Sex difference in IgE sensitization associated with alcohol consumption in the general population.

The association of alcohol consumption and immunoglobulin E (IgE) sensitization is debated. Few population-based studies have investigated whether such associations differ by sex. We explored the association of alcohol consumption with IgE sensitization in the general population, stratified by sex. We analyzed data for 1,723 adults from the 2010 Korean National Health and Nutrition Examination Survey. We divided subjects into three groups according to their self-reported alcohol consumption or serum level of gamma-glutamyltransferase (GGT), an objective marker of alcohol consumption. After adjustments, the odds ratios (ORs) of male high-risk drinkers were 2.09 (95% confidence interval [CI], 1.34-3.28) for total IgE and 1.71 (95% CI, 1.03-2.83) for Dermatophagoides farinae (DF)-specific IgE compared with male low-risk drinkers. In females, the dog-specific IgE level was associated with high-risk drinking (OR, 11.74; 95% CI, 2.04-67.24). The ORs of males in the high-serum-GGT group were 2.73 (95% CI, 1.72-4.33) for total IgE and 2.17 (95% CI, 1.35-3.47) for DF-specific IgE compared with those in the low-serum-GGT group. This study suggests a possible link between alcohol consumption and IgE sensitization, moreover, the risk of IgE sensitization was significantly higher in male high-risk drinkers. Therefore, clinicians should consider the risk of IgE sensitization possibly afflicting male high-risk drinkers.

Alcoholic Myopathy: Pathophysiologic Mechanisms and Clinical Implications.

Skeletal muscle dysfunction (i.e., myopathy) is common in patients with alcohol use disorder. However, few clinical studies have elucidated the significance, mechanisms, and therapeutic options of alcohol-related myopathy. Preclinical studies indicate that alcohol adversely affects both anabolic and catabolic pathways of muscle-mass maintenance and that an increased proinflammatory and oxidative milieu in the skeletal muscle is the primary contributing factor leading to alcohol-related skeletal muscle dysfunction. Decreased regenerative capacity of muscle progenitor cells is emerging as an additional mechanism that contributes to alcohol-induced loss in muscle mass and impairment in muscle growth. This review details the epidemiology of alcoholic myopathy, potential contributing pathophysiologic mechanisms, and emerging literature on novel therapeutic options.

Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro-inflammation.

It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro-inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels. Further, along with Pde4b, there was a robust activation of astrocytes and microglia accompanied by significant increases in the inflammatory cytokines (Tnfα, Il-1ß, Mcp-1 and Il-17) and the generalized inflammatory marker Cox-2. At the cellular level, alcohol and inflammatory mediators, particularly LPS, Tnfα and Hmgb1 significantly activated microglial cells (Iba-1 expression) and selectively induced Pde4b expression with a minimal to no change in Pde4a and d isoforms. In comparison, the alcohol-induced decrease in brain cAMP levels was completely inhibited in WT mice treated with the Pde4 specific pharmacologic inhibitor rolipram and in Pde4b-/- mice. Moreover, all the observed markers of alcohol-induced brain inflammation were markedly attenuated. Importantly, glial cell activation induced by systemic endotoxemia (LPS administration) was also markedly decreased in Pde4b-/- mice. Taken together, these findings strongly support the notion that Pde4b plays a critical role in coordinating alcohol-induced, peripheral endotoxemia mediated neuro-inflammation and could serve as a significant therapeutic target.

Wide array of T-cell subpopulation alterations in patients with alcohol use disorders.

BACKGROUND: Alcohol abuse impacts innate and adaptive immunity and predisposes to infections. However, prevalence and correlations of cellular immune alterations in large case series is underreported. We aimed to analyze quantitative alterations of T-lymphocyte subpopulations in patients with alcohol use disorder (AUD). METHODS: cross-sectional study in patients admitted for detoxification between January 1, 2002 and December 31, 2012. Socio-demographic and alcohol use characteristics and blood samples for biochemistry, hematology and immune phenotype was obtained at admission. RESULTS: 238 patients (79.8%M) were eligible; age at admission was 43 years (interquartile range [IQR]: 38-51 years), the amount of alcohol consumption was 180 g/day (IQR: 120-200 g/day) and median duration of AUD was 18 years (IQR: 9-25 years). Compared to healthy individuals, 50% of patients had significantly fewer double-negative (DN) T-lymphocytes (<34 × 10(9)/L) and 23% had more double-positive (DP) T-cells (>52 × 10(9)/L). In addition, 24% of patients had high number of CD8(+) cells (>735 × 10(9)/L) and 13% had low CD4(+) cell counts (<600 × 10(9)/L). In multivariable analysis, age, sex, serum albumin, and current cocaine use were predictors of T-cell subpopulation alterations. Women were three-times (OR=3.5, 95%CI:1.3-9.5) more likely to present with higher DP T-lymphocytes than men. CONCLUSIONS: Quantitative alterations of T-cell subpopulations are frequent in patients seeking treatment of AUD. Assessment of cellular immunity in this population may help to identify those at increased risk of immune alterations.

Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation.

Strategies to prevent organ transplant rejection whilst minimizing long-term immunosuppression are currently under intense investigation with regulatory T cells (Tregs) nearing clinical application. The clinical trial, ThRIL, recently commenced at King's College London, proposes to use Treg cell therapy to induce tolerance in liver transplant recipients, the success of which has the potential to revolutionize the management of these patients and enable a future of drug-free transplants. This is the first report of the manufacture of clinical grade Tregs from prospective liver transplant recipients via a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2 and rapamycin. We report the enrichment of a pure, stable population of Tregs (>95% CD4(+)CD25(+)FOXP3(+)), reaching adequate numbers for their clinical application. Our protocol proved successful in, influencing the expansion of superior functional Tregs, as compared to freshly isolated cells, whilst also preventing their conversion to Th17 cells under pro-inflammatory conditions. We conclude with the manufacture of the final Treg product in the clinical research facility (CRF), a prerequisite for the clinical application of these cells. The data presented in this manuscript together with the much-anticipated clinical results from ThRIL, will undoubtedly inform the improved management of the liver transplant recipient.

Opposing effects of alcohol on the immune system.

Several studies have described a dose-dependent effect of alcohol on human health with light to moderate drinkers having a lower risk of all-cause mortality than abstainers, while heavy drinkers are at the highest risk. In the case of the immune system, moderate alcohol consumption is associated with reduced inflammation and improved responses to vaccination, while chronic heavy drinking is associated with a decreased frequency of lymphocytes and increased risk of both bacterial and viral infections. However, the mechanisms by which alcohol exerts a dose-dependent effect on the immune system remain poorly understood due to a lack of systematic studies that examine the effect of multiple doses and different time courses. This review will summarize our current understanding of the impact of moderate versus excessive alcohol consumption on the innate and adaptive branches of the immune system derived from both in vitro as well as in vivo studies carried out in humans and animal model studies.

Circadian disruption: potential implications in inflammatory and metabolic diseases associated with alcohol.

Circadian rhythms are a prominent and critical feature of cells, tissues, organs, and behavior that help an organism function most efficiently and anticipate things such as food availability. Therefore, it is not surprising that disrupted circadian rhythmicity, a prominent feature of modern-day society, promotes the development and/or progression of a wide variety of diseases, including inflammatory, metabolic, and alcohol-associated disorders. This article will discuss the influence of interplay between alcohol consumption and circadian rhythmicity and how circadian rhythm disruption affects immune function and metabolism as well as potential epigenetic mechanisms that may be contributing to this phenomenon.

[Alcohol and acute respiratory distress syndrome: casuality or causality?]. / Alcohol y síndrome de distrés respiratorio agudo:¿casualidad o causalidad?

Alcohol has been considered an important risk factor for the development of pneumonia since the last century. Nevertheless, it was not thought that it had relevant effects on lung structure and functions until recently. Recent studies have shown that the risk for acute respiratory distress syndrome (ARDS) is 2-4 times higher among alcoholic patients with sepsis or trauma, and that alcoholism can play a roll in more than 50% of cases in the pathogenesis of this syndrome. Although alcoholism per se does not cause acute lung injury it predisposes to pulmonary dysfunction after inflammatory stress, that is present in clinical situations that cause ARDS leading to its development and complicating its outcome. Recent investigations in animals and humans with alcohol abuse have uncovered several alterations currently known as the "alcoholic lung". This revision discusses the association between alcohol abuse and lung injury/ARDS and tries to explain the physiopathology along with possible treatments.

A dynamic flux in natural killer cell subsets as a function of the duration of alcohol ingestion.

BACKGROUND: Chronic ethanol (EtOH) consumption is associated with a wide variety of immune abnormalities including changes in T cells, B cells, dendritic cells, and natural killer (NK) cells. However, there is conflicting information as to the direction of such immune changes. The hypothesis that was tested in this report is that, for NK cells, the changes can vary as a function of the duration of alcohol ingestion. METHODS: Using the Meadows-Cook murine model of chronic alcohol ingestion, the changes in NK cell function and subset distribution were examined as a function of the duration of alcohol ingestion. RESULTS: Acute alcohol ingestion resulted in decreased number and cytotoxic function of NK cells with no effect on intracellular interferon gamma expression. These abnormalities normalized after 12 to 14 days of alcohol ingestion and there was an increase of NK cell number and cytotoxicity after 8 weeks of continued EtOH ingestion. Ten weeks of continued alcohol consumption results in a significant decrease in the Ly49H+ CD11b+ CD27- splenic NK cell subset; this difference continued to be significant at 30 weeks. CONCLUSIONS: This report may explain some of the conflicting data in the literature that examined NK cell activity in alcoholic patients. It is apparent that various abnormalities can be seen in NK cell activity and subset distribution with the flux being a function of the duration of alcohol ingestion. The demonstration of a decrease in the Ly49H+ subset (which is known to be involved in resisting murine cytomegalovirus infection) may explain the reported increase in susceptibility to some viral infections in chronic alcohol abuse. Another novel finding is that changes of some subsets of NK cells are not evident until at least 10 weeks of continued EtOH consumption.

Alcohol-use disorders in the critically ill patient.

Alcohol abuse and dependence, referred to as alcohol-use disorders (AUDs), affect 76.3 million people worldwide and account for 1.8 million deaths per year. AUDs affect 18.3 million Americans (7.3% of the population), and up to 40% of hospitalized patients have AUDs. This review discusses the development and progression of critical illness in patients with AUDs. In contrast to acute intoxication, AUDs have been linked to increased severity of illness in a number of studies. In particular, surgical patients with AUDs experience higher rates of postoperative hemorrhage, cardiac complications, sepsis, and need for repeat surgery. Outcomes from trauma are worse for patients with chronic alcohol abuse, whereas burn patients who are acutely intoxicated may not have worse outcomes. AUDs are linked to not only a higher likelihood of community-acquired pneumonia and sepsis but also a higher severity of illness and higher rates of nosocomial pneumonia and sepsis. The management of sedation in patients with AUDs may be particularly challenging because of the increased need for sedatives and opioids and the difficulty in diagnosing withdrawal syndrome. The health-care provider also must be watchful for the development of dangerous agitation and violence, as these problems are not uncommonly seen in hospital ICUs. Despite studies showing that up to 40% of hospitalized patients have AUDs, relatively few guidelines exist on the specific management of the critically ill patient with AUDs. AUDs are underdiagnosed, and a first step to improving patient outcomes may lie in systematically and accurately identifying AUDs.

Effects of ethanol on cytokine production after surgery in a murine model of gram-negative pneumonia.

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

The medical complications of alcohol use: understanding mechanisms to improve management.

The use of alcohol in a dependent or even a regular heavy pattern predisposes the drinker to a range of adverse consequences. These include a risk of direct harm from alcohol, including organ damage, mental health disorders and a range of social and legal problems associated with behaviours due to alcohol's effects. The range of organ damage associated with regular heavy alcohol consumption is well described. Much new information on the mechanisms by which damage occurs is available and is reviewed in this paper. New knowledge can assist in the development of more appropriate management strategies for those affected by the medical complications of alcohol use. Genetic susceptibility to tissue injury is explored and the reasons why many heavy drinkers do not appear to experience organ damage are considered. Approaches to the management of certain alcohol-related disorders are outlined.

Influence of alcohol on antimicrobial immunity.

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

Immunological parameters in patients suffering from alcohol-dependence syndrome.

Alcohol abuse is a major cause of abnormal liver development and activity. In addition to enzymatic malfunction, alcohol and its metabolites induce changes in the levels of some liver antigens, resulting in immunological disturbance. The purpose of the present study is to correlate the severity of liver function impairment with the length of alcohol abuse, in order to be able to use such tests as indicative of the severity of Alcohol Dependence Syndrome. Thirty-one alcohol abusers were allocated to three groups on the basis of the levels of their liver enzymes, and were tested for a variety of immunological parameters and skin reactions. The data indicate that even though not all immunological values measured differed significantly from the control values, in those that did (granulocytes, lymphocytes, CD4/CD8 ratio, C3, IgG, IgM and some skin positive reactions), the biggest difference was between the healthy volunteers and the group with the longest abuse period. It is suggested that changes in selected immunological parameters in alcohol abusers may indicate the severity of their liver dysfunction.

Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex?

Although psychoactive drugs are commonly used by AIDS patients, it is unclear whether commonly abused drugs, such as cocaine and ethanol, affect the course of HIV-associated dementia (HADC). Epidemiological studies have resulted in conflicting conclusions as to what role, if any, abused drugs play in HADC. In this review we discuss the clinical and pathological evidence that cocaine and ethanol might exacerbate the detrimental effects of HIV infection on the brain. We also review studies of cocaine and ethanol effects on various components of the immune system both in the presence and absence of retroviral infection. Data from these studies indicate that cocaine and ethanol have profound effects on the immune system that, in many respects, are enhanced by retroviral infection. We conclude that abused drugs likely affect the course of HADC but that proof awaits an examination of their interactive effects in an appropriate in vivo system of retroviral encephalitis.

Alcohol abuse, alcoholism, and damage to the immune system--a review.

Chronic alcohol abuse exacts a major social and medical toll in the United States and other Western countries. One of the least appreciated medical complications of alcohol abuse is altered immune regulation leading to immunodeficiency and autoimmunity. The consequences of the immunodeficiency include increased susceptibility to bacterial pneumonia, tuberculosis, and other infectious diseases. In addition, the chronic alcoholic often has circulating autoantibodies, and recent investigations indicate that the most destructive complications of alcoholism, such as liver disease and liver failure, may have a component of autoimmunity. Current research on altered cytokine balance produced by alcohol is leading to new insights on the regulation of the immune system in the chronic alcoholic. There is also recent development of exciting new techniques designed to improve or restore immune function by manipulation of cytokine balance. Although much remains to be learned, both in the abnormalities produced by alcohol and in the techniques to reverse those abnormalities, current progress reflects a rapidly improving understanding of the basic immune disorders of the alcoholic.