Soluble Immune Checkpoints Are Dysregulated in COVID-19 and Heavy Alcohol Users With HIV Infection.

Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world's most serious public health challenges. A "storm" of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol misuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol misuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.

Determinants and Clinical Implications of Thyroid Peroxidase Antibodies in Middle-Aged and Elderly Individuals: The Rotterdam Study.

Background: Thyroid peroxidase antibodies (TPO-Abs) play an important role in autoimmune thyroid disease, but are also prevalent in healthy individuals. However, it is unclear what determinants may influence the occurrence of TPO-Abs in healthy individuals and how TPO-Abs may affect health outcomes in these individuals. We aimed to identify determinants of TPO-Abs in a large, prospective population-based cohort of middle-aged and elderly individuals and to subsequently assess the association between TPO-Abs and risk of overall and cause-specific mortality. Methods: We performed binomial and multinomial logistic regression analyses to obtain odds ratios (ORs) and 95% confidence intervals [95% CIs] for the association of potential determinants based on previous literature with TPO-Ab positivity (>35 kU/L), TPO-Ab detectability (>5 kU/L), and TPO-Ab categories. Cox proportional hazards regression analyses were performed to obtain hazard ratios (HRs) and CIs for the association between TPO-Abs and mortality risk. Results: In 9685 participants (57% women, median baseline age 63.3 years, median follow-up time 10.1 years), we identified female sex (OR = 2.47 [CI 2.13-2.86]) and current smoking (OR = 3.10 [CI 2.66-3.62]) as determinants of TPO-Ab positivity and TPO-Ab detectability, respectively. Higher age (OR = 0.98 [CI 0.97-0.98]) and all categories of alcohol consumption (ORs ranging from 0.71-0.78) were associated with lower odds of TPO-Ab detectability. TPO-Ab detectability was associated with a higher risk of overall (HR = 1.09 [CI 1.01-1.17]), cancer-related (HR = 1.18 [CI 1.01-1.38]), and cardiovascular mortality (HR = 1.21 [CI 1.01-1.45]). Interestingly, this was more prominent in men compared with women (HR for cardiovascular mortality 1.50 vs. 0.99, respectively). Conclusions: In community-dwelling middle-aged and elderly individuals, female sex and current smoking are the most important determinants associated with TPO-Ab levels in the detectable and positive range, whereas alcohol consumption is associated with lower odds of TPO-Abs. The clinical importance of detectable TPO-Ab levels is illustrated by the association with an increased mortality risk, mainly in men. Our results warrant further exploration of the clinical applicability of detectable TPO-Ab levels, potentially as a marker for low-grade inflammation. The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and into the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under shared catalogue number NTR6831.

Alcohol Use and Abuse Conspires With HIV Infection to Aggravate Intestinal Dysbiosis and Increase Microbial Translocation in People Living With HIV: A Review.

The intestinal microbiome is an essential so-called human "organ", vital for the induction of innate immunity, for metabolizing nutrients, and for maintenance of the structural integrity of the intestinal barrier. HIV infection adversely influences the richness and diversity of the intestinal microbiome, resulting in structural and functional impairment of the intestinal barrier and an increased intestinal permeability. Pathogens and metabolites may thus cross the "leaky" intestinal barrier and enter the systemic circulation, which is a significant factor accounting for the persistent underlying chronic inflammatory state present in people living with HIV (PLWH). Additionally, alcohol use and abuse has been found to be prevalent in PLWH and has been strongly associated with the incidence and progression of HIV/AIDS. Recently, converging evidence has indicated that the mechanism underlying this phenomenon is related to intestinal microbiome and barrier function through numerous pathways. Alcohol acts as a "partner" with HIV in disrupting microbiome ecology, and thus impairing of the intestinal barrier. Optimizing the microbiome and restoring the integrity of the intestinal barrier is likely to be an effective adjunctive therapeutic strategy for PLWH. We herein critically review the interplay among HIV, alcohol, and the gut barrier, thus setting the scene with regards to development of effective strategies to counteract the dysregulated gut microbiome and the reduction of microbial translocation and inflammation in PLWH.

Abstinent patients with alcohol use disorders show an altered plasma cytokine profile: Identification of both interleukin 6 and interleukin 17A as potential biomarkers of consumption and comorbid liver and pancreatic diseases.

BACKGROUND: Recent studies have demonstrated that alcohol consumption can modulate the immune system by directly activating natural immunity and triggering inflammatory processes in the central nervous system and in peripheral organs, such as the liver and pancreas. Patients with alcohol use disorders have an elevated frequency of comorbid mental disorders and gut diseases (i.e. fatty liver and pancreatitis) that complicate diagnosis, treatment and prognosis. AIMS: The present study aims to explore possible associations in circulating plasma cytokine concentrations in abstinent patients diagnosed with alcohol use disorders. METHODS: To this end, 85 abstinent subjects with alcohol use disorders from an outpatient setting and 55 healthy subjects were evaluated for both substance and mental disorders. The plasma levels of cytokines interleukin 1 beta, interleukin 4, interleukin 6, interleukin 17A, interferon gamma and tumour necrosis alpha were determined and their association with (a) history of alcohol consumption, (b) psychiatric comorbidity and (c) liver/pancreas comorbidities was explored. RESULTS: We found that plasma concentrations of interleukin 1 beta, interleukin 6 and tumour necrosis alpha were increased, whereas plasma concentrations of interleukin 4, interleukin 17A and interferon gamma were decreased in abstinent alcohol use disorder patients as compared with control subjects. Moreover, we found that changes in interleukin 6 and interleukin 17A plasma concentrations in alcohol use disorder patients were associated with the presence of liver and pancreatic diseases. CONCLUSION: The present results suggest alcohol use disorder is associated with alterations of plasma cytokines, being interleukin 6 and interleukin 17A potential biomarkers of the presence of comorbidities of digestive organs. The clinical relevance of these findings is discussed in the context of alcohol-induced inflammatory processes.

Systemic sporotrichosis in an alcoholic patient

Abstract A 44-year-old male patient presented with nodules that evolved with inflammation, following drainage of seropurulent secretion and ulceration. The patient had a 6 year-history of alcohol addiction and reported contact with cats. At the physical examination, the patient had skin-colored and erythematous nodules, and ulcers covered with thick, blackened crusts on the face, trunk and limbs. A culture of a nodule fluid revealed growth of Sporotrix sp. He also had pulmonary involvement and therefore the disease was classified as systemic sporotrichosis, a rare form that usually affect patients infected with HIV. Chronic alcohol abuse was considered the factor of immunosuppression for the patient.

Tuberculin skin test and predictive host factors for false-negative results in patients with pulmonary and extrapulmonary tuberculosis.

INTRODUCTION: Tuberculin skin test (TST) has been the standard test for screening for Mycobacterium tuberculosis infection for decades. Identifying persons with latent tuberculosis infection (LTBI) is crucial, as they constitute a reservoir that sustains the global tuberculosis (TB) epidemic. However, different factors, such as HIV infection, can lower the sensitivity of the test. OBJECTIVES: The aim of this study was to determine the TST sensitivity in active TB patients and to ascertain risk factors that could be associated with false-negative results. METHODS: Retrospective cohort study of all active TB notifications with a TST result (n = 8833), from 2008 to 2015. TST results were interpreted using a 5 mm and 10 mm cutoff. Bivariate and multivariate logistic regression analysis were used to evaluate the association of sociodemographic and clinical factors with false-negative TST results and to develop predictive risk models. RESULTS: TST presented an overall sensitivity of 63.8% (5 mm) and 56.1% (10 mm). HIV infection was the risk factor with the strongest association with false-negative results (aOR 4.65-5 mm; aOR 5.05-10 mm). Other factors such as chronic renal failure (CRF) (aOR 1.55-5 mm; aOR 1.73-10 mm), alcohol abuse (aOR 1.52-5 mm; aOR 1.31-10 mm), drug abuse (aOR 1.90-5 mm; aOR 1.76-10 mm) or age ≥65 years (OR 1.69-5 mm and 10 mm) were also associated with a probability of false-negative results. CONCLUSION: These results highlight the importance of knowing which factors influence TST results, such as HIV status, substance abuse or age, thus improving its usefulness as a screening method for LTBI.

Stress-related suppression of peripheral cytokines predicts future relapse in alcohol-dependent individuals with and without subclinical depression.

Chronic alcohol abuse and depressive symptoms are both associated with peripheral cytokine changes. Despite this, cytokine adaptations have not been assessed in co-morbid populations or prospectively as predictors of relapse. We examine cytokine responses to stress in alcohol-dependent individuals and social drinkers, both with and without subclinical depression. We also examine the potential link between cytokine adaptations in response to stress and prospective alcohol relapse risk. Thirty-three, alcohol-dependent individuals (21 with and 12 without high depressive symptoms) and 37 controls (16 with and 21 without high depressive symptoms) were exposed to two 5-minute personalized guided imagery conditions (stress and neutral) across consecutive days in a randomized and counterbalanced order. Alcohol craving and serum measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) were collected prior to and following imagery exposure. Following treatment discharge, follow-up interviews were conducted over 90 days to assess relapse. Dampened IL-1ra and IL-6 in response to stress was observed as a function of alcohol dependence and not moderated by depressive symptoms. Lower levels of IL-6 following stress also predicted greater drinking days following treatment. Conversely, high depressive symptomatology was associated solely with pro-inflammatory adaptations. Stress-related suppression of TNFα predicted drinking severity only in alcohol-dependent individuals with subclinical depression, and suppressed TNFR1 following stress was only seen in individuals with subclinical depression. Stress-induced suppression of pro-inflammatory TNF markers may indicate a risk factor for alcohol-dependent individuals with co-occurring depressive symptoms.

Alcohol or Gut Microbiota: Who Is the Guilty?

Alcoholic liver disease (ALD), a disorder caused by excessive alcohol intake represents a global health care burden. ALD encompasses a broad spectrum of hepatic injuries including asymptomatic steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The susceptibility of alcoholic patients to develop ALD is highly variable and its progression to more advanced stages is strongly influenced by several hits (i.e., amount and duration of alcohol abuse). Among them, the intestinal microbiota and its metabolites have been recently identified as paramount in ALD pathophysiology. Ethanol abuse triggers qualitative and quantitative modifications in intestinal flora taxonomic composition, mucosal inflammation, and intestinal barrier derangement. Intestinal hypermeability results in the translocation of viable pathogenic bacteria, Gram-negative microbial products, and pro-inflammatory luminal metabolites into the bloodstream, further corroborating the alcohol-induced liver damage. Thus, the premise of this review is to discuss the beneficial effect of gut microbiota modulation as a novel therapeutic approach in ALD management.

Activated mesenchymal stem cell administration inhibits chronic alcohol drinking and suppresses relapse-like drinking in high-alcohol drinker rats.

Neuroinflammation has been reported to follow chronic ethanol intake and may perpetuate alcohol consumption. Present studies determined the effect of human mesenchymal stem cells (hMSCs), known for their anti-inflammatory action, on chronic ethanol intake and relapse-like ethanol intake in a post-deprivation condition. Rats were allowed 12-17 weeks of chronic voluntary ethanol (10% and 20% v/v) intake, after which a single dose of activated hMSCs (5 × 105 ) was injected into a brain lateral ventricle. Control animals were administered vehicle. After assessing the effect of hMSCs on chronic ethanol intake for 1 week, animals were deprived of ethanol for 2 weeks and thereafter an ethanol re-access of 60 min was allowed to determine relapse-like intake. A single administration of activated hMSCs inhibited chronic alcohol consumption by 70% (P < 0.001), an effect seen within the first 24 hours of hMSCs administration, and reduced relapse-like drinking by 80% (P < 0.001). In the relapse-like condition, control animals attain blood ethanol ('binge-like') levels >80 mg/dl. The single hMSC administration reduced relapse-like blood ethanol levels to 20 mg/dl. Chronic ethanol intake increased by 250% (P < 0.001) the levels of reactive oxygen species in hippocampus, which were markedly reduced by hMSC administration. Astrocyte glial acidic fibrillary protein immunoreactivity, a hallmark of neuroinflammation, was increased by 60-80% (P < 0.001) by chronic ethanol intake, an effect that was fully abolished by the administration of hMSCs. This study supports the neuroinflammation-chronic ethanol intake hypothesis and suggest that mesenchymal stem cell administration may be considered in the treatment of alcohol use disorders.

The impact of alcohol use disorders on pulmonary immune cell inflammatory responses to Streptococcus pneumoniae.

Community-acquired pneumonia due to Streptococcus pneumoniae occurs commonly in alcohol use disorders (AUDs). Pneumonia in the AUD patient is associated with poorer outcomes, and specific therapies to mitigate disease severity in these patients do not exist. Numerous investigations have attributed increased severity of pneumonia in AUDs to aberrant function of the alveolar macrophage (AM), a lung immune cell critical in host defense initiation. No studies have examined the response of human AMs to S. pneumoniae in AUDs. We hypothesized that the inflammatory mediators released by AMs after S. pneumoniae stimulation would differ quantitatively in individuals with AUDs compared to non-AUD participants. We further postulated that AM inflammatory mediators would be diminished after exposure to the antioxidant, N-acetylcysteine (NAC). For comparison, responses of peripheral blood mononuclear cells (PBMCs) to pneumococcal protein were also examined. Otherwise healthy participants with AUDs and smoking-matched controls underwent bronchoalveolar lavage and peripheral blood sampling to obtain AMs and PBMCs, respectively. Freshly collected cells were cultured with increasing doses of heat-killed S. pneumoniae protein, with and without exposure to N-acetylcysteine. Cell culture supernatants were collected, and inflammatory mediators were measured, including interferon (IFN)-γ, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. IFN-γ and IL-6 were significantly higher in unstimulated AM cell culture supernatants from subjects with AUDs. After stimulation with pneumococcal protein, a dose-response and time-dependent increase in pro-inflammatory cytokine production by both AMs and PBMCs was also observed; differences were not observed between AUD and non-AUD subjects. Addition of NAC to pneumococcal-stimulated AMs and PBMCs was generally associated with diminished cytokine production, with the exception of IL-1ß that was elevated in AM culture supernatants from subjects with AUDs. Our observations suggest that AUDs contribute to basal alterations in AM pro-inflammatory cytokine elaboration, but did not support consistent differences in pneumococcal-stimulated AM or PBMC inflammatory mediator secretion that were referable to AUDs.

Alcohol and cannabis use alter pulmonary innate immunity.

PURPOSE: Cannabis use is increasing due to recent legislative changes. In addition, cannabis is often used in conjunction with alcohol. The airway epithelium is the first line of defense against infectious microbes. Toll-like receptors (TLR) recognize airborne microbes and initiate the inflammatory cytokine response. The mechanism by which cannabis use in conjunction with alcohol affects pulmonary innate immunity mediated by TLRs is unknown. METHODS: Samples and data from an existing cohort of individuals with alcohol use disorders (AUDs), along with samples from additional participants with cannabis use alone and with AUD were utilized. Subjects were categorized into the following groups: no alcohol use disorder (AUD) or cannabis use (control) (n = 46), AUD only (n = 29), cannabis use-only (n = 39), and AUD and cannabis use (n = 29). The participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and airway epithelial brushings. We measured IL-6, IL-8, TNF⍺, and IL-10 levels in BAL fluid, and performed real-time PCR for TLR1-9 on the airway epithelial brushings. RESULTS: We found significant increases in TLR2 with AUD alone, cannabis use alone, and cannabis use with AUD, compared to control. TLR5 was increased in cannabis users compared to control, TLR6 was increased in cannabis users and cannabis users with AUD compared to control, TLR7 was increased in cannabis users compared to control, and TLR9 was increased in cannabis users compared to control. In terms of cytokine production, IL-6 was increased in cannabis users compared to control. IL-8 and IL-10 were increased in AUD only. CONCLUSIONS: AUD and cannabis use have complex effects on pulmonary innate immunity that promote airway inflammation.

Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving.

BACKGROUND: Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined. METHODS: A total of 39 early abstinent, treatment-seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral. These were presented randomly across consecutive days. Plasma measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-10 (IL-10), were collected at baseline, immediately after imagery and at various recovery time-points. Ratings of alcohol craving, negative mood and anxiety were also obtained at the same time-points. RESULTS: The alcohol group demonstrated decreased basal IL-10 compared with controls particularly following exposure to alcohol cue. They also showed a dampened TNFα and TNFR1 response to stress and cue, respectively, and a generalized suppression of IL-6. In the alcohol group, these immune system adaptations occurred alongside significant elevations in anxiety, negative mood and alcohol craving. CONCLUSIONS: Findings demonstrate that broad immunosuppression is still observed in alcohol-dependent individuals after 3 weeks of abstinence and may be linked to motivation for alcohol.

The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach.

ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8(+) T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT-803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-γ-producing CD8(+)CD44(hi) memory T cells and CD8(+)CD44(hi)CD62L(lo) effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8(+) T cells, CD8(+)CD44(hi) T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment.

Effects of alcohol withdrawal on monocyte subset defects in chronic alcohol users.

Excessive alcohol consumption has a modulating effect on immune functions that may contribute to decreased immunity and host defense. It is associated with increased intestinal permeability to endotoxins that is normalized after 14 d of abstinence. Whether and how blood monocyte subsets are impaired in patients with an AUD and what their evolution is after alcohol withdrawal are the paper's objectives. With the use of flow cytometry, blood monocyte subsets were quantified in AUDs before (n = 40) and 2 wk after (n = 33) alcohol withdrawal and compared with HC donors (n = 20). Expression of TLR2 and TLR4 on monocyte subsets was also quantified. Cytokine response of monocytes was monitored following PGN and LPS stimulation. The CD14+CD16- subset was decreased, whereas the CD14dimCD16+ subset was expanded (P < 0.001) in AUD compared with HC. The frequencies of TLR2- and TLR4-expressing monocytes were reduced in AUD compared with HC. Although the basal production of IL-1, IL-6, and TNF by monocytes in AUD was compared with HC, the PGN- and LPS-mediated IL-6 and TNF production was increased in AUD. Frequencies of IL-6-expressing monocytes were higher in AUD than HC. Alcohol withdrawal partially restored the distribution of monocyte subsets and the frequency of IL-6-producing monocytes and increased the frequency of TNF-producing cells in response to LPS and PGN stimulation to levels compared with those in HC. Our findings indicate that chronic alcohol use alters the distribution as well as the phenotypic and functional characteristics of blood monocyte subsets, which are partially restored following 2 wk of alcohol withdrawal.

Alcohol use predicts elevation in inflammatory marker soluble CD14 in men living with HIV.

Independently, HIV infection and heavy alcohol use increase microbial translocation (MT) of gut products into systemic circulation. MT and consequent immune response have been linked to chronic inflammation and a host of negative health outcomes in individuals living with HIV. However, previous research has not systematically investigated the immune correlates of heavy drinking specifically within the HIV-positive population. This pilot study investigated MT and immune activation as a function of alcohol use in 21 HIV-positive men who met NIAAA criteria for heavy drinking. Participants averaged 46.7 ± 8.5 (mean ± standard deviation) years of age, 12.2 ± 9.2 years since HIV diagnosis, 337 ± 158 CD4 nadir, and 643 ± 245 current CD4 count. All participants were virologically suppressed on antiretroviral therapy. Data on alcohol use and immune function were collected at baseline and three-month follow-up. Plasma concentrations of markers of MT and immune activation (lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody immunoglobulin M (EndoCAb)) were measured using enzyme-linked immunosorbent assays. Generalized estimating equation models tested alcohol use variables as predictors of LPS, sCD14, and EndoCAb levels. Greater quantity and frequency of drinking significantly predicted higher sCD14 levels (p's < .01). Conversely, longer duration of abstinence from alcohol significantly predicted lower sCD14 levels (p < .001). These results remained significant after controlling for age, HIV duration, smoking status, current CD4 count, CD4 nadir, and antiretroviral drug type. In addition, participants with ≥50% relative reduction in drinks per week showed a significant decrease (p < .05) in sCD14 from baseline to three-month follow-up. This pilot study provides preliminary evidence that heavy drinking may increase a key inflammatory marker in HIV-infected individuals with suppressed infection.

Alcohol abuse and smoking alter inflammatory mediator production by pulmonary and systemic immune cells.

Alcohol use disorders (AUDs) and tobacco smoking are associated with an increased predisposition for community-acquired pneumonia and the acute respiratory distress syndrome. Mechanisms are incompletely established but may include alterations in response to pathogens by immune cells, including alveolar macrophages (AMs) and peripheral blood mononuclear cells (PBMCs). We sought to determine the relationship of AUDs and smoking to expression of IFNγ, IL-1ß, IL-6, and TNFα by AMs and PBMCs from human subjects after stimulation with lipopolysaccharide (LPS) or lipoteichoic acid (LTA). AMs and PBMCs from healthy subjects with AUDs and controls, matched on smoking, were cultured with LPS (1 µg/ml) or LTA (5 µg/ml) in the presence and absence of the antioxidant precursor N-acetylcysteine (10 mM). Cytokines were measured in cell culture supernatants. Expression of IFNγ, IL-1ß, IL-6, and TNFα in AMs and PBMCs was significantly increased in response to stimulation with LPS and LTA. AUDs were associated with augmented production of proinflammatory cytokines, particularly IFNγ and IL-1ß, by AMs and PBMCs in response to LPS. Smoking diminished the impact of AUDs on AM cytokine expression. Expression of basal AM and PBMC Toll-like receptors-2 and -4 was not clearly related to differences in cytokine expression; however, addition of N-acetylcysteine with LPS or LTA led to diminished AM and PBMC cytokine secretion, especially among current smokers. Our findings suggest that AM and PBMC immune cell responses to LPS and LTA are influenced by AUDs and smoking through mechanisms that may include alterations in cellular oxidative stress.

Impact of Alcohol Abuse on the Adaptive Immune System.

Alcohol exposure, and particularly chronic heavy drinking, affects all components of the adaptive immune system. Studies both in humans and in animal models determined that chronic alcohol abuse reduces the number of peripheral T cells, disrupts the balance between different T-cell types, influences T-cell activation, impairs T-cell functioning, and promotes T-cell apoptosis. Chronic alcohol exposure also seems to cause loss of peripheral B cells, while simultaneously inducing increased production of immunoglobulins. In particular, the levels of antibodies against liver-specific autoantigens are increased in patients with alcoholic liver disease and may promote alcohol-related liver damage. Finally, chronic alcohol exposure in utero interferes with normal T-cell and B-cell development, which may increase the risk of infections during both childhood and adulthood. Alcohol's impact on T cells and B cells increases the risk of infections (e.g., pneumonia, HIV infection, hepatitis C virus infection, and tuberculosis), impairs responses to vaccinations against such infections, exacerbates cancer risk, and interferes with delayed-type hypersensitivity. In contrast to these deleterious effects of heavy alcohol exposure, moderate alcohol consumption may have beneficial effects on the adaptive immune system, including improved responses to vaccination and infection. The molecular mechanisms underlying ethanol's impact on the adaptive immune system remain poorly understood.

The Role of Innate Immunity in Alcoholic Liver Disease.

The innate immune system represents the first-line response to invading microbes, tissue damage, or aberrant cell growth. Many of the proteins and cells involved in innate immunity are produced by, and reside in, the liver. This abundance in immune cells and proteins reflects the liver's adaptation to various immune challenges but also makes the organ particularly vulnerable to alcohol's effects. Heavy alcohol consumption may produce leakage of microbes and microbial products from the gastrointestinal tract, which quickly reach the liver via the portal vein. Exposure to these immune challenges and to alcohol and its breakdown products dysregulates the liver's normally fine-tuned immune signaling pathways, leading to activation of various cellular sensors of pathogen- or damage-associated molecular patterns. The ensuing expression of pro-inflammatory cytokines (e.g., tumor necrosis factor a [TNFα], interleukin [IL]-8, and IL-1b) results in cellular dysfunction that contributes to alcoholic liver disease (ALD). Investigations into the roles of the various components of liver innate immunity in ALD have begun to uncover the molecular basis of this disease. Further progress in this area may help inform the development of interventions targeting the innate system to augment current treatments of ALD. These treatments could include antibodies against pro-inflammatory cytokines, use of anti-inflammatory cytokines, or suppression of alcohol-induced epigenetic regulators of innate immunity.

Effects of Alcohol on Tumor Growth, Metastasis, Immune Response, and Host Survival.

Most research involving alcohol and cancer concerns the relationship between alcohol consumption and cancer risk and the mechanisms of carcinogenesis. This review relates the amount and duration of alcohol intake in humans and in animal models of cancer to tumor growth, angiogenesis, invasion, metastasis, immune response, and host survival in specific types and subtypes of cancer. Research on the influence of alcohol drinking on human cancer patients is limited. Although there is more information in animal models of cancer, many aspects still are ill defined. More research is needed to define the mechanisms that underlie the role of alcohol on cancer progression in both animals and humans. Activation of the immune system can play a positive role in keeping cancer under control, but this also can facilitate cancer progression. Additionally, a functional immune system is required for cancer patients to achieve an optimal response to conventional chemotherapy. Insight into the underlying mechanisms of these interactions could lead to effective immunotherapeutic approaches to treat alcoholics with cancer. Defining the epigenetic mechanisms that modulate cancer progression also has great potential for the development of new treatment options not only for treating alcoholics with cancer but also for treating other alcohol-induced diseases.