared to abstainers and heavy drinkers. Several mechanisms have been suggested by which moderate alcohol consumption could lower risk of CHD. However, changes in lipids, such as increased HDL cholesterol and apolipoprotein A I or a favourable haemostatic profile, can only partly explain the beneficial effects. Recently, anti-inflammatory effects of moderate intake of alcohol have been considered as an additional possible explanation, as inflammation has a fundamental role in the initiation, progression and the thrombotic complications of atherosclerosis.

Islam SN; Hossain KJ; Kamal M; Ahsan M. Serum immunoglobulins and white blood cells status of drug addicts: influence of illicit drugs and sex habit. Addiction Biology 9(1): 27-33, 2004. (43 refs.)

The aim of this study was to investigate the serum immunoglobulins and white blood cells status of drug addicts and to assess the extent of influence of drug habit and sexual practice on the immune components. The study was conducted among 253 male drug addicts and 100 non-addict controls of aged 18-45 years. An enzyme-linked immunosorbent assay (ELISA) was employed to analyse the serum immunoglobulin concentrations. White blood cells pro. le was estimated by counting 200 cells. Results showed a significant increase (p<0.03) of serum IgG, IgA and IgM in the drug addicts (6.93&PLUSMN;1.53 g/l, 2.90&PLUSMN;1.13 g/l and 1.72&PLUSMN;0.73 g/l, respectively) compared to those in the cohort controls (6.52&PLUSMN;1.05 g/l, 2.61&PLUSMN;0.83 g/l and 1.52&PLUSMN;0.59 g/l, respectively). A significant (p=0.00) decrease of peripheral lymphocytes (51.8&PLUSMN;15.2 vs. 71.9&PLUSMN;11.5) was noted in the drug addicts. Monocytes (8.3&PLUSMN;4.9), neutrophils (128.2&PLUSMN;18.9) and eosinophils (11.4&PLUSMN;5.8) were found to be increased in the drug addicts against those in the controls (5.2&PLUSMN;2.5, 113.2&PLUSMN;13.0 and 9.6&PLUSMN;5.8, respectively). Multiple drug abuse for longer period had resulted in a significant (p<0.05) decrease of serum immunoglobulins and lymphocytes. The longer period of addiction had also made a significant (p<0.05) decrease of eosinophils (p=0.05) and an increase of monocytes and neutrophils. Sex with multiple sexual partners had shown a significant (p<0.01) decrease of serum immunoglobulins and eosinophils.

Kantak KM. Vaccines against drugs of abuse - A viable treatment option? Drugs 63(4): 341-352, 2003. (63 refs.)

Drug addiction is a chronically relapsing brain disorder. There is an urgent need for new treatment options for this disease because the relapse rate among drug abusers seeking treatment is quite high. During the past decade, many groups have explored the feasibility of using vaccines directed against drugs of abuse as a means of eliminating illicit drug use as well as drug overdose and neurotoxicity. Vaccines work by inducing drug-specific antibodies in the bloodstream that bind to the drug of abuse and prevent its entry into the brain. The majority of work in this area has been conducted with vaccines and antibodies directed against cocaine and nicotine. On the basis of preclinical work, vaccines for cocaine and nicotine are now in clinical trials because they can offer long-term protection with minimal treatment compliance. In addition, vaccines and antibodies for phencyclidine, methamphetamine and heroin abuse are currently under development. An underlying theme in this research is the need for high concentrations of circulating drug-specific antibodies to reduce drug-seeking and drug-taking behaviour when the drug is repeatedly available, especially in high doses. Although vaccines against drugs of abuse may become a viable treatment option, there are several drawbacks that need to be considered. These include: (i) a lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice; (ii) a lack of an effect on drug craving that predisposes an addict to relapse; and (iii) tremendous individual variability in antibody formation. Forced or coerced vaccination is not likely to work from a scientific perspective, and also carries serious legal and ethical concerns. All things considered, vaccination against a drug of abuse is likely to work best with individuals who are highly motivated to quit using drugs altogether and as part of a comprehensive treatment programme. As such, the medical treatment of drug abuse will not be radically different from treatment of other chronic diseases.

Katona S; Kaminski E; Sanders H; Zajicek J. Cannabinoid influence on cytokine profile in multiple sclerosis. Clinical and Experimental Immunology 140(3): 580-585, 2005. (22 refs.)

Cannabinoids have been suggested as possessing immunomodulatory properties, and cannabinoid receptors are present on leucocytes. Clinically, there is some evidence that cannabinoids may be therapeutically useful in treating multiple sclerosis, which is generally believed to be an autoimmune condition. This paper reports data derived from the Cannabinoids in MS (CAMS) study, which was the largest randomized controlled trial yet conducted to evaluate the therapeutic efficacy of cannabinoids. We found no evidence for cannabinoid influence on serum levels of interferon (IFN)-gamma, interleukin (IL)-10, IL-12 or C-reactive protein as measured using enzyme-linked immunosorbent assay (ELISA), in comparison to control values. Mitogenic stimulation experiments also failed to demonstrate any significant reduction in percentage of CD3(+), IFN-gamma producing cells after exposure to cannabinoids in vivo, although numbers were small. Further work is needed to establish the functional significance of cannabinoid receptors on immune cells.

Kim SH; Ensunsa JL; Zhu QY; Kim JS; Shin HS; Keen CL. An 18-month follow-up study on the influence of smoking on blood antioxidant status of teenage girls in comparison with adult male smokers in Korea. Nutrition 20(5): 437-444, 2004. (29 refs.)

OBJECTIVES: The influence of cigarette smoking on blood antioxidant status in teenage girls with a history of short-term smoking was followed over 18 mo. METHODS: Data obtained from female senior high school students (ages 14 to 18 y) in Korea were compared with data obtained from adult male smokers (ages 36 to 51 y) with a long history of smoking and living in the same geographic areas as the teenage subjects. A snicker was a person who had smoked at least three cigarettes a day for at least 1 y for teenagers (n = 35) or at least 10 cigarettes a day for at least 13 y for adults (n = 20). Serum, urine, and anthropometric data were obtained from teenagers every 6 mo over an 18-mo period. Samples were collected once from adults. Data were analyzed by Student's t test and Fisher's protected least significant difference test for comparing smokers and non-smokers and for analyzing period effects in each group. RESULTS: Serum nicotine and cotinine concentrations were higher in smokers than in non-smokers. Blood pressures were higher in teenage (at 0 and 12 mo) and adult smokers than in non-smokers. Extracellular superoxide dismutase activities and concentrations of serum vitamin C and folate were lower in smokers in the teenage (at 0, 12, or 18 mo) and adult groups. Serum ceruloplasmin activities and thiobarbituric acid-reactive substance production were not influenced by smoking. In adults, serum copper concentrations were higher in smokers than in non-smokers. This parameter for teenagers did not change consistently throughout the study. CONCLUSIONS: Similar to adults, cigarette smoking by teenagers has a negative effect on oxidant defense systems.

Kosten T; Owens M. Immunotherapies for substance abuse. IN: Dewey WL, ed. Problems of Drug Dependence 2003: Proceedings of the 65th Annual Scientific Meeting. Rockville MD: National Institute on Drug Abuse, 2004. pp. 31-33. (0 refs.)

Medications based on immunological therapies are currently in pre-clinical and human trials for cocaine, nicotine, methamphetamine, and phencyclidine (PCP). The purpose of this symposium is to show experimental data from animal and human models of clinical scenarios in which these new therapeutic approaches might prove useful. These modes include reduction of drug self-administration, treatment of excessive drug use, and prevention of brain or cardiac toxicity. As an example, pre-clinical behavioral studies in rats show active immunization against cocaine and nicotine, or passive administration with anti-methamphetamine monoclonal antibodies might be used to reduce drug self-administrant, even when the drug dowse appears to exceed the apparent antibody binding capacity. Experimental data is show about the use methamphetamine and phencyclidine monoclonal antibodies for the treatment of excessive drug use. Data is also presented on the immunization of rats with a nicotine conjugate vaccine for the passive transfer of nicotine-specific antibodies substantially reduce maternal nicotine distribution to the fetal brain and attenuates the acquisition of nicotine self-administration. Finally, results from human outpatient clinical trials of a cocaine vaccine, along with their urine toxicology results. These data show that more frequent vaccinations of humans can lead to higher antibody levels. excellent reductions in cocaine use with minimal side effects.

Public Domain

Kovacs EJ; Faunce ED; Messingham KAN. Ethanol and burn injury: Estrogen modulation of immunity. Alcohol 33(3): 209-216, 2004. (121 refs.)

A good deal of clinical evidence supports the idea that ethanol exposure is a causative factor in the occurrence of burn or other traumatic injury. In addition, more recent evidence reveals that individuals who sustain injury while under the influence of ethanol suffer from increased morbidity and mortality compared with those with comparable injuries who did not consume ethanol. Many of the complications seen in ethanol-exposed, burn-injured subjects result from depressed immune responses, which render the host unable to fight off infectious organisms. Both injury and ethanol exposure independently affect cellular immune responses, including delayed-type hypersensitivity and splenocyte proliferative responses, and the combined insult of ethanol exposure and injury acts in conjunction to increase further the magnitude and duration of immunosuppression. It is interesting that these immune responses can be restored experimentally in male, but not in female, mice by administration of low, proestrous levels of estrogen. The complexity of the responses after injury in ethanol-exposed subjects is multiplied when the sex of the subjects is added to the equation. This is due, in part, to the effect of the combined insult of injury and ethanol on the production of gonadal steroid hormones in males and females and the direct effects of those hormones on cytokine gene expression in sensitive cell types such as the macrophage. Evidence seems to indicate that cellular immune responses after ethanol exposure and burn injury differ in kinetics and magnitude for male and female subjects, and, hence, the therapeutic interventions to treat burn-injured patients should take into account both sex and ethanol exposure.

Kovacs EJ; Jerrells TR. Alcohol and immunology: Introduction to and summary of the 2003 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 33(3): 171-174, 2004. (8 refs.)

The 8th Meeting of the Alcohol and Immunology Research Interest Group (AIRIG) was held at Loyola University Medical Center, Maywood, Illinois, USA, on November 21, 2003. Reports from multiple laboratories reveal that the functional integrity of the immune system is of paramount importance to the survival of the individual after infection or injury. Evidence supports the idea that exposure to alcohol causes dysregulation of both the innate and the adaptive arms of the immune system. Gaining a better understanding of how alcohol interferes with normal inflammatory and immunoregulatory processes will aid researchers in the design of therapeutic interventions that can be used to improve these responses to better fight infection and maintain the health of the individual. At this meeting, nine speakers presented a summary of their recent work on the combined effects of ethanol and injury, infection, or inflammatory challenge. Topics were (1) T-cell activation after chronic ethanol ingestion in mice, (2) effect of ethanol consumption on the severity of acute viral-mediated pancreatitis, (3) ethanol and alveolar macrophage dysfunction, (4) impaired intestinal immunity and barrier function: a cause for enhanced bacterial translocation in alcohol intoxication and burn injury, (5) immune consequences of the combined insult of acute ethanol exposure and burn injury, (6) consequences of alcohol-induced dysregulation of immediate hemodynamic and inflammatory responses to trauma/hemorrhage, (7) regulation of tumor necrosis factor-alpha production by Kupffer cells after chronic exposure to ethanol, (8) acute exposure to ethanol and suppression of cytokine responses induced through Toll-like receptors, and (9) inhibition of antigen-presenting cell functions by alcohol: implications for hepatitis C virus infection. We anticipate that the work presented at the 8th Meeting of AIRIG, summarized in this article, and presented in the nine articles to follow in this Special Issue of Alcohol will stimulate ideas that will develop into research projects in these topical areas.

Kraft B; Kress HG. Cannabinoids and the immune system. Of men, mice and cells. (review). Schmerz 18(3): 203-+, 2004. (40 refs.)

The medical use of cannabis or cannabinoid compounds is controversial. Cannabinoids like the Delta9-THC (tetrahydrocannabinol) or the synthetic derivative Nabilone are available against cancer- and HIV-associated cachexia, nausea and vomiting. Over the last 20 years, the cannabinoid receptors CB1 and CB2 and their endogenous ligands have been found. The involvement of this endogenous cannabinoid signalling system in feeding, appetite, pain perception and immunomodulation could be demonstrated using animal and in vitro studies. Thus,the concern about immunosuppressive effects in humans using medical cannabinoid preparations grew. However, up to now most human studies have failed to demonstrate a well-defined and reproducible immunosuppressive cannabinoid-effect. Only the smoking of marijuana showed a significant local immunosuppression of the bactericidal activity of human alveolar macrophages. In animal studies, cannabinoids were identified as potent modulators of cytokine production, causing a shift from Th1 to Th2 cytokines. In consequence, a compromised cellular immunity was observed in these animals, resulting in enhanced tumor growth and reduced immunity to viral infections. In vitro, immunosuppressive effects were shown in all immune cells, but only at high micromolar cannabinoid concentrations not reached under normal clinical conditions. In conclusion,there is no evidence that cannabinoids induce a serious, relevant immunosuppression in humans,with the exception of marijuana-smoking which may affect local brocho-alveolar immunity.

Laso FJ; Vaquero JM; Almeida J; Marcos M; Orfao A. Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells. Alcoholism: Clinical and Experimental Research 31(5): 846-854, 2007. (47 refs.)

Background: Alcoholism is frequently associated with altered immune responses, limited information being available on its effects on dendritic cells (DC). In the present study we analyze the effects of chronic alcoholism on circulating DC. Methods: For the first time we studied the numerical distribution of DC in peripheral blood (PB), their immunophenotype, and their ex vivo pattern of spontaneous cytokine secretion, in chronic alcoholic patients without liver disease (AWLD group; n=17) and active ethanol (EtOH) intake, as well as in subjects with alcohol liver cirrhosis (ALC group; n=21). Results: A significantly decreased HLADR expression and an increased reactivity for CD123 was observed on PB DC from AWLD patients; additionally, increased secretion of interleukin (IL) 1 beta, IL6, IL12, and tumor necrosis factor-alpha (TNF alpha) by DC was also noted in this group. Conversely, patients with ALC and at least 1 year of alcohol withdrawal (ALCAW group) showed a decreased number of total circulating DC, whereas ALC patients with active EtOH intake (ALCET group) had an abnormally low production of IL1 beta and TNF alpha by PB DC. Conclusion: Chronic alcoholism in the absence of liver disease is associated with an increased secretion of inflammatory cytokines by PB DC, whereas ALCAW and ALCET patients show decreased numbers of circulating DC and reduced secretion of these cytokines, respectively.

Ma Y; Meregalli M; Hodges S; Davies N; Bogdanos DP; Fargion S. Alcohol dehydrogenase: An autoantibody target in patients with alcoholic liver disease. International Journal of Immunopathology and Pharmacology 18(1): 173-182, 2005. (32 refs.)

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13%, P<0.005), HBV infection (2/8, 25%, P=0.03), non-alcohol related disease (9/29, 23%, P<0.0001) and in normal controls (3/22, 14%, P<0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76% vs 34/64, 53%, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P<0.05), immunoglobulin A (P<0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.

Manfredsdottir VF; Vikingsdottir T; Jonsson T; Geirsson AJ; Kjartansson O; Heimisdottir M et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology 45(6): 734-740, 2006. (36 refs.)

Objective. To study the effect of tobacco smoking and rheumatoid factor (RF) isotypes on disease activity and joint damage in early rheumatoid arthritis (RA). Methods. One hundred early RA patients were followed prospectively for 2 yr. They were evaluated at recruitment and at 6 and 24 months. Sociodemographic information included smoking history, and radiographs of hands and feet were obtained. RF was monitored by IgM- and IgA-specific RF enzyme-linked inummosorbent assay and by agglutination, and serial measurements were also obtained for C-reactive protein. The influence of tobacco smoking and RF positivity on disease outcome was evaluated using multivariate analysis. Covariates for the regression analysis included sex, age, coffee consumption and IgA-RF positivity. Results. A gradient of increase in disease activity was observed from never smokers to former smokers to current smokers during the 2 yr of observation, defined by number of swollen joints (SJC), tender joints (TJC) and visual analogue scale for pain (P < 0.001, P = 0.02 and P = 0.005, respectively), but smoking status did not influence radiological progression. Ever smokers were more often IgA RF positive (P < 0.05). IgA RF-positive patients had more active disease (SJC P = 0.002, TJC P = 0.01) and showed more radiological progression (P < 0.0001) compared with IgA RF-negative patients. Of the RF-positive patients 22% had elevated IgM RF without IgA RF and these patients showed similar disease activity and radiological joint progression to the RF-negative patients. None of these associations were explained by possible confounders. Conclusion. Tobacco smoking has an adverse effect on patients with early RA and this is possibly immunologically mediated. IgM RF does not predict poorer prognosis in RA unless it is associated with a concomitant elevation of IgA RF.

Massi P; Vaccani A; Parolaro D. Cannabinoids, immune system and cytokine network. (review). Current Pharmaceutical Design 12(24): 3135-3146, 2006. (102 refs.)

How cannabinoids influence immune function has been examined extensively in the last 30 years. Studies on drug-abusing humans and animals, as well as in vitro models employing immune cell cultures, have shown that marijuana, natural and endogenous cannabinoid compounds are immunomodulators. These substances modulate host resistance to bacterial, protozoan and viral infections as well as they can profoundly affect the Th1/Th2 response. Recently, two types of cannabinoid receptor, CB1 and CB2, have been discovered. While CBI is expressed primarily in the brain, CB2 is peculiar of the immune cells. Cannabinoid receptors have been shown to be involved in some but not all of immune effects. Nevertheless, their identification provides a specific mechanism of action in the attempting to find out how exogenous cannabinoids and endogenous cannabinoid system affect the immune apparatus, strengthen the hypothesis of cannabinoids as immunomodulators. As support to this theory, enough evidence exists to suggest that the cannabinoid system significantly affects almost every component of the immune response machinery and impacts the functioning also of the cytokine network. The evaluation of the biological consequences of these drug-induced cytokine changes has also dramatically become important considering not only the impact of cytokines on immune system per se but also envisaging their influence in cancer, inflammation, autoimmune disease, brain injury, hematopoictic colony formation in which cannabinoids have demonstrated a clear role as important modulators.

Miller GE; Cohen S; Pressman S; Barkin A; Rabin BS; Treanor JJ. Psychological stress and antibody response to influenza vaccination: When is the critical period for stress, and how does it get inside the body? Psychosomatic Medicine 66(2): 215-223, 2004. (41 refs.)

Objectives: This study attempted to determine whether stress of moderate intensity could modulate the antibody response to an influenza vaccination in healthy young adults, identify critical periods during which stress could influence antibody response, and delineate behavioral and biological pathways that might explain relations between stress and antibody. Methods: A cohort of 83 healthy young adults underwent 13 days of ambulatory monitoring before, during, and after vaccination. Four times daily, subjects reported the extent to which they felt stressed and overwhelmed and collected a saliva sample that was later used to measure cortisol. A battery of health practices (cigarette smoking, alcohol use, physical activity, sleep hygiene) was assessed daily. Antibody titers to the vaccine components were measured at baseline and at 1-month and 4-month follow-up assessments. Results and Conclusions: To the extent that they reported higher levels of stress across the monitoring period, subjects exhibited poorer antibody responses to the New Caledonia strain of the vaccine. Stress ratings on the 2 days before the vaccine and the day it was given were not associated with antibody response. However, the 10 days afterward appeared to be a window of opportunity during which stress could shape the long-term antibody response to varying degrees. With respect to potential mediating pathways, little evidence emerged in favor of cortisol secretion, alcohol consumption, physical activity, or cigarette smoking. However, analyses were consistent with a pattern in which feelings of stress and loss of sleep become locked into a feed-forward circuit that ultimately diminishes the humoral immune response. These findings may shed light on the mechanisms through which stress increase vulnerability to infectious disease.

Misery L. Nicotine effects on skin: Are they positive or negative? (review). Experimental Dermatology 13(11): 665-670, 2004. (69 refs.)

The adverse effects of tobacco on the skin are well known but the role of nicotine is more controversial. Nicotinic receptors are expressed in the skin, on keratinocytes, fibroblasts and blood vessels. Nicotine induces vasoconstriction associated with local hyperaemia. It inhibits inflammation through effects on central and peripheral nervous system and through direct effect on immune cells. It delays wound healing and accelerates skin aging. The role of nicotine on skin diseases remains unclear. Therapeutic effects of nicotine could be possible and this a new stimulating field of research.

Molina PE; Zambell KL; Norenberg K; Eason J; Phelan H; Zhang P et al. Consequences of alcohol-induced early dysregulation of responses to trauma/hemorrhage. Alcohol 33(3): 217-227, 2004. (75 refs.)

Acute alcohol intoxication is a frequent underlying condition associated with traumatic injury. Studies from our laboratory have been designed to examine the early hemodynamic, proinflammatory, and neuroendocrine alterations in responses to hemorrhagic shock in surgically catheterized, conscious, unrestrained, male Sprague-Dawley rats during acute alcohol intoxication (1.75-g/kg bolus, followed by a constant 15-h infusion at a rate of 250-300 mg/kg/h). With both fixed-pressure (40 mm Hg) and fixed-volume (50%) hemorrhagic shock, followed by fluid resuscitation with Ringer's lactate, acute (15 h) alcohol intoxication has been shown to impair significantly the immediate hemodynamic, metabolic, and inflammatory counterregulatory responses to hemorrhagic shock. Alcohol intoxication enhanced hemodynamic instability during blood loss and impaired the recovery of mean arterial blood pressure during fluid resuscitation. Activation of neuroendocrine pathways involved in restoring hemodynamic stability was significantly attenuated in alcohol-intoxicated hemorrhaged animals. The hemodynamic and neuroendocrine impairment is associated with enhanced expression of lung and spleen tumor necrosis factor, and it suppressed circulating neutrophil function. In addition, neuroimmune regulation of cytokine production by spleen-derived macrophages obtained from alcohol-intoxicated hemorrhaged animals was impaired when examined in vitro. We hypothesize that impaired neuroendocrine activation contributes to hemodynamic instability, which, in turn, prolongs tissue hypoperfusion and enhances risk for tissue injury. Specifically, the early dysregulation in counterregulatory responses is hypothesized to affect host defense mechanisms during the recovery period. We examined host response to systemic (cecal ligation and puncture) and localized (pneumonia) infectious challenge in animals recovering from hemorrhage during acute alcohol intoxication. Increased morbidity and mortality from infection were observed in alcohol-intoxicated hemorrhaged animals. Our results indicate that alcohol-induced alterations in early hemodynamic and neuroimmune responses to shock have an impact on susceptibility to an infectious challenge during the early recovery period.

Moran A; Harbour DV; Teeter LD; Musser JM; Graviss EA. Is alcohol use associated with cavitary disease in tuberculosis? Alcoholism: Clinical and Experimental Research 31(1): 33-38, 2007. (30 refs.)

Background: Alcohol mediates detrimental alterations in the immune response to Mycobacterium tuberculosis. The association between quantity and frequency of alcohol use and the prevalence of cavitary disease in tuberculosis (TB) has not been analyzed. To investigate the relationship of alcohol use and the prevalence of cavitary disease in a 6-year population-based data set of individuals with TB. Methods: We assessed quantity and frequency of alcohol use (daily alcohol use, years of alcohol use, and lifetime alcohol use) with a standardized questionnaire. The study group consisted of 1,250 patients analyzed for cavitary disease (HIV sero-negative subjects that were 18 years or older). Significant covariates for cavitary disease were entered into multiple logistic regression models. Results: Although daily alcohol use, years of alcohol use, and alcohol use 30 days or 6 months before symptom onset were significant predictors of cavitary disease in univariate analysis, no independent associations were found between alcohol use and cavitary disease in the multivariate analysis. Only diabetes mellitus was independently associated with cavitary disease at any level or frequency of alcohol use. Conclusion: Alcohol use is not independently associated with increased prevalence of cavitary disease in adult patients with TB.

Motivala SJ; Dang J; Obradovic T; Meadows GG; Butch AW; Irwin MR. Leptin and cellular and innate immunity in abstinent alcoholics and controls. Alcoholism: Clinical and Experimental Research 27(11): 1819-1824, 2003. (38 refs.)

Background: Basic studies indicate that in vitro and in vivo doses of leptin modulate cellular immune responses. Given evidence that concentrations of leptin are altered in alcoholics who also show immune abnormalities, this study examined the relationships between circulating levels of leptin and markers of cellular and innate immunity. Methods: Circulating levels of leptin, natural killer cell (NK) activity, interleukin-2 (IL-2)-stimulated NK activity, and concanavalin A-stimulated production of IL-2, IL-6, IL-10, and IL-12 were compared between abstinent DSM-IV alcohol-dependent men (n = 27) and age- and gender-matched controls (n 34). Results: As compared with controls, alcoholics showed lower NK activity (p < 0.01) and a trend for lower levels of leptin (p = 0.055). In the total sample, leptin predicted NK activity (β = 0.33; p < 0.05) after controlling for the confounding influence of body mass index, alcohol intake, and smoking. Leptin was not correlated with any of the cytokine measures. To examine whether the effects of leptin were mediated by its direct action on NK, additional studies examined in vitro effects of leptin on NK activity in healthy volunteers (n = 10); leptin doses (0.1, 1, and 10 nM) yielded levels of NK activity comparable to those with media alone. Conclusions: These data show that circulating levels of leptin are associated with NK activity in humans and suggest that abnormal in vivo concentrations of leptin may contribute to the declines of NK activity in alcoholics who are at risk for infectious diseases.

Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. (review). Experimental Biology and Medicine 228(8): 882-890, 2003. (102 refs.)

The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of alcoholic liver disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of disease is by disrupting the signal transduction cascades mediating the innate immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogenactivated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of alcoholic liver disease.

Nakata A; Takahashi M; Irie M; Fujioka Y; Haratani T; Araki S. Relationship between cumulative effects of smoking and memory CD4+T lymphocyte subpopulations. Addictive Behaviors 32(7): 1526-1531, 2007. (11 refs.)

Previous studies have found that smoking is a strong factor that increases peripheral blood CD4+ T lymphocytes. However, most studies did not assess the cumulative long-life exposure of smoking on differential lymphocyte populations. In this study, to clarify the association of smoking habits and circulating lymphocytes, we conducted a cross-sectional study of 60 male current smokers. Smoking status was estimated by number of cigarettes smoked per day, smoking years, and Brinkman Index (BI) as calculated by multiplying the number of cigarettes smoked per day by the smoking years. Counts of CD4+CD45RO+CD69+ T and CD4+CD45RO+ T lymphocytes were strongly and positively correlated with BI and remained highly significant after controlling for alcohol drinking, leisure-time physical activity, and caffeine intake (r(p)>.465, p<.001). These lymphocytes were also significantly correlated with the number of cigarettes smoked per day and smoking years, but the association was weaker than the BI. The findings suggest that the CD4+CD45RO+CD69+ T and CD4+CD45RO+ T lymphocytes are sensitive to cumulative effect of smoking, and may serve as a potential immuno-biomarker for active smoking.

Neri S; Bruno CM; Pulvirenti D; Malaguarnera M; Italiano C; Mauceri B et al. Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers. Psychopharmacology 179(3): 700-704, 2005. (18 refs.)

Rationale: Buprenorphine may be a useful alternative option to methadone in addicts. Opioids can produce severe changes in the immune system. Objectives: The objectives of this study are to compare the effect of sublingual buprenorphine and methadone on the immune system and to compare the two substances on the drying-out program compliance. Methods: We studied 62 randomized outpatients for a period of 12 months. Subjects (55 males and 7 females; mean age 25 +/- 4 years; average history of heroin abuse being 2 years) on maintenance treatment were assigned in two groups (A and B). Methadone chloride (medium dose 100 mg/day) was administered to group A, whereas group B received sublingual buprenorphine (32.40 +/- 2.8 mg/day). Urine toxicological screening, plasma levels of TNF-alpha interleukin-1, interleukin-beta, lymphocyte CD14 and a self-rating depression questionnaire were measured. Results: Urine screening was negative for opiates in 17.6% of group A and in 10.7% of group B (p< 0.001; r= 0.62). Depression score was 62 +/- 2 in group A and 55 +/- 3 in group B (p< 0.01). Cytokine and CD14 revealed higher concentrations both in groups A and B without significant differences (p> 0.05) between the two groups. Conclusions: The effects of buprenorphine and methadone tested on the immune system were overlapping in our patients. The elevated cytokine levels observed may suggest that the two drugs stimulate immunologic hyperactivation of an immune system that was formerly inhibited by heroin. Furthermore, our data suggest that buprenorphine can be a valid alternative to methadone in maintenance treatment of chronic heroin abuse and referred a marked decline in depression.

Nouri-Shirazi M; Guinet E. A possible mechanism linking cigarette smoke to higher incidence of respiratory infection and asthma. Immunology Letters 103(2): 167-176, 2006. (48 refs.)

T helper type 1 (Th1) cells are responsible for cell-mediated immunity against invading pathogens, while Th2 cells provide help to B cells and control allergic responses. The polarization of naive Th cells into Th1 or Th2 subsets is controlled by dendritic cells (DCs) migrating from the periphery to draining lymph nodes. Migrating DCs carry not only antigen-specific 'signal I' and costimulatory 'signal 2', but also Th-polarizing,signal 3' that reflects the nature of the pathogen and the character of the infected tissue. Any changes imposed by external factors on the DC lifecycle may result in an inappropriate immune response. Here we show that DCs developed in a nicotinic environment (nicDCs) fail to support the terminal development of effector memory Th1 cells due to their differential expression of costimulatory molecules and lack of IL-12 production. Interestingly, they adopt critical Th1-promoting function necessary to prevent and fight infections only when the total balance of environmental signals strongly favors Th1 immunity. Notably, in a Th2-biased environment, nicDCs provoke stronger than normal Th2 responses which predisposes the development and exacerbation of asthma. These results help explain the two opposing effects of cigarette smoke on respiratory immune defense mechanisms: (a) immunosuppression against infectious agents and (b) exacerbation of asthma.

Nutt D; Lingford-Hughes A. Infecting the brain to stop addiction? (editorial). Proceedings of the National Academy of Sciences 101(31): 11193-11194, 2004. (7 refs.)

Drug abuse is a major public health problem, and, although there are many treatments of proven efficacy, the majority of patients are not permanently cured, with relapse rates on the order of 70% or more in the first years for the treatment of almost all drugs of addiction. Therefore, there is a great need for new and improved therapies. Carrera et al. have pioneered the use of one of the oldest proven medical interventions, immunization, in the treatment of cocaine dependence. Their initial studies revealed that it is possible to vaccinate animals against cocaine by using either a blocking antibody or catalytic antibody approach. The blocking antibody binds cocaine and therefore extracts it from the blood; this seems to be the more promising method, because the current catalytic antibodies only minimally accelerate the clearance of cocaine. However, the blocking antibody technique provides only a peripheral blockade, and so any cocaine that is not "mopped up" by antibodies in plasma can enter the brain and give the reinforcing actions that perpetuate the cycle of addiction and dependence. The work by Carrera et al. in a recent issue of PNAS moves the field by utilizing a concept originated for the treatment of Alzheimer's disease in which an antibody to -amyloid was delivered to the brain in a (bacterio)phage vector. Here, the animal is infected with a phage that targets the brain and that has been engineered to express thousands of copies of the cocaine-binding antibody. It reproduces in the brain, thereby generating large amounts of blocking antibody. When cocaine enters the brain, some of it binds to the antibody and, therefore, is not available to perform its usual action: to increase dopamine, the neurotransmitter that is thought to mediate its actions. To maximize access of phage to the brain and minimize peripheral infection, the phage vaccine was administered intranasally, where it is presumed to enter the olfactory nerve endings and move down the axons into the brain. Antagonist therapies are not appealing as because they are not reinforcing. Perhaps an alternative strategy would be to produce an enduring blockade before first exposure as a preventative measure, such as is done with vaccination against measles and other infectious diseases. This would, of course, be ethically controversial, although given the fact that cocaine dependence is more damaging to many individuals than measles, it is an option that should be debated.

Pacifici R; Zuccaro P; Farre M; Poudevida S; Abanades S; Pichini S et al. Combined immunomodulating properties of 3,4-methylenedioxymethamphetamine (MDMA) and cannabis in humans. Addiction 102(6): 931-936, 2007. (12 refs.)

Aims Cell-mediated immune function and the occurrence of mild infectious diseases was investigated. Participants Polydrug consumers of 3,4-methylenedioxymethamphetamine (MDMA) and cannabis (n = 37) compared to cannabis users only (n = 23) and control group (n = 34). Design A longitudinal prospective study with three cross-sectional evaluations at time 0 and at 6 months and 1 year was performed. Findings At baseline, a significant decrease in interleukin (IL)-2 and an increase in anti-inflammatory transforming growth factor (TGF)-beta 1, together with a decrease in the number of total lymphocytes, CD4 and natural killer (NK) cells were observed in the MDMA-cannabis group, with intermediate alterations in the cannabis group. Immune alterations observed at baseline were sustained over time. No differences were found between regular and occasional MDMA users. A significantly higher rate of mild infections in regular MDMA-cannabis users compared with occasional MDMA-cannabis users and the remaining groups was observed. Conclusions The present data confirm that long-term alterations in immunological homeostasis may result in general health status impairment and subsequent increased susceptibility to infection and immune-related disorders.

Pavia CS; La Mothe M; Kavanagh M. Influence of alcohol on antimicrobial immunity. Biomedicine & Pharmacotherapy 58(2): 84-89, 2004. (60 refs.)

Prolonged consumption of excessive amounts of alcohol by itself, as well as possibly leading to a state of alcoholism, has been a long-standing biological/social problem. As a major public health concern, there is an estimated expenditure of about 20% of total health care costs for medical/hospital care related to alcohol-induced illness. In addition, a significant proportion of both men and women who are hospitalized can be classified as alcoholics. This review focuses primarily on one of the many biomedical problems attributed to alcohol abuse-its adverse effects on our immune-defense system. A considerable body of evidence has mounted, over the past several decades, indicating that those who abuse alcohol are more susceptible to certain infectious disorders and are more prone to bacteremia. Such infections tend to be continuous and are often associated with a high rate of mortality. Also, along these lines, various and suitable animal models have been developed to further elucidate what the causes are for the greater frequency and severity of infectious illnesses, and this review deals primarily with those studies linking alcohol abuse to disruption in the normal functioning of the host's immune surveillance system. Based on the results from both clinical and experimental studies, it would seem that exposure to high levels of alcohol causes decreased humoral and cellular immune responses, thereby seriously limiting our ability to be protected from certain infectious agents.

Peterson E; Owens SM; Henry RL. Monoclonal antibody form and function: manufacturing the right antibodies for treating drug abuse. AAPS Journal 8(2): e383-390, 2006. (32 refs.)

Drug abuse continues to be a major national and worldwide problem, and effective treatment strategies are badly needed. Antibodies are promising therapies for the treatment of medical problems caused by drug abuse, with several candidates in preclinical and early clinical trials. Monoclonal antibodies can be designed that have customized affinity and specificity against drugs of abuse, and because antibodies can be designed in various forms, in vivo pharmacokinetic characteristics can be tailored to suit specific clinical applications (eg, long-acting for relapse prevention, or short-acting for overdose). Passive immunization with antibodies against drugs of abuse has several advantages over active immunization, but because large doses of monoclonal antibodies may be needed for each patient, efficient antibody production technology is essential. In this minireview we discuss some of the antibody forms that may be effective clinical treatments for drug abuse, as well as several current and emerging production systems that could bridge the gap from discovery to patient use.

Pruett BS; Pruett SB. An explanation for the paradoxical induction and suppression of an acute phase response by ethanol. Alcohol 39(2): 105-110, 2006. (31 refs.)

Binge ethanol (EtOH) consumption suppresses inflammatory responses and resistance to infection, but paradoxically it is associated with increased levels of acute phase proteins (which are indicators of inflammation) and an increased risk of inflammation-mediated pathologies such as cardiovascular disease and cirrhosis of the liver. The latter effect may be mediated by increased translocation of bacteria leading to activation of toll-like receptor 4 (TLR4). In this study, the dose-response and time course of the effects of EtOH alone or EtOH in conjunction with a TLR4 agonist (lipopolysaccharide [LPS]) were evaluated in mice. EtOH alone at a dosage of 6 g/kg induced an acute phase response (as indicated by enzyme-linked immunosorbent assay for serum amyloid A and serum amyloid P) that was maximal 24 h after dosing. Lower dosages of EtOH did not have this effect but did suppress the acute phase response to LPS and the production of interleukin-6 up to 3 h after dosing. EtOH at 6 g/kg did not induce an acute phase response in C3H/HeJ (TLR4 mutant) mice, indicating that this response is mediated through TLR4. These results provide a resolution for the apparently paradoxical pro- and anti-inflammatory actions of EtOH with regard to acute phase responses.

Pruett SB; Zheng Q; Fan R; Matthews K; Schwab C. Acute exposure to ethanol affects Toll-like receptor signaling and subsequent responses: An overview of recent studies. Alcohol 33(3): 235-239, 2004. (28 refs.)

Ethanol suppresses innate resistance to a variety of microbes, and findings of studies from both our laboratory and other laboratories indicate suppression of responses is mediated through two Toll-like receptors (TLRs): TLR3 and TLR4. In this article, we review recent findings from studies in our laboratory, indicating that ethanol also suppresses responses mediated through other TLRs. Considering the importance of TLR-mediated responses in innate immunity, this supports the possibility that suppression of these responses may constitute a major mechanism by which ethanol suppresses innate immunity. In addition, ethanol-induced changes in cellular signaling and in patterns of gene expression induced through TLR3 were examined in mouse peritoneal macrophages, and these results are reviewed in this article. Signaling through TLR3 was inhibited, and results of DNA microarray analysis supported the notion that inhibition of an interferon-related amplification loop might be responsible for suppression of gene expression for several effector molecules of innate immunity and inflammation not previously known to be altered by ethanol. Thus, ethanol alters responses through most or all mouse TLRs, and this suppresses expression of a wide range of innate immune mediators.

Redwine L; Dang J; Hall M; Irwin M. Disordered sleep, nocturnal cytokines, and immunity in alcoholics. Psychosomatic Medicine 65(1): 75-85, 2003. (58 refs.)

The authors examine the relationships between sleep, nocturnal expression of immunoregulatory cytokines, and natural killer (NK) cell activity in alcoholic patients as compared with control subjects. 24 alcoholic patients and 23 comparison control subjects underwent all-night polysomnography and serial blood sampling at 23:00, 03:00, and 06:30 hrs. Stimulated expression of TH1 (interferon gamma, IFN-gamma), anti-inflammatory/TH2 (interleukin 10, IL-10), and proinflammatory cytokines (IL-6) was measured along with NK cell activity across the night. Alcoholic patients showed lower levels of IL-6 production, suppression of the IL-6/IL-10 ratio, and a reduction of NK cell activity, coupled with losses of delta sleep and increases of rapid eye movement sleep, as compared with control subjects. In addition, alcoholics showed a persistent low ratio of IFN-gamma/IL-10 and reduced levels of NK cell activity, whereas controls had increases of these 2 immune measures across the night. IL-6 also differentially changed in the 2 groups; alcoholics showed increases and controls had decreases of IL-6 from 03:00 hrs to 06:30 hrs. At 06:30 hrs, rapid eye movement sleep predicted increases of IL-6 and decreases of NK cell activity independent of the relative contribution of age and chronic alcohol consumption.

Romeo J; Warnberg J; Nova E; Diaz LE; Gomez-Martinez S; Marcos A. Moderate alcohol consumption and the immune system: A review. British Journal of Nutrition 98(Supplement 1): S111-S115, 2007. (46 refs.)

Increasing evidence suggests that light to moderate amounts of polyphenol-rich alcoholic beverages like wine or beer could have health benefits. Scientists have long debated the effects of alcohol on immune function, showing on the one hand, that high doses of alcohol consumption can directly suppress a wide range of immune responses, and that alcohol abuse is associated with an increased incidence of a number of infectious diseases. On the other hand, moderate alcohol consumption seems to have a beneficial impact on the immune system compared to alcohol abuse or abstinence. Therefore, the link between alcohol consumption, immune response, as well as infectious and inflammatory processes remains not completely understood. With this in mind, it is important to realise that other factors, unrelated or indirectly related to immune function, like drinking patterns, beverage type, amount of alcohol, or gender differences, will affect the influence that alcohol consumption may have on the immune system. This review summarises published data describing the effects that light to moderate amounts of polyphenol-rich beverages like wine or beer seem to have on immunity in healthy adults.

Roth MD; Whittaker K; Salehi K; Tashkin DP; Baldwin GC. Mechanisms for impaired effector function in alveolar macrophages from marijuana and cocaine smokers. Journal of Neuroimmunology 147(1-2): 82-86, 2004. (49 refs.)

Lung macrophages provide a first line of host defense against inhaled pathogens and their function is impaired in the lungs of inhaled substance abusers. In order to investigate the mechanism for this impairment, alveolar macrophages (AM) were recovered from nonsmokers (NS), regular tobacco smokers (TS), marijuana smokers (MS), or crack cocaine smokers (CS), and evaluated for their production of nitric oxide (NO) and the role of NO as an antimicrobial effector molecule. AM from NS and TS efficiently killed Staphylococcus aureus and their antibacterial activity correlated closely with the production of nitrite and the expression of mRNA encoding for inducible nitric oxide synthase (iNOS). In contrast, AM collected from MS and CS exhibited limited antimicrobial activity that was not affected by an inhibitor of iNOS, or associated with expression of iNOS. Treatment with either granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma restored the ability of these cells to produce NO and to kill bacteria. These findings confirm a significant role for NO as an antibacterial effector molecule used by normal human AM and suggest that this host defense mechanism is suppressed by habitual exposure to inhaled marijuana or crack cocaine in vivo.

Sacerdote P. Opioids and the immune system. Palliative Medicine 20(Supplement 1): S9-S15, 2006. (27 refs.)

Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid's profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent mu-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity to preoperative levels, while in morphine-treated rats NK-lymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity.

Schleifer SJ; Keller SE; Czaja S. Major depression and immunity in alcohol-dependent persons. Brain, Behavior, and Immunity 20(1): 80-91, 2006. (61 refs.)

Altered immunity has been associated with both alcoholism and major depression (MD). We investigated the contribution of MD, as well as alcoholism, to in vitro measures of immunity in inner-city alcohol-dependent (SCID-DSM-III-R) persons and community nonabusers, all otherwise in good health. Methods. Alcohol-dependent persons at an ambulatory alcohol treatment center who did not abuse other substances were studied along with the comparison sample (total n=122). Enumerative and functional immune measures included leukocyte and lymphocyte subsets, mitogen response, natural killer cell activity (NKCA), and granulocytic phagocytosis. Results. Controlling for alcohol dependence, age, gender, racial background, and medical status, major depression was associated with decreased phytohemagglutinin (PHA) responses (p<.03), possibly decreased NKCA (p<.08), and increased circulating monocytes (p<.04). Controlling for major depression, age, gender, racial background, and medical status, alcohol dependence was associated with decreased circulating B lymphocytes (p<.02), possibly decreased CD56(+) (NK) cells (p<.06), and increased monocytes (p<.04). Responses to concanavalin A and pokeweed mitogen, granulocyte functions, and the composition of other leukocyte and lymphocyte subsets showed no evidence of being associated with major depression or with alcoholism (p>.1). Secondary analyses exploring factors such as recent alcohol use, cigarette use, and nutrition suggested that these factors accounted for the altered lymphocyte subsets associated with alcoholism and the possibly decreased NKCA with major depression. They did not account for the association of major depression with increased monocytes and decreased PHA. Discussion. major depression-associated immune changes in alcoholics are modest and consistent with those seen in major depression without alcoholism. Some major depression- and many alcoholism-associated immune effects appear related to factors such as cigarette use and recent alcohol exposure.

Schmid JMP; Kuehni CE; Strippoli MPF; Roiha HL; Pavlovic R; Latzin P; Swiss Pediatric Respiratory Research Group. Maternal tobacco smoking and decreased leukocytes, including dendritic cells, in neonates. Pediatric Research 61(4): 462-466, 2007. (22 refs.)

Maternal smoking in pregnancy is associated with respiratory diseases in the offspring, possibly due to prenatal influences on the developing immune system. We investigated whether maternal smoking in pregnancy was associated with cord blood leukocyte numbers, including precursor dendritic cells, adjusting for concomitant factors. In a prospective healthy birth cohort study, total leukocyte counts were reduced in neonates of smoking mothers [10.7 (8.4-13.0), n = 14] compared with nonexposed infants [14.7 (13.7-15.7), n = 74, p = 0.002] [geometric mean cells X 10(3)/mu L (95% confidence interval)]. All leukocyte subsets were decreased, most prominently segmented neutrophils [4.3 (2.8-5.7) versus 6.2 (5.5-6.8), p = 0.021], lymphocytes [3.8 (2.9-4.8) versus 5.0 (4.5-5.6), p = 0.036], and myeloid precursor dendritic cells [12.7 cells/mu L (9.1-17.8) versus 18.3 (15.8-21.2), p = 0.055]. These differences persisted after adjustment for possible confounders. Predictors of myeloid precursor dendritic cell numbers in multivariable models were maternal smoking (-5.1 cells/mu L, p = 0.042), age (-0.5 cells/mu L/y, p = 0.035), and, marginally, asthma (+8.1 cells/mu L, p = 0.075). The decrease of all leukocytes in neonates of smoking mothers could be clinically significant and suggests a decreased cell production, increased peripheral recruitment, or retention in bone marrow. Given the importance of dendritic cells in early immune responses, their decrease might reflect an impact of maternal smoking on the developing fetal immune system.

Sergio N; Salvatore T; Gaetano B; Davide P; Claudio I; Massimo L et al. Immune response in addicts with chronic hepatitis C treated with interferon and ribavirine. Journal of Gastroenterology and Hepatology 22(1): 74-79, 2007. (48 refs.)

The role played by the immune system in the progression of chronic hepatitis C (CHC) is not completely clear. Opioids may facilitate the outbreak of infections through marked immunomodulating effects on the immune response against a virus. To asses if addicts can be treated successfully with interferon (IFN) during detoxification treatment, we evaluated some immune response mediators in addicts affected by CHC. A cohort of heroin users with CHC were enrolled during the detoxification period, divided into two groups and treated with IFN pegilate plus ribavirin (group A treated during methadone administration and group B treated at week 8 after methadone treatment completed). A group of patients with CHC and no history of drug addiction were enrolled as controls. Leukocyte subpopulation NK, CD4+, CD8+ and some cytokines Th-1 (IFN gamma, interleukin [IL]2) and Th-2 (IL-6, IL-10) were evaluated prior to, during and after methadone treatment. Sustained virological response was evaluated 24 weeks after antiviral treatment was completed. During methadone treatment, significantly (P < 0.05) higher cytokine Th-1 and NK and lower cytokine Th-2 levels were observed in groups A and B compared with levels obtained before treatment in the same groups. Relapse occurred at 56 +/- 8 weeks in 34/55 group A patients, at 24 +/- 8 weeks in 33/52 group B patients and at 24 +/- 4 weeks in group C, there being a significant difference (P < 0.05) between group A and B and between group A and C. No significant differences between all groups were detected in CD4+ and CD8+ cell counts. Our results revealed that drug addicts with CHC can be treated successfully with IFN pegilate and ribavirin. This therapy can be recommended during the early phase of detoxification treatment to achieve a sustained response.

Shay AH; Choi R; Whittaker K; Salehi K; Kitchen CMR; Tashkin DP et al. Impairment of antimicrobial activity and nitric oxide production in alveolar macrophages from smokers of marijuana and cocaine. Journal of Infectious Diseases 187(4): 700-704, 2003. (15 refs.)

Human alveolar macrophages (AMs) were recovered from the lungs of healthy nonsmokers (NS) or smokers of tobacco (TS), marijuana (MS), or crack cocaine (CS) and challenged in vitro with Staphylococcus aureus. AMs from NS and TS exhibited potent antibacterial activity that correlated with the production of nitric oxide (NO) and induction of NO synthase without the requirement for priming with exogenous cytokines. In contrast, AMs from MS and CS exhibited minimal antibacterial activity and failed to produce NO unless primed with additional cytokines. These results confirm that NO plays a significant role as an effector molecule used by normal human AMs, but this capacity is suppressed in AMs from MS and CS because of a lack of intrinsic cytokine priming.

Simhan HN; Caritis SN; Hillier SL; Krohn MA. Cervical anti-inflammatory cytokine concentrations among first-trimester pregnant smokers. American Journal of Obstetrics and Gynecology 193(6): 1999-2003, 2005. (30 refs.)

Objective: Anti-inflammatory cytokines play a role in the lower genital tract immune defense. We examined the impact of cigarette smoking in pregnancy on the detection of the 3 most important anti-inflammatory cytokines (interleukin-4, -10, and -13) in the cervix. Study design: One hundred fourteen gravid women from 4 to 16 weeks of gestation without bacterial vaginosis or sexually transmitted disease were queried regarding demographic factors and smoking. Concentrations of cytokines were determined with a multiplex assay for cervical swabs. Results: There was a positive linear relationship between the number of cigarettes that were smoked per day and cervical concentrations of interleukin-4, -10, and -13 (P < .001 for each). Median concentrations of interleukin-4 and -10 were greater among women who smoked >= 20 cigarettes per day than among non-smokers or less heavy smokers (P < .05 for both). There was no difference in concentrations of proinflammatory cytokines between smokers and non-smokers. Conclusion: Cigarette smoking in pregnancy is associated with an increase of cervical anti-inflammatory cytokines without a commensurate increase of proinflammatory cytokines. This may have important impact on the host response to infection.

Singh SP; Razani-Boroujerdi S; Pena-Philippides JC; Langley RJ; Mishra NC; Sopori ML. Early postnatal exposure to cigarette smoke impairs the antigen-specific T-cell responses in the spleen. Toxicology Letters 167(3): 231-237, 2006. (40 refs.)

Annually, approximately two million babies are exposed to cigarette smoke in utero and postnatally through cigarette smoking of their mothers. Exposure to mainstream cigarette smoke is known to impair both innate and adaptive immunities, and it has been hypothesized that the effects of in utero exposure to cigarette smoke on children's health might primarily stem from the adverse effects of cigarette smoke on the immune system. To simulate the environment that babies from smoking mothers encounter, we examined the effects of prenatal mainstream and postnatal sidestream cigarette smoke on spleen cell responses. Results show that postnatal exposure of newborn Balb/c mouse pups to sidestream cigarette smoke through the first 6 weeks of life strongly suppresses the antibody response of spleen cells to the T-cell-dependent antigen, sheep red blood cells. The reduction in the antibody response seen within 6 weeks of postnatal smoke exposure is much quicker than the published data on the time 25 weeks) required to establish reproducible immunosuppression in adult rats and mice. Moreover, the immumosuppression is not associated with significant changes in T-cell numbers or subset distribution. While the postnatal exposure to cigarette smoke did not affect the mitogenic response of T and B cells, the exposure inhibited the T cell receptor-mediated rise in the intracellular calcium concentration. These results suggest that the early postnatal period is highly sensitive to the immunosuppressive effects of environmental tobacco smoke, and the effects are causally associated with impaired antigen-mediated signaling in T cells.

Smith AJ; Vollmer-Conna U; Bennett B; Hickie IB; Lloyd AR. Influences of distress and alcohol consumption on the development of a delayed-type hypersensitivity skin test response. Psychosomatic Medicine 66(4): 614-619, 2004. (46 refs.)

Objective: This paper reports the effects of naturally occurring levels of distress on the development of delayed-type hypersensitivity (DTH) skin test responses. These in vivo measures provide a biologically relevant assessment of cellular immune competence. Methods: Subjects (N = 166) were immunized (baseline) with the novel antigen, keyhole limpet hemocyanin (KLH), and DTH skin test responses against KLH were assessed 3 weeks later (follow-up). The CMI Multitest (Merieux, France), which evaluates DTH responses to a panel of seven antigens, was also administered at follow-up. Emotional distress was assessed at baseline and follow-up by the Profile of Mood States. Results: Distress levels at baseline were associated with a reduced likelihood of developing DTH responses against KLH at follow-up (r = -0.22, p = .01). There was no relationship between distress at follow-up and cutaneous DTH in response to KLH (r = 0.09, p = .24) or in the Multitest (r = -0.03, p = .70). In addition, higher levels of alcohol consumption at baseline (r = -0.19, p = .02) and at follow-up (r = -0.20, p = .01) were associated with a decreased likelihood of developing cutaneous DTH against KLH. Conclusions: Everyday levels of distress predicted the capacity of the cellular arm of the immune system to exhibit recall responses to an antigen, when the experimental paradigm allowed the assessment of distress at the time of antigen sensitization. Moderate alcohol consumption independently affected cutaneous DTH.

Spies C; Eggers V; Szabo G; Lau A; von Dossow V; Schoenfeld H et al. Intervention at the level of the neuroendocrine-immune axis and postoperative pneumonia rate in long-term alcoholics. American Journal of Respiratory and Critical Care Medicine 174(4): 408-414, 2006. (55 refs.)

Rationale: Postoperative pneumonia is three to four times more frequent in patients with alcohol use disorders followed by prolonged intensive care unit (ICU) stay. Long-term alcohol use leads to an altered perioperative hypothalamus-pituitary-adrenal (HPA) axis and immunity. Objectives: The aim of this study was to evaluate HPA intervention with low-dose ethanol, morphine, or ketoconazole on the neuroendocrine-immune axis and development of postoperative pneumonia in long-term alcoholic patients. Methods: In this randomized, double-blind controlled study, 122 consecutive patients undergoing elective surgery for aerodigestive tract cancer were included. Long-term alcohol use was defined as consuming at least 60 g of ethanol daily and fulfilling the Diagnostic and Statistical Manual of Mental Disorders IV criteria for either alcohol abuse or dependence. Nonalcoholic patients were included but only as a descriptive control. Perioperative intervention with low-dose ethanol (0.5 g/kg body weight per day), morphine (115 mu g/kg body weight per hour), ketoconazole (200 mg four times daily), and placebo was started on the morning before surgery and continued for 3 d after surgery. Blood samples to analyze the neuroendocrine-immune axis were obtained on the morning before intervention and on Days 1, 3, and 7 after surgery. Measurements and Main Results: In long-term alcoholic patients, all interventions decreased postoperative hypercortisolism and prevented impairment of the cytotoxic T-lymphocyte type 1:type 2 ratio. All interventions decreased the pneumonia rate from 39% to a median of 5.7% and shortened intensive care unit stay by 9 d (median) compared with the placebo-treated long-term alcoholic patients. Conclusions: Intervention at the level of the HPA axis altered the immune response to surgical stress. This resulted in decreased postoperative pneumonia rates and shortened intensive care unit stay in long-term alcoholic patients.

Standridge JB; Zylstra RG; Adams SM. Alcohol consumption: An overview of benefits and risks. (review). Southern Medical Journal 97(7): 664-672, 2004. (73 refs.)

Published health benefits of regular light-to-moderate alcohol consumption include lower myocardial infarction rates, reduced heart failure rates, reduced risk of ischemic stroke, lower risk for dementia, decreased risk of diabetes and reduced risk of osteoporosis. Numerous complimentary biochemical changes have been identified that explain the beneficial effects of moderate alcohol consumption. Heavy alcohol consumption, however, can negatively affect neurologic, cardiac, gastrointestinal, hematologic, immune, psychiatric and musculoskeletal organ systems. Binge drinking is a significant problem even among moderate drinkers and is associated with particularly high social and economic costs. A cautious approach should be emphasized for those individuals who drink even small amounts of alcohol. Physicians can apply the research evidence describing the known risks and benefits of alcohol consumption when counseling their patients regarding alcohol consumption.

Szabo G; Dolganiuc A; Mandrekar P; White B. Inhibition of antigen-presenting cell functions by alcohol: Implications for hepatitis C virus infection. Alcohol 33(3): 241-249, 2004. (43 refs.)

The mechanisms of alcohol-induced immunosuppression include defects in innate and adaptive immune responses. Monocytes and dendritic cells (DCs) link innate and adaptive immune responses as they recognize viral antigens and induce antigen-specific T-cell activation. We investigated the effects of alcohol on antigen-presenting cell functions. Acute alcohol consumption by healthy volunteers (vodka, 2 ml/kg) resulted in significantly reduced antigen-presenting cell function of monocyte-derived DCs. Reduced allostimulatory capacity of DCs treated with alcohol in vitro correlated with decreased co-stimulatory molecule (B7.1 and B7.2) expression, as well as with reduced interleukin (IL)-12 and increased IL-10 concentrations, in mixed lymphocyte cultures. Dendritic cells recognize viral antigens in hepatitis C virus (HCV) infection, and HCV disease is accelerated in alcohol-dependent individuals. For patients with chronic HCV infection, we found reduced allostimulatory capacity of myeloid DCs. Furthermore, DC function was reduced by in vitro alcohol treatment of DCs obtained from HCV-infected patients, supporting the suggestion that viral factors and alcohol may interact to doubly suppress DC functions. We found that induction of maturation with lipopolysaccharide could not fully ameliorate the reduced DC allostimulatory capacity caused by alcohol treatment, HCV infection, or their combination. In addition, soluble factors in the supernatants obtained from mixed lymphocyte cultures containing alcohol-treated DCs or DCs obtained from HCV-infected patients could transfer inhibition of T-cell proliferation in cultures containing DCs obtained from healthy volunteers. Anti-IL-10 neutralizing antibody ameliorated the reduced mixed lymphocyte reaction containing DCs obtained from HCV-infected patients, whereas exogenous IL-12, but not anti-IL-10, treatment ameliorated the reduced T-cell proliferation induced by alcohol treatment of DCs obtained from healthy volunteers. Our results support the suggestion that both acute alcohol intake and in vitro alcohol treatment inhibit DC antigen-presenting cell function and support the hypothesis that viral factors interact with alcohol to reduce DC functions in HCV infection.

Tekes K; Hantos M; Gyenge M; Csaba G. Perinatal alcohol exposure enhances nocistatin levels in adulthood. Addiction Biology 12(2): 173-175, 2007. (17 refs.)

In earlier experiments perinatal hormonal imprinting by alcohol decreased the hormone content of immune cells for life. In the present study, both a single day (15% on the third postnatal day) and a long-term treatment schedule of alcohol exposure (3% for 21 days) of dams during lactation significantly (P < 0.01) enhanced endogenous levels of nocistatin in the blood plasma as well as in the cerebrospinal fluid of the offspring, measured in 3-month-old rats. Our data suggest that alcohol consumption during lactation can cause a life-long influence on nocistatin levels in the offspring and most likely modify nocistatin-related functions such as pain tolerance.

Theodorou S; Haber PS. The medical complications of heroin use. Current Opinion in Psychiatry 18(3): 257-263, 2005. (59 refs.)

Purpose of review: Heroin use is associated with numerous adverse sequelae. As clinical services develop, addiction psychiatrists will increasingly be called upon to help identify and manage the complications of heroin use. This review focuses on recent research into the medical complications of heroin use and looks at strategies to minimize harm associated with this practice. Recent findings: Mortality associated with heroin overdose has increased substantially in many countries. Parenteral use of opioid drugs is a central factor and other risk factors include polydrug use, particularly benzodiazepines and alcohol, mental health issues and environmental factors not conducive to resuscitation. Unravelling the determinants of blood-borne virus transmission continues, the focus shifting from needle sharing to inadvertent sharing of other injecting equipment. Trials addressing the challenges of antiviral therapy in injecting drug users are emerging. A greater understanding of the effects of opioids on immune functioning complements our knowledge of infection in the heroin-using group as well as possibly explaining the reduced response to vaccination in this group. Summary: Medical complications of heroin affect a number of different organ systems. The role of the addiction specialist is to be aware of these so that early diagnosis and appropriate management is instituted. The latter will generally be done in collaboration with other specialists. The addictions specialist can play a significant role in the development of clinical systems to minimize these complications.

Thiele GM; Freeman TL; Klassen LW. Immunologic mechanisms of alcoholic liver injury. (review). Seminars in Liver Disease 24(3): 273-287, 2004. (148 refs.)

Clinically, the association of alcoholic liver disease (ALD) with circulating autoantibodies, hypergammaglobulinemia, antibodies to unique hepatic proteins, and cytotoxic lymphocytes reacting against autologous hepatocytes strongly suggests altered immune regulation with an increased activity toward normal self-proteins (loss of tolerance). Experimentally, there are several immune responses generated specifically recognizing self-proteins that are modified by metabolites of alcohol. These data strongly suggest that immune reactions may play a significant role in inducing and sustaining an inflammatory cascade of tissue damage to the liver. Additional support for this comes from the observation that the histological appearance of livers with ALD is that of a chronic active hepatitis-like inflammatory disease. Therefore, the hypothesis that immune mechanisms are involved in recurrent alcoholic hepatitis, although not summarily proven, is reasonable, supported by clinical and experimental evidence, and the subject of this article.

Trimarchi M; Miluzio A; Nicolai P; Morassi ML; Bussi M; Marchisio PC. Massive apoptosis erodes nasal mucosa of cocaine abusers. American Journal of Rhinology 20(2): 160-164, 2006. (17 refs.)

Background: A threatening occurrence in some cocaine abusers is the progressive destruction of nasal structures (cocaine-induced midline destructive lesions [CIMDL]) that may end in a highly severe disease. Methods: Thirty patients with CIMDL, 10 healthy patients, 10 patients affected by nasal polyposis, and 10 patients affected by Wegener granulomatosis were observed. Biopsy specimens of nasal mucosa were analyzed by immunohistochemistry for caspases-3, -9 and -8 and by the terminal deoxynucleotidyl transferase-mediated dUTP-digoxygenin nick end labeling (TUNEL) method. The time and concentration-dependent effects of cocaine in vitro were studied in HaCat cells by TUNEL and Western blotting. Results: All CIMDL biopsy specimens showed abundant caspase-3 and caspase-9 expression but no caspase-8 positive cells. No obvious expression of any caspases was detected in biopsy specimens front healthy subjects or in patients affected by nasal polyposis or Wegener granulomatosis. In HaCat cells cellular changes were observed, which confirmed induction of massive apoptotic events. The rate of apoptosis in HaCat cells was dependent on the concentration of cocaine. After 1 hour, 2.5, 5, and 10 mM of cocaine induced 16, 45, and 84% of apoptotic figures, respectively, while 6 hours of exposure increased apoptosis to 25, 54, and 94% at the same concentrations. Caspase expression and activation in HaCat cells treated with 100 mu M and 1 mM of cocaine for 1 hour were confirmed by Western blotting. Conclusion: Cultured epithelial cells show both time- and dose-dependent increases in apoptosis and cellular damage on cocaine treatment. We suggest that some abusers trigger CIMDL by abnormally boosting apoptosis within nasal epithelial cells. Cocaine abusers with higher apoptotic rates may predict whether they will eventually develop CIMDL.

Ussher M; West R; Evans P; Steptoe A; McEwen B; Clow A et al. Acute reduction in secretory immunoglobulin A following smoking cessation. Psychoneuroendocrinology 29(10): 1335-1340, 2004. (22 refs.)

Smokers report an increase in upper respiratory infections in the early phase of stopping smoking. One possible cause is a depletion in secretory immunoglobulin A (S-IgA) which has been observed in one study. The present study sought to establish this finding in smokers using nicotine patches. Ninety-two smokers, trying to stop smoking, were assessed whilst smoking and for up to six weeks of abstinence. All smokers were prescribed 15 mg 16-h nicotine patches. Among abstinent smokers, changes in S-IgA and saliva volume were assessed. During the preliminary analyses, we observed that for the pre-smoking cessation measure a longer time since the last cigarette was significantly related to Lower S-IgA levels (P = 0.006). Consequently, the main analysis, of changes in S-IgA from pre-cessation to post-cessation, was confined to those who had smoked within 0.5-1.5 h of the pre-cessation measure (n = 51). There was a significant decline in S-IgA, relative to pre-smoking abstinence levels, following abstinence of one day (P = 0.027), but Levels returned to pre-abstinence values after one week. There was no evidence of any significant changes in saliva volume following smoking cessation, relative to pre-cessation levels. Users of 15 mg patches are likely to experience a decline in S-IgA levels on the first day of smoking cessation, independent of saliva volumes, and this decline in S-IgA is Likely to occur acutely, within the first few hours of smoking abstinence. This acute drop in S-IgA appears to stem from a factor other than depletion of nicotine from the body. The observed decrease in S-IgA may help to explain the increased susceptibility of smokers to upper respiratory tract infections in the immediate post-cessation period.

Whetzel CA; Corwin EJ; Klein LC. Disruption in Th1/Th2 immune response in young adult smokers. Addictive Behaviors 32(1): 1-8, 2007. (31 refs.)

Interferon (IFN)-_ and IL-10 cytokines, measures of Th1 and Th2 immunity, were examined in 20 healthy nonsmokers (12 males, 8 females) and 19 smokers (11 males, 8 females), aged 19-41 years (23.46 ± 0.82 years). Nonsmokers came to the laboratory once; smokers came to the laboratory after ad lib smoking and following 24-h smoking abstinence. Salivary cotinine and expired CO confirmed smoking status. Plasma was collected at the end of each lab session and assayed for peripheral IFN-_ and IL-10 levels. Among smokers, peripheral IFN-_, IL-10, or IFN-_/IL-10 ratio levels did not change in response to 24-h smoking abstinence. IFN-_ levels and IFN-_/IL-10 ratios were higher among female smokers while smoking and following 24-h abstinence compared to male smokers in both conditions and compared to male and female nonsmokers. There was no sex or smoking status difference in IL-10 levels. Results suggest that cigarette smoking may have at least short-term damaging effects on the body's normal immune balance, particularly for women.

Whetzel CA; Corwin EJ; Klein LC. Disruption in Th1/Th2 immune response in young adult smokers. Addictive Behaviors 32(1): 1-8, 2007. (31 refs.)

Interferon (IFN)-gamma and IL-10 cytokines, measures of Th1 and Th2 immunity, were examined in 20 healthy nonsmokers (12 males, 8 females) and 19 smokers (11 males, 8 females), aged 19-41 years (23.46 +/- 0.82 years). Nonsmokers came to the laboratory once; smokers came to the laboratory after ad lib smoking and following 24-h smoking abstinence. Salivary cotinine and expired CO confirmed smoking status. Plasma was collected at the end of each lab session and assayed for peripheral IFN-gamma and IL-10 levels. Among smokers, peripheral IFN-gamma, IL-10, or IFN-gamma/IL-10 ratio levels did not change in response to 24-h smoking abstinence. IFN-gamma levels and IFN-gamma/IL-10 ratios were higher among female smokers while smoking and following 24-h abstinence compared to male smokers in both conditions and compared to male and female nonsmokers. There was no sex or smoking status difference in IL-10 levels. Results suggest that cigarette smoking may have at least short-term damaging effects on the body's normal immune balance, particularly for women.

2007, Elsevier Science

Yu QL; Larson DF; Watson RR. Heart disease, methamphetamine and AIDS. Life Sciences 73(2): 129-140, 2003. (80 refs.)

Methamphetamine (MA) not only affects the nervous system but also has cardiac toxicity and immunosuppressive properties. This manuscript will provide support that there is a relationship between MA use and heart disease as well as immune dysfunction. The cardiovascular manifestations of acute MA use include tachycardia, atrioventricular arrhythmias, myocardial ischemia, myocardial ischemia and hypertension, resulting in cardiac lesions. Chronic use of MA causes cardiomyopathy including cellular infiltration, myocardial hypertrophy, myocardium rupture and fibrosis. The increased catecholamine levels are responsible for the cardiac lesions induced by MA. The additional problem with MA use is its potential to disrupt the immune system function leading to suppression of mitogen-stimulated lymphocyte, a reduction in circulating lymphocyte numbers and alternation T-lymphocyte cytokine secretion as well as B cell proinflammatory cytokine secretion. Concomitant MA use and Human Immunodeficiency Virus (HIV) infection not only enhances immunosuppression associated with HIV but also increases the heart disease occurrence with a coincidentally complication of AIDS or AIDS medications.

Zajicova A; Wilczek H; Holan V. The alterations of immunological reactivity in heroin addicts and their normalization in patients maintained on methadone. Folia Biologica 50(1): 24-28, 2004. (28 refs.)

Drug addiction influences many physiological functions including reactions of the immune system. The higher occurence of infectious and other diseases in drug addicts has been explained by the depression of immunity due to the harmful effects of the drug. To test this assumption, we tested the proliferative responsiveness and cytokine production of PBL from a group of heroin addicts (N = 19), patients maintained on methadone (N = 15) and healthy controls (N = 15). The results show that Con A-induced proliferation of PBL from heroin addicts was even enhanced in comparison with PBL from the control group. Similarly, production of IL-2, IL-10 and IFNgamma was higher in the group of heroin addicts than in healthy controls. The enhanced proliferation of PBL or the increased production of cytokines observed in heroin addicts was partially or completely normalized in the group of patients maintained on methadone. A significantly higher production of IL-6 was found in both unstimulated and stimulated PBL from heroin addicts and patients maintained on methadone, when compared with PBL from healthy controls. The results thus showed enhanced proliferative activity and increased production of various cytokines in heroin addicts and partial or complete adjustment of these alterations in patients maintained on methadone.

Zenda T; Kobayashi T; Miyamoto S; Okada T. Severe alcoholic hepatitis accompanied by Fournier's gangrene. European Journal of Gastroenterology and Hepatology 15(4): 419-422, 2003. (16 refs.)

This case report describes the medical history of a debilitated 62-year-old Japanese man who presented with jaundice and a 3-day history of high fever, genital pain, edema, and marked penoscrotal swelling. The patient had a long history of alcohol abuse and poor diet. Laboratory tests revealed leucocytosis, anemia, marked thrombocytopenia, intense inflammatory reaction and liver injury, renal dysfunction, and malnutrition. Urinalysis showed microscopic hematuria. Computed tomography showed soft tissue thickening of the penoscrotum and diffuse enlargement of the liver. The patient was diagnosed as having severe alcoholic hepatitis concurrent with Fournier's gangrene. Treatment procedures included disinfection of the necrotizing tissue and use of broad-spectrum antibiotics and prednisolone, which produced a successful outcome. The route of bacterial intrusion was not defined, but the Fournier's gangrene is believed to have developed from impaired immunological defenses primarily associated with heavy alcohol consumption and profound liver dysfunction. The potential for life threatening urogenital area infection in alcoholic liver disease patients is discussed.