In mice, the ability of DCs to prime T cells is lessened with advanced age, both in vitro 237, 247, 248 and in vivo 222, 231, 249. Conversely, some studies have demonstrated that DCs from older and younger animals and humans have the same capacity to serve as APCs or that DCs from aged hosts have slightly augmented APC abilities 242, 244, 250, 251, 252–253. The inconsistencies in findings examining the ability of DCs to prime T cells are probably due to differences in the ages, locations, and population purities (ratio of cDCs to pDCs) used in each study, suggesting further work is necessary to elucidate exactly how aging negatively influences DC function. Both chronic and binge alcohol consumption results in a decline in the capacity of DCs to stimulate T cells 232, 233, 234–235.
The studies found that when animals consumed ethanol before BCG vaccination, they were not protected against a subsequent pulmonary challenge with M. In contrast, mice that consumed ethanol after the BCG vaccination were protected against a subsequent M. Taken together, these data suggest that chronic ethanol exposure interferes with immunity to new antigens but not with immunity established before alcohol consumption. Alcohol also activates an enzyme acting at the thymocyte membrane called adenylate cyclase, which increases the intracellular concentration of cyclic AMP (Atkinson et al. 1977). CAMP has multiple regulatory functions in the cell, and increased cAMP levels can stimulate DNA fragmentation, leading to thymocyte apoptosis (McConkey et al. 1990).
However, similarly to the in vitro studies described above, at 2 and 5 hours post-binge the numbers of circulating monocytes were reduced and levels of antiinflammatory IL-10 levels were increased (Afshar, Richards et al. 2014). In addition to laboratory studies confirming the impact of alcohol consumption on the innate immune system, several studies have looked at how heavy drinking can alter plasma cytokine levels. To this end, one study analyzed IL-10, IL-6, IL-18, and tumor necrosis factor α (TNF-α) levels in 25 non-treating seeking heavy drinkers after they had consumed an alcoholic drink. The researchers reported significant reductions in the TNF-α levels three and six hours after the alcohol consumption.
Alcohol and immunity on a cellular level
Monocytes express Toll-like receptor (TLR) 4, which is the PRR responsible for recognizing the endotoxin LPS on the surface of Gram negative bacteria. Upon LPS binding, monocytes become activated, mature into macrophages and migrate into tissues where they respond to infection by secreting various cytokines, recruiting additional leukocytes via production of chemokines and presenting pathogen-derived peptides to T cells to activate them. These events depend on the activation of the nuclear factor kappa B (NFκB) heterodimer p50–p65 and its translocation to the nucleus leading to the expression and production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-12, and tumor necrosis factor (TNF)-α (Hoffmann, Natoli et al. 2006, Janeway 2008). Often, investigators stimulate with LPS after pre-exposure to ethanol to mimic inflammation observed in trauma patients with high blood alcohol levels and explore the alterations in immunity that lead to frequent subsequent infections among this group. The inhibitory effect of acute ethanol on production of pro-inflammatory cytokines in response to a variety of microbial compounds has been recapitulated using mouse models of acute ethanol exposure (reviewed in27,33). A handful of studies based in rodent models of chronic ethanol consumption have reported increased pathogen burden and impaired ability to clear Listeria monocytogenes34, Mycobacterium tuberculosis35, and influenza virus36.
- Suppression of inflammatory factors like cytokines is further achieved by the inhibition of histone deacetylases (HDACs) activity.
- Acute alcohol administration through gastric gavage or intraperitoneal injection have been used and resulted in alcohol-related alterations in immune functions (Plackett and Kovacs, 2008).
- However, additional studies are needed to fully uncover the mechanisms that underlie increased Ig production while B-cell numbers are reduced.
- However, experimental data suggests that alcohol and HCV infection can be additive in inhibition of the T cell activating capacity of human myeloid dendritic cells (Dolganiuc et al., 2003a).
- To be absorbed into the bloodstream, alcohol has to pass through the gastrointestinal (GI) tract, therefore making it especially vulnerable to its negative effects.
- The extent of immune system impairment due to alcohol consumption varies depending on factors such as frequency and quantity of consumed alcohol, as well as individual susceptibility.
Impact of AUD on Adaptive Immune Responses
Each of these events is mediated by the activation of nuclear factor kappa B (NFκB), which can be inhibited by alcohol consumption and thus prevent the production of pro-inflammatory cytokines. In vivo studies have confirmed that binge drinking with a blood alcohol concentration (BAC) of approximately 0.4% can reduce the production of various inflammatory cytokines including interleukin-6 (IL-6), IL-10, and IL-12. Not only does the immune system mediate alcohol-related injury and illness, but a growing body of literature also indicates that immune signaling in the brain may contribute to alcohol use disorder. The article by Crews, Sarkar, and colleagues presents evidence that alcohol results in neuroimmune activation. This may increase alcohol consumption and risky decisionmaking and decrease behavioral flexibility, thereby promoting and sustaining high levels of drinking. They also offer evidence that alcohol-induced neuroimmune activation plays a significant role in neural degeneration and that the neuroendocrine system is involved in controlling alcohol’s effects on peripheral immunity.
Alcohol’s Effects on Adaptive Immunity
Both enzymes convert alcohol to acetaldehyde, which is further metabolized to acetate by acetaldehyde dehydrogenase (ALDH) in the mitochondria. Acetate is then released into the blood where it is oxidized to carbon dioxide in the heart, skeletal muscle, and brain (Zakhari 2006). Additionally, incorporating healthy lifestyle practices such as regular exercise, adequate sleep, consuming a balanced diet rich in immune-boosting nutrients and proper hydration can further support your immune resilience and overall wellness.
NK cells
Although this chronic weakening of lung function may not cause any immediate symptoms, these effects can manifest when a severe respiratory infection occurs. The gastrointestinal (GI) system is typically the first point of contact for alcohol as it passes through the body and is where alcohol is absorbed into the bloodstream. One of the most significant immediate effects of alcohol is that it affects the structure and integrity of the GI tract. For example, alcohol alters the numbers and relative abundances of microbes in the gut microbiome (see the article by Engen and colleagues), an extensive community of microorganisms in the intestine that aid in normal gut function. Alcohol consumption also damages epithelial cells, T cells, and neutrophils in the GI system, disrupting gut barrier function and facilitating leakage of microbes into the circulation (see the article by Hammer and colleagues). By comprehending the impact of alcohol on the immune system, individuals can make informed decisions about their alcohol consumption.
However, unlike other mechanisms that cause classical immunocompromised states, such as HIV or tuberculosis infection, alcohol use typically results in a subclinical immunosuppression that becomes clinically significant only in case of a secondary insult. Molecular mechanisms of the dose-dependent effects of alcohol on the immune system and HPA regulation remain poorly understood due to a lack of systematic studies that examine the effect of multiple doses and different time courses. There may be important differences in the effects of ethanol on the immune system depending on whether the study is conducted in vitro or in vivo, as the latter allows for a complex psychogenic component in which stress-related hormones and immune-signaling molecules interact. In addition, most studies have been done in vitro using primary cells or cell lines in the presence of rather high, constant doses of ethanol. Similarly, most rodent studies to date have focused on acute/short-term binge models utilizing high concentration of ethanol (20% ethanol) as the sole source of fluid, a possible stressor in itself. Therefore, there is a pressing need for in depth studies that examine dose-dependent effects of chronic ethanol consumption on immunity in vivo to allow for the complex interactions between ethanol, its metabolites, HPA signaling, nutritional deficiencies, and the immune system.
- These cells play a crucial role in identifying and destroying foreign invaders, including bacteria, viruses, and other pathogens.
- Acute high dose exposures inhibit whereas long-term treatments stimulate proinflammatory cytokine production.
- Rodent studies offer several advantages such as availability of transgenic models that can facilitate mechanistic studies.
- Intestinal pathogenic bacteria facilitate immune-mediated liver injury by activating dendritic cells (DCs) and natural killer T (NKT) cells in the liver 34.
While B cell functions appear to be relatively unaffected by alcohol, secondary modification through stress response may still occur. Together, the alcohol-induced specific changes in immune cell functions result in a impaired host defense and inappropriate immune response to invading pathogens leading to higher incidence of pneumonias and other infection as well as prolonged recovery from infections, burn or trauma injury. Further investigation of the specific effects of alcohol on immune functions should help to define potential therapeutic options for amelioration of alcohol-induced immune defects.
Numerous studies have demonstrated that ethanol, its impact of alcohol abuse on the adaptive immune system metabolites, and alterations of the gut microbiome suppress intestinal tight junction protein expression 58,59,60,61 producing that the epithelial layer becomes leaky or “permeable”. Alcohol increased gut permeability affects mucosal immunity and allows the translocation of bacterial or some critical components of their membrane into the bloodstream 47, reaching other organs that can be damaged. LPS (lipopolysaccharide), Gram-negative bacteria membrane main product, and other bacterial metabolites reach the liver via the portal vein where they are enabled to induce the activation of the inflammatory processes. A study in rats has shown that only two weeks of alcohol administration disrupts the intestinal barrier and after two weeks more, liver injury occurs 62. In the liver, gut-derived molecules interact with the hepatocytes, parenchymal cells, and immune cells causing injuries including hepatic steatosis, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma 63.
In a study by Momen-Heravi et al., a significant increase was observed in the number of circulating EVs following alcohol consumption in mice, which were primarily composed of exosomes, a smaller subcategory of EVs 76. Analyzing these exosomes using microarray screening, they identified nine inflammatory miRNAs with altered expression in mice with chronic alcohol consumption compared with the control mice. ROC analysis confirmed that miRNA-192, miRNA-122, and miRNA-30a had strong diagnostic potential for detecting alcohol-induced liver injury. Subsequently, these findings were validated in human samples, where a similar increase in total EVs, mainly exosomes, was observed in individuals with AH. Furthermore, both miRNA-192 and miRNA-30a showed significant elevation in patients with AH, with miRNA-192 holding promise as a diagnostic marker for AH 76. According to the available literature, alterations in cellular protein and mRNA due to alcohol align with corresponding changes in cargoes carried by EVs (Figure 2).
Alcohol-related impairments of adaptive immune responses render the organism more vulnerable to viral and bacterial infections, contributing to more severe or accelerated disease progression. In addition, dysregulation of normal immune responses may contribute to such conditions as alcoholic liver disease and pancreatitis, altered gut permeability and gastrointestinal inflammation, neuroinflammation in the brain, and the development of cancer (see the article by Meadows and Zhang). In a recent study, chronic alcohol administration in the drinking water evaluated T and B cell functions in various strains of mice. Alcohol feeding from 8-32 weeks resulted in no changes in serum immunoglobulin levels, pre-B cells or in the percentage of double positive thymocytes (Cook et al, 2007). Exposure of mice to similarly low levels of alcohol for 4-8 weeks (5% alcohol in the drinking water) resulted in significant changes in the splenic, thymic and bone marrow T cell subpopulations and increased T cell expression of STAT5 while it decreased STAT5 activation in NK cells (Guo et al., 2002).