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CORK Bibliography: Immune System

35 citations. January 2010 to present

Prepared: March 2012

Babu DK; Diaz A; Samikkannu T; Rao KVK; Saiyed ZM; Rodriguez JW et al. Upregulation of serotonin transporter by alcohol in human dendritic cells: Possible implication in neuroimmune deregulation. Alcoholism: Clinical and Experimental Research 33(10): 1731-1738, 2009. (47 refs.)

Background: Alcohol is the most widely abused substance and its chronic consumption causes neurobehavioral disorders. It has been shown that alcohol affects the function of immune cells. Dendritic cells (DC) serve as the first line of defense against infections and are known to accumulate neurotransmitters such as 5-hydroxytryptamine (5-HT). The enzyme monoamine oxidase-A (MAO-A) degrades 5-HT that is associated with clinical depression and other neurological disorders. 5-HT is selectively transported into neurons through the serotonin transporter (SERT), which is a member of the sodium- and chloride-dependent neurotransmitter transporter (SLC6) family. SERT also serves as a receptor for psychostimulant recreational drugs. It has been demonstrated that several drugs of abuse such as amphetamine and cocaine inhibit the SERT expression; however, the role of alcohol is yet to be elucidated. We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. Methods: Dendritic cells were treated with different concentrations (0.05% to 0.2%v/v) of alcohol for 24-72 hours and processed for SERT and MAO-A expression using Q-PCR and Western blots analysis. In addition, SERT function in DC treated with alcohol both in the presence and absence of imipramine, a SERT inhibitor was measured using 4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide uptake assay. 5-HT levels in culture supernatant and intracellular 5-hydroxy indole acetic acid (5-HIAA) and cyclic AMP were also quantitated using ELISA. Results : Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. We also observed that 0.1% alcohol enhanced the function of SERT and decreased extracellular 5-HT levels compared with untreated DC cultures, and this was associated with the elevation of intracellular 5-HIAA and cyclic AMP levels. Conclusions: Our study suggests that alcohol upregulates SERT and MAO-A by elevating cyclic AMP, which may lead to decreased concentration of 5-HT in the extracellular medium. As 5-HT is a major neurotransmitter and an inflammatory mediator, its alcohol-mediated depletion may cause both neurological and immunological deregulation.

Benard A; Mercie P; Alioum A; Bonnet F; Lazaro E; Dupon M et al. Bacterial pneumonia among HIV-infected patients: Decreased risk after tobacco smoking cessation. ANRS CO3 Aquitaine Cohort, 2000-2007. PLoS ONE 5(1): e-8896, 2010. (32 refs.)

Background: Bacterial pneumonia is still a substantial cause of morbidity and mortality in HIV-infected patients in the era of combination Antiretroviral Therapy. The benefit of tobacco withdrawal on the risk of bacterial pneumonia has not been quantified in such populations, exposed to other important risk factors such as HIV-related immunodeficiency. Our objective was to estimate the effect of tobacco smoking withdrawal on the risk of bacterial pneumonia among HIV-infected individuals. Methodology/Principal Findings: Patients of the ANRS CO3 Aquitaine Cohort with >= two visits during 2000-2007 and without bacterial pneumonia at the first visit were included. Former smokers were patients who stopped smoking since >= one year. We used Cox proportional hazards models adjusted on CD4+ lymphocytes (CD4), gender, age, HIV transmission category, antiretroviral therapy, cotrimoxazole prophylaxis, statin treatment, viral load and previous AIDS diagnosis. 135 cases of bacterial pneumonia were reported in 3336 patients, yielding an incidence of 12 parts per thousand patient-years. The adjusted hazard of bacterial pneumonia was lower in former smokers (Hazard Ratio (HR): 0.48; P = 0.02) and never smokers (HR: 0.50; P = 0.01) compared to current smokers. It was higher in patients with,200 CD4 cells/mu L and in those with 200 to 349 CD4 cells/mL (HR: 2.98 and 1.98, respectively; both P, 0.01), but not in those with 350 to 499 CD4 cells/mu L (HR: 0.93; P = 0.79), compared to those with >= 500 CD4 cells/mu L. The interaction between CD4 cell count and tobacco smoking status was not statistically significant. Conclusions/Significance: Smoking cessation dramatically reduces the risk of bacterial pneumonia, whatever the level of immunodeficiency. Smoking cessation interventions should become a key element of the clinical management of HIV-infected individuals.

Bhatty M; Pruett SB; Swiatlo E; Nanduri B. Alcohol abuse and streptococcus pneumoniae infections: Consideration of virulence factors and impaired immune responses. Alcohol 45(6): 523-539, 2011. (191 refs.)

Alcohol is the most frequently abused substance in the world. Both acute and chronic alcohol consumption have diverse and well-documented effects on the human immune system, leading to increased susceptibility to infections like bacterial pneumonia. Streptococcus pneumonine is the most common bacterial etiology of community-acquired pneumonia worldwide. The frequency and severity of pneumococcal infections in individuals with a history of alcohol abuse is much higher than the general population. Despite this obvious epidemiological relevance, very few experimental studies have focused on the interaction of pneumococci with the immune system of a host acutely or chronically exposed to alcohol. Understanding these host-pathogen interactions is imperative for designing effective prophylactic and therapeutic interventions for such populations. Recent advances in pneumococcal research have greatly improved our understanding of pneumococcal pathogenesis and virulence mechanisms. Additionally, a large body of data is available on the effect of alcohol on the physiology of the lungs and the innate and adaptive immune system of the host. The purpose of this review is to integrate the available knowledge in these diverse areas of for a better understanding of the how the compromised immune system derived from alcohol exposure responds to pneumococcal infections.

Boeckler P; Cosnes A; Frances C; Hedelin G; Lipsker D. Association of cigarette smoking but not alcohol consumption with cutaneous lupus erythematosus. Archives of Dermatology 145(9): 1012-1016, 2009. (27 refs.)

Objective: To ascertain whether smoking or alcohol consumption is associated with lupus erythematosus (LE), because this topic is still subject to debate and part of the debate could be related to the fact that smoking and alcohol consumption are specific risk factors for cutaneous LE. Design: Prospective multicenter case-control study. Setting: Three French university hospitals. Patients: One hundred eight patients with LE and 216 control subjects. Intervention: Standardized questionnaire evaluating cigarette smoking and alcohol consumption. Main Outcome Measures: The statistical significance of smoking history and alcohol consumption as associated risk factors for LE by estimating matched case-control odds ratios and their 95% confidence intervals, using multiple conditional logistic regression and the Breslow-Day test to investigate differences in quantities of cigarette and alcohol consumption. Results: of the LE patients, 73.1% smoked compared with 49.5% of controls, (odds ratio, 2.77; 95% confidence interval, 1.63-4.76). There was no significant difference in alcohol consumption between LE patients and controls. Among the 79 LE patients who smoked, 72 (91.1%) had started smoking before the first manifestation of LE (mean delay between initiation of smoking and first signs of LE, 14.1 years). The LE patients smoked significantly more than controls did (11.7 vs 7.0 pack-years; P = .002). The prevalence of smoking among patients who met more than 4 American College of Rheumatology (ACR) criteria and/or with antinuclear DNA antibodies was lower than the prevalence in patients who met fewer than 4 ACR criteria or than the prevalence in controls (P < .001). Conclusions: Cigarette smoking is associated with LE, but alcohol consumption is not. The risk conferred by cigarette smoking seems highest in patients who meet fewer than 4 ACR criteria and/or who do not have antinuclear DNA antibodies.

Boyle NT; Connor TJ. Methylenedioxymethamphetamine ('Ecstasy')-induced immunosuppression: A cause for concern? (review). British Journal of Pharmacology 161(1): 17-32, 2010. (103 refs.)

Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a ring-substituted amphetamine and a popular drug of abuse. In addition to ability to induce euphoria, MDMA abuse is associated with a range of acute and long-term hazardous effects. This paper is focused on once such adverse effect: its ability to negatively impact on functioning of the immune system. Research demonstrates that MDMA has immunosuppressive properties, with both innate and adaptive arms of the immune system being affected. The ability of MDMA to suppress innate immunity is indicated by impaired neutrophil phagocytosis and reduced production of dendritic cell/macrophage-derived pro-inflammatory cytokines including tumour necrosis factor-alpha, interleukin (IL)-1 beta, IL-12 and IL-15. MDMA also suppresses innate IFN-gamma production, and considering the role of IFN-gamma in priming antigen-presenting cells, it is not surprising that MDMA reduces MHC class II expression on dendritic cells and macrophages, and inhibits co-stimulatory molecule expression. Paradoxically, studies demonstrate that MDMA elicits pro-inflammatory actions in the CNS by activating microglia, the resident innate immune cells in the brain. In terms of adaptive immunity, MDMA reduces circulating lymphocyte numbers, particularly CD4+ T-cells; suppresses T-cell proliferation; and skews cytokine production in a Th-2 direction. For the most part, the immunosuppressive effects of MDMA cannot be attributed to a direct action of the drug on immune cells, but rather due to the release of endogenous immunomodulatory substances. In this regard, peripheral beta-adrenoceptors and cholinergic receptors have been shown to mediate some immunosuppressive effects of MDMA. Finally, we discuss emerging evidence indicating that MDMA-induced immunosuppression can translate into significant health risks for abusers.

Chao C; Jacobson LP; Tashkin D; Martinez-Maza O; Roth MD; Margolick JB et al. Recreational amphetamine use and risk of HIV-related non-Hodgkin Lymphoma. Cancer Causes and Control 20(5): 509-516, 2009. (44 refs.)

The results of many laboratory studies suggest that amphetamine use may lead to altered immune function and cytokine expression, both of which are implicated in HIV-related lymphomagenesis. We examined the hypothesis that use of amphetamines modifies risk of non-Hodgkin lymphoma (NHL) in HIV-infected men in the Multicenter AIDS Cohort Study. Data on amphetamine use were collected every six months during the follow-up period between 1984 and 2002. A total of 171 NHL cases were diagnosed from the 19,250 person-years accrued. Multivariable Cox models were used to estimate the effects of baseline exposures, time-varying recent exposures, and three years lagged exposures on risk of NHL adjusting for potential confounders such as demographics, use of other substances, and risky sexual behaviors. We found that weekly or more frequent use of amphetamines was associated with an increased risk of NHL, with hazard ratios of 1.75 (95% CI = 0.81-3.77) for use at baseline, 4.73 (1.41-15.81) for recent use, and 3.05 (1.19-7.82) for three years prior use. Similar associations were observed when we separately examined systemic NHL and diffuse large B-cell lymphoma. Given these observations, the impact of amphetamines on lymphomagenesis among HIV-infected populations should be assessed more thoroughly.

Ciancio G; Colina M; La Corte R; Lo Monaco A; De Leonardis F; Trotta F et al. Nicotine-patch therapy on mucocutaneous lesions of Behcet's disease: A case series. Rheumatology 49(3): 501-504, 2010. (18 refs.)

Objective. We report the use of nicotine-patch therapy on active mucocutaneous lesions of Behcet's disease (BD). Methods. Five BD ex-smoker patients with refractory active mucocutaneous manifestations were treated with nicotine patches for 6 months. Results. Four out of five patients quickly responded to nicotine-patch therapy and experienced a complete regression of mucocutaneous lesions. Other manifestations of BD did not respond and new manifestations appeared during this treatment. One patient had no benefit from therapy but on restarting smoking it was promptly effective. Conclusions. Mucocutaneous lesions associated with BD may be modulated by smoking. Both smoking and nicotine-replacement therapy may be efficacious not only on oral aphthae, but also on other mucocutaneous manifestations, whereas the efficacy in the treatment and prevention of other systemic manifestations of BD is not proven. At least in ex-smokers, nicotine in its pure form is well tolerated and its use could be justified in selected cases of BD with predominant and recurrent refractory mucocutaneous manifestations.

dos Santos RG; Valle M; Bouso JC; Nomdedeu JF; Rodriguez-Espinosa J; McIlhenny EH et al. Autonomic, neuroendocrine, and immunological effects of ayahuasca: A comparative study with D-amphetamine. Journal of Clinical Psychopharmacology 31(6): 717-726, 2011. (56 refs.)

Ayahuasca is an Amazonian psychotropic plant tea combining the 5-HT(2A) agonist N,N-dimethyltryptamine (DMT) and monoamine oxidase-inhibiting beta-carboline alkaloids that render DMT orally active. The tea, obtained from Banisteriopsis caapi and Psychotria viridis, has traditionally been used for religious, ritual, and medicinal purposes by the indigenous peoples of the region. More recently, the syncretistic religious use of ayahuasca has expanded to the United States and Europe. Here we conducted a double-blind randomized crossover clinical trial to investigate the physiological impact of ayahuasca in terms of autonomic, neuroendocrine, and immunomodulatory effects. An oral dose of encapsulated freeze-dried ayahuasca (1.0 mg DMT/kg body weight) was compared versus a placebo and versus a positive control (20 mg D-amphetamine) in a group of 10 healthy volunteers. Ayahuasca led to measurable DMT plasma levels and distinct subjective and neurophysiological effects that were absent after amphetamine. Both drugs increased pupillary diameter, with ayahuasca showing milder effects. Prolactin levels were significantly increased by ayahuasca but not by amphetamine, and cortisol was increased by both, with ayahuasca leading to the higher peak values. Ayahuasca and amphetamine induced similar time-dependent modifications in lymphocyte subpopulations. Percent CD4 and CD3 were decreased, whereas natural killer cells were increased. Maximum changes occurred around 2 hours, returning to baseline levels at 24 hours. In conclusion, ayahuasca displayed moderate sympathomimetic effects, significant neuroendocrine stimulation, and a time-dependent modulatory effect on cell-mediated immunity. Future studies on the health impact of long-term ayahuasca consumption should consider the assessment of immunological status in regular users.

Du Y; Fryzek J; Sekeres MA; Taioli E. Smoking and alcohol intake as risk factors for myelodysplastic syndromes (MDS) (review). Leukemia Research 34(1): 1-5, 2010. (44 refs.)

The term myelodysplastic syndromes (MDS) include a diverse group of diseases in which the bone marrow production of blood cells is disrupted. In spite of the wealth of information on therapeutic options, little is known about the epidemiology of MDS, including population variations and risk factors. A narrative review of published literature and meta-analyses were conducted, identifying and summarizing key reports that describe the association between smoking, alcohol and MDS. There were 10 case-control studies that looked at the association between smoking and MDS, for a total of 1839 cases and 2831 controls. The meta-estimate for the association between ever smoking and MDS was 1.45 (95% CI: 1.21-1.74), with heterogeneity among studies (p = 0.05), but no evidence of publication bias. The relationship between alcohol consumption and MDS has been examined in five studies, including 745 cases and 1642 controls. The overall association was 1.31 (95% CI: 0.79-2.18), with significant heterogeneity (p = 0.003) and no evidence of publication bias. This re-analysis of published data strongly suggests that smoking is significantly associated with MDS, while alcohol does not seem to play a major role in MDS etiology. Large epidemiological studies incorporating biomarkers of exposure, along with pooled analysis are needed to better address the contribution of lifestyle factors to the development of MDS.

Edwards D. Immunological effects of tobacco smoking in "Healthy" smokers. (review). COPD: Journal of Chronic Obstetric Pulmonary Disease 6(1): 48-58, 2009. (80 refs.)

The history of tobacco smoking is quite extensive having existed for many years. Over the past 10-15 years significant gains have been made in curbing exposure to tobacco smoke, but tobacco smoke continues to contribute to significant disease. The immunological effects of cigarette smoking have been evaluated and can provide important insight into mechanism of disease. With the extensive growth in elucidation of basic immune processes within healthy host, further research is possible to aide understanding of immune alterations associated with smoking. Specifically, in the area of cellular immunity in which over 30 different cytokines contributing various regulatory functions in immunity, there are many proteins and mechanisms that may be altered. This review will cover the current state of knowledge in the areas of humoral, cellular immunity including results of cytokine studies in healthy smokers.

Freeman WM; VanGuilder HD; Guidone E; Krystal JH; Grant KA; Vrana KE. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration. International Journal of Neuropsychopharmacology 14(7): 899-911, 2011. (58 refs.)

Objective. diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. Two-dimensional difference in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within-subject samples collected before exposure to ethanol and after 3 months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of serum amyloid A4 (SAA4), retinol-binding protein, inter-alpha inhibitor H4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption.

Guaderrama MM; Corwin EJ; Kapelewski CH; Klein LC. Sex differences in effects of cigarette smoking and 24-hr abstinence on plasma arginine vasopressin. Addictive Behaviors 36(11): 1106-1109, 2011. (33 refs.)

The present study examined plasma arginine vasopressin (AVP) levels in 18 smokers (10 men, 8 women) and in 22 non-smokers (12 men, 10 women). Non-smokers came to the laboratory once, whereas smokers came twice: while smoking freely and following 24-hr abstinence. Plasma was collected for AVP assessment: salivary cotinine and expired carbon monoxide levels confirmed smoking status. Among non-smokers, men had higher AVP levels than did women (p<0.05). Among smokers, however, women displayed higher AVP levels than did men both while smoking and following abstinence (p's<0.05). Among men, smoking resulted in lower AVP levels compared to non-smoking men. In contrast, women who smoked displayed higher AVP levels compared to their non-smoking counterparts. AVP levels were not affected by 24-hr abstinence among smokers, regardless of sex, which suggests that dysregulation in AVP levels in tobacco smokers continues even following 24-hr abstinence. Findings are consistent with previous reports of elevated Th1/Th2 immune function among female smokers compared to male smokers and to male and female non-smokers. Data suggest sex-dependent AVP changes during smoking that could contribute to negative impact of smoking on cardiovascular health.

Gupta D; Singh AD; Agarwal R; Aggarwal AN; Joshi K; Jindal SK. Is tobacco smoking protective for sarcoidosis? A case-control study from north India. Sarcoidosis Vasculitis and Diffuse Lung Diseases 27(1): 19-26, 2010. (36 refs.)

Background: While tobacco smoking is commonly believed to be negatively associated with the occurrence of sarcoidosis, the relationship of environmental tobacco smoke (ETS) exposure with sarcoidosis is largely un-explored. We studied the impact of active smoking and ETS exposure on disease severity in newly diagnosed cases of sarcoidosis from India. Methods: Data on demographic variables, smoking habits and exposure to environmental tobacco smoke (ETS) among non-smoker sarcoidosis patients was collected prospectively. Presence of smoking and ETS exposure were compared among cases and controls. Among the sarcoidosis patients, clinical manifestations, radiology, spirometry and histopathological grading of lung biopsy were compared between the smokers vs. non-smokers and ETS exposed vs. not-exposed. Results: We studied 98 newly diagnosed cases of sarcoidosis and 196 age, sex and religion- matched healthy volunteers. The study group comprised of 62 (63%) men and 36 (37%) women. The prevalence of smoking was similar in cases and controls (12.2% vs. 15.3%, p = 0.48). Among the never smoker patients with sarcoidosis, 20 (23%) reported ETS exposure vis-a-vis 57 (34%) in the matched controls. A conditional logistic regression analyses showed insignificant negative association with active smoking (OR 0.75; 95% CI, 0.35-1.56) or ETS exposure (OR 0.58; 95% CI, 0.32-1.06) after adjusting for age, gender, religion, and education. There were no differences in the clinical manifestations, radiological staging, spirometry and histopathological grading of lung biopsy in any of the group comparisons studied. Conclusion: Smoking or ETS exposure may not have significant negative association with sarcoidosis. Also, tobacco smoke might not have any effect on the clinical behavior or disease severity in sarcoidosis. The belief that smoking is protective for sarcoidosis is not substantiated in this study and appears to be misfounded.

Hagedorn HJ; Rettmann NA; Dieperink EW; Durfee J; Aqel B. Antibody response to hepatitis B vaccine in substance use disorder patients. Drug and Alcohol Dependence 107(1): 39-43, 2010. (39 refs.)

The objectives of this study were to assess the prevalence of prognostic factors previously known to be associated with poor antibody response to hepatitis B vaccination in a sample of veterans presenting for substance use disorders treatment at a Veterans Health Administration (VA) Medical Center, assess vaccination response, and identify markers for poor response in this population. Results: indicated that most participants had multiple prognostic factors previously known to be associated with poor antibody response including male gender, age over 40, smoking, and obesity. The rate of seroconversion in this sample was 51.9%. This is substantially lower than seen in healthy adults. Alcohol dependence was the only significant independent negative predictor of seroconversion in this sample. Substance use disorders treatment providers who are considering adding hepatitis B vaccination services to their clinics should be aware that the antibody response to the hepatitis B vaccination is inconsistent and that patients with particular demographic characteristics may be at heightened risk of poor antibody response.

Han DY; Fraser AG; Dryland P; Ferguson LR. Environmental factors in the development of chronic inflammation: A case-control study on risk factors for Crohn's disease within New Zealand. Mutation Research 690(1/2 (special issue)): 116-122, 2010. (37 refs.)

The role of environmental factors in the risk for Crohn's disease (CD), an inflammatory bowel disease (IBD), was investigated in a North Island-based New Zealand case-control cohort. A total of 315 CD patients and 536 controls were recruited through various sources to the Auckland CD Risk Factor Study. As well as demographic characteristics, the self-reported questionnaire included (1) smoking and drinking alcohol, (2) breastfeeding in infancy, (3) early life exposures to allergens and microbes, (4) health conditions lasting 6 months or longer and (5) taking antibiotics and any medications. There was strong evidence for familial associations of the disease, and minor effects of birth order and number of siblings. Being a smoker, especially over a long time period, and exposure to smoking during childhood and adolescence periods increased risk, whereas drinking alcohol at least once per week showed a slight protective effect. Long term use of the oral contraceptive pill increased the risk of developing CD, but breastfeeding and immunisation during infancy showed no significant association. Long term and debilitating illness (lasting 6 months or more), taking antibiotics prior to developing CD, or taking four or more antibiotics or any regular medication in a year during adolescence substantially increased the CD risk. Having a pet during childhood was a protective factor, but regularly feeding an animal was not sufficient to protect. Many of these significant factors are likely to impact on the colonic microflora and/or immune system. We conclude that, in addition to strong evidence for genetic associations, factors likely to impact on immune response or reduce early exposure to microbes provide a main risk factor for CD in this New Zealand population.

Hansen BT; Hagerup-Jenssen M; Kjaer SK; Munk C; Tryggvadottir L; Sparen P et al. Association between smoking and genital warts: Longitudinal analysis. Sexually Transmitted Infections 86(4): 258-262, 2010. (33 refs.)

Objectives: To assess the association between smoking and the reported clinical diagnosis of genital warts. Methods: A sample of 58 094 women (aged 18-45) randomly drawn from the general female population of Denmark, Iceland, Norway and Sweden answered a questionnaire on lifestyle and health. Longitudinal data were reconstructed based on self report of age-specific events. In a Cox regression model, women who reported having been clinically diagnosed with genital warts were followed up until the age at first diagnosis, while women who reported never having been diagnosed with genital warts were censored at the age of interview. Age-specific smoking doses and ages at onset of smoking, sexual intercourse, condom use, hormonal contraceptive use, first pregnancy and alcohol drinking were included in the model as time-dependent covariates. The model also included lifetime number of coital partners and country of origin as fixed covariates. Results: Ever-smokers reported a lower age at first intercourse and more coital partners than never-smokers. The adjusted model showed that sexual behaviour strongly influenced the risk of being diagnosed with genital warts, and that smokers in addition had an increased risk compared with non-smokers (adjusted HR = 1.27, 95% CI 1.17 to 1.37). There was also a modest additional dose-response effect of smoking, with smokers experiencing a 0.6% increased risk of being diagnosed with genital warts for each additional cigarette smoked daily (adjusted HR = 1.006, 95% CI 1.001 to 1.012). Conclusions: Smokers experienced a moderately increased risk of being diagnosed with genital warts. This finding could be explained by the immunosuppressive effects of nicotine, or by confounding not accounted for in the adjusted model.

Herberth M; Krzyszton DN; Koethe D; Craddock MR; Bulger E; Schwarz E et al. Differential effects on T-cell function following exposure to serum from schizophrenia smokers. Molecular Psychiatry 15(4): 364-371, 2010. (45 refs.)

Cigarette smoking is more prevalent in subjects with schizophrenia compared to those with other psychiatric disorders or the general population and could therefore affect molecular pathways that impact the pathophysiology of this disorder. As smoking is also known to suppress immune responses, we investigated the effects of 'smoking-conditioned' serum obtained from schizophrenia and control subjects on healthy T cell in vitro. We found that T-cell proliferation was significantly increased following exposure to serum from smoking schizophrenia patients whereas no effect was observed when using serum from smoking control subjects or non-smoking patients and controls. We eliminated the possibility that these effects were due to quantitative differences in cigarette consumption as serum levels of the stable nicotine metabolite cotinine were similar in schizophrenic and control smokers. Molecular characterization showed that serum from patient smokers increased expression of T-cell activation markers CD69(high), CD25(high), co-stimulatory molecules CD26+, CD27+ and CD28+, and decreased T-cell receptor complex components TCR alpha/beta and CD3. Moreover, analysis of supernatants collected after T-cell exposure to serum from smoking patients showed a time-dependent decline in interleukin (IL)-2 levels, suggesting that the proliferation effect is promoted by enhanced IL-2 processing. These results suggest that cigarette smoking has selective effects on serum components that, in turn, lead to altered immune function in schizophrenia patients relative to healthy subjects. Further studies aimed at characterizing these components could result in a better understanding of the onset and aetiology of schizophrenia and potentially lead to novel therapeutic strategies.

Horvathova M; Jahnova E; Szabova M; Tulinska M; Kuricova M; Liskova A et al. The relationship between cell surface markers, cytokines, ageing, and cigarette smoking. Bratislava Medical Journal 110(7): 394-400, 2009. (81 refs.)

The purpose of this study was to investigate the modulation of selected cell surface markers and proinflammatory cytokines production in relation to ageing, and cigarette smoking. The analysis of cell surface receptors was performed by the flow cytometry and cytokines levels were evaluated by the sandwich enzyme immunoassays. We found a decreased expression of CD69, CD28, CD11b, CD95 markers in old population compared to young people (p<0.05; p<0.001). The memory CD45RO lymphocytes were markedly expanded in older population in comparison to young donors (12.93 +/- 5.92%, p<0.001) and the selectin CD62L was significantly increased on granulocytes in aged people (p<0.05). Our findings demonstrated an augmented level of CD3 and CD28 on lymphocytes in smokers (p<0.05; p<0.005). The significant depression of CD16+56 molecule was recorded in smokers (10.86 +/- 0.80%) when compared to non-smokers (14.44 +/- 0.46; p<0.05). Our results showed a significantly diminished levels of interleukin (IL)-1 beta (1.93 +/- 0.48 pg/ml), and increased levels of IL-6 and tumor necrosis factor (TNF)-alpha in elderly population compared to young people (p<0.05; p<0.001). The present data support previous suggestions that senescence and cigarette smoking may contribute to changes in the immune system activity, resulting in altered cell surface marker expression and cytokine levels (Tab. 1, Fig. 3, Ref. 81). Full Text (Free, PDF) www.bmj.sk.

Ilic G; Gligorijevic J; Karadzic R; Antovic A; Kostic-Banovic L; Stojanovic J et al. Myocardial damage in heroin abuse: Immunohistochemical investigations with LCA, CD68, and CD45R0. Romanian Journal of Legal Medicine 19(2): 89-94, 2011. (38 refs.)

Background. Myocardial insufficiency is suspected to be implicated in fatal lung edema complicating heroin-overdosage. The pathogenetic mechanism is not fully understood, but defects in myocardial contractility were proposed. Methods. The qualification and quantification of leukocytes, monocytes, and T-lymphocytes was done on the myocardial samples from 13 heroin/morphine related deaths, compared to six controls by histological and immunohistochemical examination. The quantification of cell types was done by counting speciffic cell type of 30 high power fealds in each myocardial sample. Mean values were then tested by Student t-test. Results. The results showed that the control group had a higher mean number of observed leukocyte common antigen (LCA) and CD45R0 positive white blood cells, without significant difference. The mean number of CD68 positive white blood cells was significantly lower in drug addicts group than in the control group (p=0.013, Cohen's d=1.41, power 0.86). Conclusions. Deterioration of immune cell function in heroin abusers will produce in time left ventricular disfunction and susceptibility to lung edema complicating heroin-overdose.

Kaartinen K; Niemela O; Syrjanen J; Alatalo P; Porsti I; Harmoinen A et al. IgA Immune responses against acetaldehyde adducts and biomarkers of alcohol consumption in patients with IgA glomerulonephritis. Alcoholism: Clinical and Experimental Research 33(7): 1231-1237, 2009. (47 refs.)

Background: The pathogenesis of IgA glomerulonephritis (IgAGN) involves intense deposition of IgAs within the glomerulus. Although previous studies have shown that heavy drinking frequently leads to the generation of IgA antibodies against neo-antigens induced by ethanol metabolites and tissue deposition of IgAs, the associations between alcohol consumption, IgA immune responses, and kidney disease have not been examined. Methods: A total of 158 IgAGN patients (96 men, 62 women) were classified as abstainers (n = 38), moderate drinkers (n = 114), and heavy drinkers (n = 6) based on self-reported alcohol consumption. The reference population included 143 individuals (99 men, 44 women) who were either apparently healthy abstainers (n = 31), moderate drinkers (n = 43), or heavy drinkers devoid of liver disease (n = 69). The assessments included various biomarkers of alcohol consumption: carbohydrate-deficient transferrin (CDT), glutamyl transferase, gamma-CDT (combination of GGR and CDT), mean corpuscular volume (MCV), tests for liver and kidney function, serum immunoglobulin A (IgA), and specific IgA antibodies against acetaldehyde-protein adducts. Results: In male IgAGN patients, drinking status was significantly associated with MCV, p < 0.001; CDT, p < 0.01; and gamma -CDT, p < 0.05. In the reference population, all biomarkers and anti-adduct IgA levels were found to vary according to drinking status. In IgAGN patients, anti-adduct IgA levels were elevated in 63% of the cases but the titers did not associate with self-reported ethanol intake. Conclusions: These data indicate high levels of IgA antibodies against acetaldehyde-derived antigens in IgAGN patients, which may hamper the use of the immune responses as markers of alcohol consumption among such patients. Future studies on the pathogenic and prognostic significance of anti-adduct immune responses in IgAGN patients are warranted.

Lau A; von Dossow V; Sander M; MacGuill M; Lanzke N; Spies C. Alcohol use disorder and perioperative immune dysfunction. (review). Anesthesia and Analgesia 108(3): 916-920, 2009. (48 refs.)

The anesthesiological sequelae of long-term alcohol abuse include a three to fivefold increased risk of postoperative infection, prolonged intensive care unit stays and longer hospital stays. The cause of the higher infection rates is an altered immune response in long-term alcoholic patients. Preoperatively, the T helper cells 1 to T helper cells 2 ratio is depressed in long-term alcoholic patients and remains suppressed after surgery. The lower preoperative T helper cells 1 to T helper cells 2 ratio is predictive of later onset of infections. Postoperatively, the cytotoxic lymphocyte (Tc1/Tc2) ratio is decreased in long-term alcoholic patients and remains depressed for 5 days. The interleukin (IL)-6/IL-10 ratio and the lipopolysaccharide-stimulated interferon gamma/IL-10 ratio in whole blood cells are decreased after surgery in long-term alcoholic patients. Depressed Tc1/Tc2, IL-6/IL-10 and lipopolysaccharide-stimulated interferon gamma/IL-10 ratios in the postoperative period are predictive of subsequent postoperative infections. Perioperative interventions should aim to minimize dysregulation of the immune system.

Machado M; Antunes WD; Tamy ALM; Azevedo PG; Barreto JG; Hackney AC et al. Effect of a single dose of caffeine supplementation and intermittent-interval exercise on muscle damage markers in soccer players. Journal of Exercise Science & Fitness 7(2): 91-97, 2009. (21 refs.)

This study examined the effect of caffeine supplementation on the white cell count and muscle damage marker responses to intermittent-interval exercise as performed by soccer players. Subjects (n = 20) completed a placebo-controlled double-blind test protocol. Forty-five minutes before exercise, participants ingested 4.5 mg . kg(-1) body mass of caffeine (EXP) or placebo (CONT). Blood samples were collected before and after exercise to measure hematological parameters, serum creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), asparrate aminotransferase (AST), alkaline phosphatase (AP) and gamma-glutamyl transferase (gamma-GT) activity. To compare differences among all variables, 2 (time) x 2 (group) repeated measures ANOVA (with Tukey's post hoc tests) was conducted. Exercise caused leukocytosis (38.5% and 36.1% in EXP and CONT, respectively), lymphocytosis (42.1% and 44.9%, p < 0.05) and neutrophilia (38.2% and 31.5%; p < 0.05) without an additional effect due to caffeine (p > 0.05). Also, serum CK and LDH activity were enhanced by exercise in both groups (p < 0.05), without a synergistic effect of caffeine. ALT, AST, AP and gamma-GT serum activity was not modulated by exercise or caffeine. The findings demonstrate that white cells and muscle damage markers increase after intense intermittent exercise, but acute caffeine supplementation has no influence on immune responses or muscle cellular integrity.

McGuinness TM. Update on marijuana. Journal of Psychosocial Nursing and Mental Health Services 47(10): 19-22, 2009. (17 refs.)

Marijuana, the illicit drug most widely used by adolescents, is not a benign substance. Inhalation of marijuana smoke is more harmful than tobacco smoke; cannabis smoke delivers 50% to 70% more carcinogens. Other physiological effects include decreased immune function, higher rates of cardiac arrhythmias, and documented cases of cerebellar infarction. Mood and cognitive effects of marijuana include exacerbation of depression and anxiety (including panic attacks), as well as memory problems that may persist for a month after last use. Cannabis abuse is a risk factor for psychosis in genetically predisposed people and may lead to a worse outcome of schizophrenia. The cumulative respiratory, cardiovascular, metabolic, and mental health risks of marijuana are significant and should be emphasized by nurses who work with adolescents.

Molina PE; Happel KI; Zhang P; Kolls JK; Nelson S. Focus on: Alcohol and the immune system. Alcohol Research & Health 33(1-2): 97-108, 2010. (79 refs.)

Alcohol abuse suppresses multiple arms of the immune response, leading to an increased risk of infections. The course and resolution of both bacterial and viral infections is severely impaired in alcohol-abusing patients, resulting in greater patient morbidity and mortality. Multiple mechanisms have been identified underlying the immunosuppressive effects of alcohol. These mechanisms involve structural host defense mechanisms in the gastrointestinal and respiratory tract as well as all of the principal components of the innate and adaptive immune systems, which are compromised both through alcohol's direct effects and through alcohol-related dysregulation of other components. Analyses of alcohol's diverse effects on various components of the immune system provide insight into the factors that lead to a greater risk of infection in the alcohol-abusing population. Some of these mechanisms are directly related to the pathology found in people with infections such as HIV/AIDS, tuberculosis, hepatitis, and pneumonia who continue to use and abuse alcohol.

Moreno AY; Azar MR; Warren NA; Dickerson TJ; Koob GF; Janda KD. A critical evaluation of a nicotine vaccine within a self-administration behavioral model. Molecular Pharmaceutics 7(2): 431-441, 2010. (30 refs.)

Nicotine is a psychostimulant legal drug responsible for causing addiction to tobacco smoking. Tobacco smoking has been irrevocably linked to a number of serious diseases and at present is considered the leading cause of preventable death in the United States. Despite well-documented adverse medical consequences, nicotine addiction has historically been one of the hardest to break. Current therapies have offered limited success and show high rates of relapse, emphasizing the need to engineer alternative therapies to aid nicotine cessation. The current study presents a protein-based immunopharmacotherapy approach for the treatment of nicotine addiction. Immunopharmacotherapy aims to use highly specific antibodies to blunt passage of drug into the brain thus minimizing reinforcing effects on the reward pathways of the central nervous system. Generation of a successful vaccine heavily relies on appropriate optimization of hapten design, immunogenic carrier and adjuvant. Modification of a classical nicotine hapten in conjugation with three distinct carrier proteins allowed for priming of a nicotine vaccine able to elicit significant amounts of nicotine-specific antibodies. Increased self-administration with use of a high drug dose (0.03 mg/kg/infusion; similar to 2 cigarettes in human) was observed in the vaccinated versus control animals suggesting a compensatory pattern and possibly reduced passage of nicotine to the brain. These results support the hypothesis that proper optimization of vaccine formulations could lead to successful nicotine vaccines for human use.

Nakata A; Swanson NG; Caruso CC. Nurses, smoking, and immunity: A review. (review). Rehabilitation Nursing 35(5, special issue): 198-205, 2010. (74 refs.)

Nurses regularly are exposed to a variety of occupational hazards. In addition to documented occupational hazards, exposure to smoking remains a major concern. This article reviews the prevalence of smoking among nurses working in the United States and discusses their reasons for smoking. Researchers conducted a state-of-the-art review on the effects of cigarette smoking and exposure to secondhand smoke (Si-IS) on the immune system. Smoking prevalence among nurses working in the United States ranged from 7%-12%, and high work stress, poor work environment, shift work, and peer influence were suspected major risk factors influencing smoking behavior. A review of the effects of smoking on immunity revealed that both active smoking and exposure to SHS negatively affects immune function. When rehabilitation nurses stop smoking, their health improves and nonsmokers are exposed to less SHS. Rehabilitation nurses are encouraged to share knowledge of the immunological benefits of smoking cessation with patients to facilitate nurse-led rehabilitation programs.

Porzionato A; Macchi V; Parenti A; De Caro R. Chronic carotid glomitis in heroin addiction. Histology and Histopathology 24(6): 707-715, 2009. (52 refs.)

The aim of the present work was to investigate the occurrence and immunological characteristics of chronic carotid glomitis in opiate addicts. Carotid bodies were sampled at autopsy from 50 subjects who died of heroin intoxication (mean age 28 years), and from 16 young (24 years) and 10 older subjects (66 years) who died of trauma. Sections were stained with haematoxylin-eosin and azan-Mallory, and immunohistochemistry was carried out with anti-CD45, -CD3, -CD8, -CD4, -CD20, -CD68, -CD56. Inflammatory aggregates were not observed in young cases, but were found in 21/50 (42%) opiate cases and in 4/10 (40%) older cases. Infiltrates were mainly located in subcapsular and interlobular positions, and were also found around nerve fibres. Inflammatory aggregates were mainly composed of T suppressor/cytotoxic lymphocytes (50-80%). Monocytic/macrophagic cells and B lymphocytes comprised about 10% and 5-20% of inflammatory cells, respectively. T helper lymphocytes were fewer and only rare Natural Killer cells were found. Chronic carotid glomitis must be included among the autopsy findings of opiate addiction, and may be ascribed to inflammatory reactions to exogenous immunogens or to responses to drug-induced degenerative changes of carotid body components.

Potula R; Hawkins BJ; Cenna JM; Fan SS; Dykstra H; Ramirez SH et al. Methamphetamine causes mitrochondrial oxidative damage in human t lymphocytes leading to functional impairment. Journal of Immunology 185(5): 2867-2876, 2010. (80 refs.)

Methamphetamine (METH) abuse is known to be associated with an inordinate rate of infections. Although many studies have described the association of METH exposure and immunosuppression, so far the underlying mechanism still remains elusive. In this study, we present evidence that METH exposure resulted in mitochondrial oxidative damage and caused dysfunction of primary human T cells. METH treatment of T lymphocytes led to a rise in intracellular calcium levels that enhanced the generation of reactive oxygen species. TCR-CD28 linked calcium mobilization and subsequent uptake by mitochondria in METH-treated T cells correlated with an increase in mitochondrion-derived superoxide. Exposure to METH-induced mitochondrial dysfunction in the form of marked decrease in mitochondrial membrane potential, increased mitochondrial mass, enhanced protein nitrosylation and diminished protein levels of complexes I, III, and IV of the electron transport chain. These changes paralleled reduced IL-2 secretion and T cell proliferative responses after TCR-CD28 stimulation indicating impaired T cell function. Furthermore, antioxidants attenuated METH-induced mitochondrial damage by preserving the protein levels of mitochondrial complexes I, III, and IV. Altogether, our data indicate that METH can cause T cell dysfunction via induction of oxidative stress and mitochondrial injury as underlying mechanism of immune impairment secondary to METH abuse.

Radenkova-Saeva J; Kostadinova R; Michova A; Petrunov B. Pulmonary complications related to heroin overdose and some changes in immune reactivity. Central European Journal of Medicine 5(4): 508-512, 2010. (29 refs.)

To examine the clinical spectrum of complications in pulmonary system and changes of some parameters of humoral and cell mediated immunity related to heroin overdose. The study includes 16 patients who are long-term heroin abusers with acute heroin and mixed with other psychoactive drugs intoxications with an average age of 21,5 +/- 5.04 years (12 men and 4 woman). All patients were hospitalized in the Clinic of Toxicology, MHATEM "N.I.Pirogov", Sofia. We have used clinical, clinico-laboratory, immunological, chimicotoxicological, instrumental methods. In severe intoxications with heroin and other psychoactive drugs, we observed pulmonary system complications, i.e. pneumonia, aspiration of gastric contents, noncardiogenic pulmonary edema (NCPE) and acute respiratory distress syndrome (ARDS.). Of the 16 patients in our study, 3 patients died due to complications. Some changes in the immune reactivity observed in the study were (1) statistically significant lower mean levels of IgG and (2) tendency to lower mean levels of IgA, IgM and complement components - C3 in the studied patients in comparison with the values in healthy people. The changes were more demonstrative in the group with pulmonary complications compared to the group without pulmonary complications. We observed that the CD4 lymphocytes were significantly less in the studied patients; in addition, a lower level of CD56-bearing lymphocytes (natural killer /NK/ cells) was observed in comparison to healthy controls. The results show that the mixture of acute heroin with other psychoactive drugs leads to complications in the pulmonary system and changes of some parameters of cell-mediated and humoral immunity.

Schwaeble W; Constantinescu CS. Special Issue: Cannabinoids and Immunology - Introduction. (editorial). Immunobiology 215(8): 587-587, 2010. (0 refs.)

Shuper PA; Neuman M; Kanteres F; Baliunas D; Joharchi N; Rehm J. Causal considerations on alcohol and HIV/AIDS: A systematic review. Alcohol and Alcoholism 45(2): 159-166, 2010. (92 refs.)

Methods: A review based on meta-analyses and reviews was conducted according to standard epidemiological criteria to distinguish causality from association, examining (i) the potential impact of alcohol on the incidence of HIV and (ii) alcohol's impact on worsening the disease course. Results: In terms of incidence of HIV, although we found a consistent and strong association with consumption, there was not enough evidence for a causal connection. In particular, it is not clear whether personality traits such as sensation seeking or sexual compulsivity and psychiatric disorders such as antisocial personality disorder impact both alcohol consumption and risky sex, subsequently creating an association between both behaviors. In terms of worsening the disease course of HIV/AIDS, we found enough evidence for a causal impact of alcohol. Alcohol affects the immune system, thus contributing to a worsened course of HIV/AIDS. In addition, alcohol negatively impacts on behaviors that include support seeking and medication adherence. Conclusions: A randomized controlled clinical trial targeted toward at-risk HIV-negative individuals who live in areas with high HIV prevalence is suggested to test the effects of proven effective alcohol interventions on HIV incidence.

Singh SP; Gundavarapu S; Pena-Philippides JC; Rir-sima-ah J; Mishra NC; Wilder JA et al. Prenatal secondhand cigarette smoke promotes Th2 polarization and impairs goblet cell differentiation and airway mucus formation. Journal of Immunology 187(9): 4542-4552, 2011. (74 refs.)

Parental, particularly maternal, smoking increases the risk for childhood allergic asthma and infection. Similarly, in a murine allergic asthma model, prenatal plus early postnatal exposure to secondhand cigarette smoke (SS) exacerbates airways hyperre-activity and Th2 responses in the lung. However, the mechanism and contribution of prenatal versus early postnatal SS exposure on allergic asthma remain unresolved. To identify the effects of prenatal and/or early postnatal SS on allergic asthma, BALB/c dams and their offspring were exposed gestationally and/or 8-10 wk postbirth to filtered air or SS. Prenatal, but not postnatal, SS strongly increased methacholine and allergen (Aspergillus)-induced airway resistance, Th2 cytokine levels, and atopy and activated the Th2-polarizing pathway GATA3/Lck/ERK1/2/STAT6. Either prenatal and/or early postnatal SS downregulated the Th1-specific transcription factor T-bet and, surprisingly, despite high levels of IL-4/IL-13, dramatically blocked the allergen-induced mucous cell metaplasia, airway mucus formation, and the expression of mucus-related genes/proteins: Muc5ac, gamma-aminobutyric acid A receptors, and SAM pointed domain-containing Ets-like factor. Given that SS/nicotine exposure of normal adult mice promotes mucus formation, the results suggested that fetal and neonatal lung are highly sensitive to cigarette smoke. Thus, although the gestational SS promotes Th2 polarization/allergic asthma, it may also impair and/or delay the development of fetal and neonatal lung, affecting mucociliary clearance and Th1 responses. Together, this may explain the increased susceptibility of children from smoking parents to allergic asthma and childhood respiratory infections.

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.

Szabo G; Wands JR; Eken A; Osna NA; Weinman SA; Machida K et al. Alcohol and hepatitis C virus-interactions in immune dysfunctions and liver damage. (review). Alcoholism: Clinical and Experimental Research 34(10): 1675-1686, 2010. (135 refs.)

Hepatitis C virus infection affects 170 million people worldwide, and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis, and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV-infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis, but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these processes by alcohol and HCV produces an environment of impaired antiviral immune response, greater hepatocellular injury, and activation of cell proliferation and dedifferentiation.

Ye L; Wang SH; Wang X; Zhou Y; Li JL; Persidsky Y; Ho WZ. Alcohol impairs interferon signaling and enhances full cycle hepatitis C virus JFH-1 infection of human hepatocytes. Drug and Alcohol Dependence 112(1-2): 107-116, 2010. (49 refs.)

Alcohol drinking and hepatitis C virus (HCV) infection frequently coexist in patients with chronic liver disease. There is limited information, however, about the impact of alcohol on host cell innate immunity and full cycle replication of HCV. This study investigated whether alcohol impairs the intracellular innate immunity in human hepatocytes, promoting HCV infection and replication. Alcohol treatment of human hepatocytes before, during and after viral infection significantly enhanced full cycle HCV replication. Alcohol suppressed intracellular expression of type I interferons (IFN-alpha/beta) in human hepatocytes. Investigation of the mechanisms responsible for the alcohol action revealed that alcohol inhibited the expression of the IFN regulatory factors (IRF-5 and IRF-7), and signal transducer and activator of transcription (STAT-1 and STAT-2), the key positive regulators in type I IFN signaling pathway. In addition, alcohol induced the expression of suppressors of cytokine signaling (SOCS-2 and SOCS-3), the key negative regulators of IFN-alpha/beta expression. These in vitro findings suggest that alcohol, through modulating the expression of key regulators in IFN signaling pathway, inhibits type I IFN-based intracellular innate immunity in hepatocytes, which may contribute to the chronicity of HCV infection and the poor efficacy of IFN-alpha-based therapy.