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Home , White blood cell

’s Contribution to Compromised

GYONGYI SZABO, M.D., PH.D.

Alcoholics frequently suffer from infectious and have increased rates of some , indicating that alcohol impairs the , which protects the body against this type of damage. Alcohol interferes with the functions of many of the cells and molecules that are part of the immune system. For example, alcohol inhibits the functions of the cells that ingest and destroy invading microorganisms (i.e., , , and ). Both acute and chronic alcohol exposure also alter the production of signaling molecules that help coordinate the (i.e., ). Finally, alcohol adversely affects the functions of the cells that mediate the immune response against specific microorganisms and long-term immunity (i.e., T cells and B cells). As a result, alcoholics have an increased susceptibility to diseases caused by bacterial , such as and . Alcoholics also may be more susceptible to infections from the that causes AIDS. In addition, alcohol intoxication can exacerbate the immune suppression that occurs after traumatic injuries. KEY WORDS: immune system; immune disorder; immune response; AODE (alcohol and other drug effects); cytokines; ; oxygen radicals; bacterial ; HIV ; trauma; injury; pathologic process; literature review

he immune system serves as the increased risk of developing tumors, THE IMMUNE SYSTEM—AN body’s defense against infections particularly in the head, neck, and OVERVIEW Tby microorganisms; damage upper gastrointestinal tract. Although caused by other foreign substances; alcohol-induced malnutrition—includ- The immune system has two main and the uncontrolled, tumorous growth ing vitamin deficiencies—and ad- arms: innate, or nonspecific, immunity of the body’s own cells. Impairment of vanced liver cirrhosis likely contribute and acquired, or specific, immunity. this system can increase a person’s to some abnormalities in the immune Innate immunity exists before the risk for developing various illnesses, system of alcoholics, alcohol itself body is exposed to a for the including infectious diseases, such as also is a potent modulator of immune first time. Moreover, this system does tuberculosis, and certain types of can- functions. Interestingly, not only not respond to specific but cer. Alcohol can modulate this de- chronic alcohol abuse but also single- instead responds to any pathogen it fense, and clinicians have known for a episode (i.e., acute) and/or moderate encounters. For example, the cells long time that chronic alcohol abusers alcohol consumption can affect the involved in innate immunity immedi- have an impaired immune system. immune system. ately attack any kind of bacterium or This impairment manifests itself in This article briefly reviews the several ways. For example, alcoholics main features and components of the GYONGYI SZABO, M.D., PH.D., is a are prone to infections by various immune system and summarizes some research associate professor of medi- disease-causing microorganisms (i.e., of the consequences and mechanisms cine in the Department of Medicine, pathogens); have a decreased ability to of alcohol use on the body’s defense University of Massachusetts Medical fight these infections; and have an against pathogens. Center, Worcester, Massachusetts.

30 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and Compromised Immunity

virus that enters the body, whether it is cules that function cooperatively to nize and bind to . Like T cells, the first or second infection by that mount a complex host defense and each B also recognizes only one organism. Acquired immunity, in thereby amplify and focus the protection specific and becomes activated contrast, is activated only after the offered by the innate immunity. The when it comes into contact with it. body is exposed to a pathogen for the most important cells involved in ac- Most activated B cells develop into so- first time. In addition, the acquired quired immunity are T , or called plasma cells, which secrete their response is specific to one particular T cells, and B lymphocytes, or B cells. into the or lymph. pathogen. For example, when Myco- These cells circulate in the blood or There the antibodies can bind to their bacterium tuberculosis, the bacterium reside in special lymphoid tissues (e.g., target antigens (e.g., a virus or a virus- that causes tuberculosis, enters the the , lymph nodes, and tonsils), infected cell) and thus mark them for body, the contact with that pathogen where they can encounter antigens and destruction. Other B cells become activates cells involved in acquired initiate an immune response. memory cells, which help the body immunity. These activated cells attack T cells and B cells are the corner- fight a second infection by the same only M. tuberculosis and no other stones of two types of immune re- pathogen more expeditiously. or . The activated cells sponses, the cell-mediated immunity The T-cell and B-cell responses are also generate a kind of immune “mem- and the -mediated (i.e., hu- not independent of each other, however, ory” that allows the body to fight a moral) immunity. The cell-mediated but are intricately intertwined. Thus, B second infection by the same pathogen immunity relies primarily on T cells cells that have bound an antigen serve even faster and more efficiently. that are activated by exposure to anti- as antigen-presenting cells that can The elements of innate immunity gen-presenting cells (e.g., monocytes, activate a T-cell response. Moreover, B include white blood cells that ingest and macrophages, and B cells). Each anti- cells and T cells communicate with each destroy microorganisms (i.e., phago- gen-presenting cell displays only one other and with other immune cells by cytes); certain proteins that circulate in antigen (e.g., a viral protein) on its secreting numerous cytokines that can the blood, called the complement1 surface and thus stimulates only T influence various components of both system; and signaling molecules (i.e., cells that recognize this specific anti- the nonspecific and specific immune cytokines) that are produced and secret- gen. The activated then can responses. For example, some T cells ed by some of the . Several bind to other cells carrying the same produce cytokines that stimulate their different types of phagocytes exist, with antigen (e.g., virus-infected cells) and own activity or that of other T cells. specific functions as follows: initiate their destruction. Several sub- Other subgroups of T cells secrete cy- populations of T cells have specific ¥ Neutrophils ingest and thereby de- tokines that inhibit the cell-mediated functions in the complex chain of and and thus prevent stroy pathogens, primarily invading events occurring during an immune bacteria. an excessive reaction of the immune response: system. Finally, some T-cellÐderived ¥ Monocytes that circulate in the ¥ Helper T cells produce and secrete cytokines enhance B-cell multiplication, blood or that have entered the cytokines that stimulate the activity differentiation, and antibody production. tissues (i.e., macrophages) ingest of other immune cells. The largest family of cytokines are the and destroy a variety of foreign (IL’s), which are produced substances and microorganisms. ¥ Cytotoxic T cells recognize anti- in various cell types and have numerous Monocytes also exhibit pathogen- gens on the surface of virus-infect- functions (see table). derived proteins and other mole- ed or transplanted cells and destroy The following example may help cules (i.e., antigens) on their surfaces these cells. illustrate some of the complex interac- in order to activate other cells in ¥ Suppressor T cells inhibit other tions that take place during an immune the immune system. Finally, mono- immune responses, thereby pre- response. When a person sustains a cytes and macrophages secrete venting overreaction of the im- small injury, such as a cut, bacteria can cytokines that help regulate im- mune system. enter the body and the bloodstream mune system activity. through the wound. Phagocytes (e.g., ¥ Delayed-type T ¥ Natural killer (NK) cells recognize monocytes and neutrophils) patrolling cells produce cytokines that induce the blood encounter some of these and eliminate cells in the body that a localized inflammatory response bacteria; identify them as foreign to have been infected by parasites or and attract macrophages and cyto- the body; and engulf, ingest, and de- that have turned into cells. toxic T cells to that site to elimi- stroy them. During the intracellular nate the antigen. The elements of acquired immunity breakdown of the ingested bacteria, include numerous cell types and mole- The B cells produce the humoral the phagocytes generate small proteins immunity. These cells carry immune or protein fragments that serve as 1For a definition of this and other technical terms used throughout this article, see the proteins (i.e., antibodies, or immuno- antigens. The phagocytes display these central glossary, pp. 93Ð96. globulins) on their surface that recog- antigens on their cell surface, together

VOL. 21, NO. 1, 1997 31 Important Cytokines of the Immune System

Cytokine Primary Source Principal Functions

Inflammatory cytokines

Interferon alpha (IFN-α) Macrophages Induces protection against viral infections; activates macrophages; and inhibits the growth of various cell types

Interleukin 1 (IL-1) Macrophages and other cells Produces inflammatory responses; induces ; stimulates proliferation of helper T cells; and promotes B- and differentiation

Interleukin 6 (IL-6) Macrophages, T cells, and other cells Promotes maturation of stimulated B cells to antibody-secreting plasma cells; acts with other cytokines to stimulate immature and mature T cells; and stimulates production of complement factors and other mediators of inflammatory responses

Tumor factor alpha Macrophages, T cells, natural killer (NK) Promotes inflammatory responses; stimulates (TNF-α) cells, and other cells neutrophils and macrophages; induces fever; and induces macrophages to produce IL-1, IL-6, and TNF-α

Immunoregulatory cytokines

Interleukin 10 (IL-10) Macrophages and T cells Inhibits T-cell proliferation; reduces production of inflammatory cytokines; and promotes B-cell proliferation and antibody secretion

Interleukin 12 (IL-12) Monocytes and macrophages Activates NK cells; activates a subtype of T cells (i.e., CD4 T cells); and induces the cell- mediated (i.e., Th1) immune response

Transforming beta Macrophages and T cells Inhibits T-cell proliferation; reduces production (TGF-β) of inflammatory cytokines; augments B-cell proliferation and antibody secretion; and promotes collagen production

Chemokines

Interleukin 8 (IL-8) Macrophages Attracts neutrophils to the site of an infection

Lymphokines

Interferon gamma (IFN-γ) T cells Induces protection against viral infection; stimulates macrophages and neutrophils; enhances expression of major histocom- patibility complex (MHC) proteins on many cells; and promotes B-cell and T-cell differentiation

Interleukin 2 (IL-2) T cells Stimulates proliferation of T cells; enhances activity of NK cells; and stimulates B-cell proliferation and antibody production

Interleukin 4 (IL-4) A subtype of T cells (i.e., CD4 T cells) Stimulates T-cell growth; induces B-cell activation and growth; and modulates antibody production by B cells

32 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and Compromised Immunity

with certain of their own proteins B cells. Alcohol can interfere with Increased known as major histocompatibility both phases of the immune response. even occurred in rats that received a complex (MHC) proteins. In addition one-time alcohol injection. In contrast, to the phagocytes, proteins of the com- Alcohol’s Effects on the chemotaxis decreased plement system also recognize the in- Inflammatory Response under the same conditions. These vading bacteria and bind to proteins on results suggest that alcohol can differ- the bacterial surface. This binding trig- Effects on Phagocytic Cells. During entially affect the functions of various gers several biochemical processes an inflammatory response, chemical phagocytic cell types. Studies with that eventually lead to the destruction substances released by cells at the site cultured human cells, however, of the bacteria. of the infection induce phagocytes to demonstrated decreased neutrophil T cells circulating in the blood migrate from their normal locations chemotaxis after the cells were ex- recognize phagocytes simultaneously in the bloodstream or the tissues to posed to alcohol. displaying antigens and MHC proteins. the site of the inflammation. This Chronic as well as acute alcohol The T cells bind to the - process is called chemotaxis. Various consumption also reduces the ability bound antigens through the help of substances can serve as chemotactic of phagocytes to ingest and break docking molecules, called T-cell re- agents, including activated compo- down pathogenic bacteria. For exam- ceptors. The activated T cells multiply nents of the , a ple, cultured human monocytes ex- and begin secreting cytokines, which, group of white -derived posed to alcohol showed reduced in turn, activate cytotoxic T cells that proteins called , and other phagocytic functions; moreover, the can then recognize, bind to, and de- proteins produced by immune cells cells produced less of a receptor pro- stroy cells infected by the invading (i.e., , such as interleukin- tein that is required for the ingestion bacteria. 8 [IL-8]). The neutrophils and mono- of antibody-coated particles. In mice, Parallel to the T-cell response, the cytes recruited from the bloodstream both short-term and long-term alcohol B cells mount another line of defense must adhere to and migrate through feeding reduced the phagocytic ability against the invading bacteria. Thus, the cell layer lining the blood vessels of macrophages residing in the mem- antibodies on the B-cell surface recog- at the site of the infection, ingest the brane lining the abdominal cavity. nize and bind to antigens on the bacte- microorganisms, and destroy the in- Thus, abnormal neutrophil adherence rial surface. This binding activates the gested pathogens using specific en- and chemotaxis, as well as reduced B cells, which then differentiate into zymes or toxic, oxygen-derived free phagocytic function of macrophages, plasma cells that secrete large amounts radicals. may contribute to the impaired de- of antibodies. The antibodies are dis- Alcohol can affect this sequence of fense against microorganisms ob- tributed throughout the bloodstream events at several levels. Alcohol’s served after alcohol consumption. and bind to the bacteria wherever they effects on phagocyte adhesion to the encounter them, aided by proteins of blood-vessel walls and chemotaxis Effects on Inflammatory Cytokines. the complement system. The antibody- were studied in chronically alcohol- Phagocyte contact with pathogens covered bacteria clump together and fed rats. Neutrophils from these ani- induces the release of cytokines by the become new targets for monocytes and mals exhibited increased levels of phagocytes that help initiate and other phagocytes. CD18 molecules on their surface, maintain the inflammatory response which are required for adhesion. and thus play a pivotal role in the Furthermore, chemokines (e.g., IL-8) body’s immune defense. The most ALCOHOL’S EFFECTS ON THE secreted by macrophages residing in common inflammatory cytokines— IMMUNE DEFENSE the liver (i.e., Kupffer cells) of the alpha (TNF-α), The body’s response to an invading alcohol-fed rats increased the chemo- IL-1, and IL-6—are primarily pro- pathogen can be divided into two taxis of normal neutrophils. Increased duced by monocytes and macrophages phases. The first phase is an inflam- infiltration of neutrophils into the (see figure). During an overwhelming matory reaction, which protects the liver, in turn, can lead to liver injury. inflammatory response, however, body from the immediate effects of Thus, an alcohol-induced increase in neutrophils, lymphocytes, and other the infection. The inflammatory re- production by Kupffer tissue cells also can be sources of in- sponse primarily involves phagocytic cells may lead to neutrophil accumu- flammatory cytokines. Excessive lev- cells that help eliminate the pathogen, lation and thus to liver damage (e.g., els of these cytokines may cause cytokines secreted mainly by these alcoholic ). This hypothesis is tissue damage, whereas reduced levels phagocytes, and other molecules (e.g., consistent with observations that in may result in an insufficient immune oxygen radicals) that assist in killing patients with acute alcoholic hepatitis, response. the pathogen. The second phase, the IL-8 levels in the blood are elevated In chronic alcohol abusers, particu- development of immunity to the and may be associated with neutrophil larly those with alcoholic liver dis- pathogen, is mediated by T cells and accumulation in the liver. ease, the levels of TNF-α, IL-1, and

VOL. 21, NO. 1, 1997 33 rial antigens and thus may interfere with the normal interaction of the cell- mediated and humoral immunities. Immunoregulatory Inflammatory The other controlling cytokines cytokines (e.g., TGF-β, IL-10) α inflammatory reactions and T-cell (e.g., TNF- , β IL-1, IL-6) proliferation is TGF- . In experiments using cultured monocytes, physio- logically relevant alcohol concentra- tions2 activated both the baseline and the bacterial antigen-induced TGF-β T-cell β activating production. Elevated TGF- levels Chemokines cytokines may have multiple implications for (e.g., IL-8) (e.g., IL-12) immune-system functioning, includ- ing inhibition of inflammatory cyto- kine production by monocytes and Other factors (e.g., proteins Antibacterial compounds other cells, inhibition of T-cell prolif- involved in blood clotting, (e.g., oxygen radicals, nitric oxide) eration, and augmentation of the proteins stimulating the humoral immune response. As a re- growth of other cells) sult, the drinker becomes more sus- ceptible to infections and exhibits decreased immune system activity in /-derived substances potentially affected by alcohol. Mono- eliminating infections. In addition, cytes and macrophages produce numerous substances that initiate and regulate β inflammatory reactions; attract other immune cells (i.e., chemokines); stimulate T elevated TGF- levels promote colla- cells; help in the elimination of pathogens, such as bacteria; and perform other gen production. Collagen molecules functions throughout the body. Alcohol may interfere with the production and se- normally form the fibers making up cretion of all these substances, thereby impairing the body’s immune response. tendons and ligaments. However, excessive collagen production result- β α IL = interleukin; TGF- = transforming growth factor beta; TNF- = tumor necrosis factor alpha. ing from alcohol-induced TGF-β may result in abnormal collagen deposits IL-6 in the blood are significantly fense against microorganisms, im- in the liver that have been implicated elevated. These increased cytokine paired inflammatory cytokine produc- in the development of some types of levels may contribute to most of the tion after acute alcohol exposure . signs and symptoms observed in pa- significantly compromises the body’s Alcohol also increases the produc- tients with alcoholic hepatitis (e.g., defense system. tion of nonprotein regulatory generally increased metabolism, fever, molecules that inhibit the antigen- weight loss, elevated levels of pro- Effects on Immunoregulatory presenting capacity of monocytes, teins produced in the liver, and mark- Cytokines. The initial inflammatory inflammatory cytokine production, ers of malnutrition). It is unknown, response to pathogens normally is and T-cell proliferation. however, which cells cause the eleva- turned off by regulatory cytokines By increasing the levels of these ted inflammatory cytokine production whose production typically is induced substances as well as of IL-10 and β in alcoholics. in a later phase of the infection. The TGF- , alcohol can interfere with Acute, moderate alcohol consump- most studied immunoregulatory cy- the body’s normal defense against tion, in contrast, transiently reduces tokines are IL-10 and transforming invading microorganisms in two the pathogen-induced production of growth factor beta (TGF-β), both of ways: by reducing inflammatory- inflammatory cytokines. For example, which are produced by macrophages cytokine production and by inhibit- cultured human monocytes exposed to and T cells. IL-10 promotes humoral ing T-cell proliferation. alcohol before being stimulated with immunity and inhibits cell-mediated various bacterial antigens produced immunity by reducing the production 2 lower-than-normal levels of TNF-α, of several cytokines, including inflam- The alcohol concentrations used in these α experiments were 10 to 100 millimoles per liter IL-1, and IL-6. Similarly, the TNF- matory cytokines, and by preventing (mmol/L). Concentrations of 25 mmol/L levels produced in response to a chal- the multiplication (i.e., proliferation) approximate blood alcohol levels of 0.1 per- lenge with a bacterial antigen were of T cells. Acute alcohol exposure cent, the legal limit for driving in many States. decreased in mice that had received a increases IL-10 production in cultured Concentrations of 100 mmol/L correspond to blood alcohol levels of approximately 0.4 single dose of alcohol. Considering human monocytes both in the absence percent, which are sometimes seen in alco- the pivotal role of TNF-α in the de- and presence of stimulation by bacte- holics after acute alcohol consumption.

34 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and Compromised Immunity

Effects on Oxygen-Radical Production. cells in the blood, in the —the reduced T-cell proliferation, accom- Oxygen radicals (e.g., superoxide anions gland where T cells mature—and in panied by an enhanced humoral im- and hydrogen peroxide) are unstable the spleen, where immune reactions munity marked by increased antibody oxygen-containing molecules that are initiated. The mechanism underly- levels. This shift in the immune re- readily interact with other molecules ing the alcohol-induced decrease in T- sponse likely impairs the body’s defense in a cell. Oxygen radicals produced by cell numbers still is unknown. Some against bacterial infections requiring a macrophages and other phagocytes researchers have suggested that acute predominantly cell-mediated immune play a crucial role in destroying micro- alcohol exposure induces programmed response, such as infections with M. organisms, especially in the lungs. cell death, or apoptosis, in immature T tuberculosis or Listeria monocytogenes, Researchers found that macrophages cells in the thymus. Acute alcohol which are discussed in the section in the lungs of acutely or chronically exposure also results in increased “Consequences of Alcohol’s Effects on alcohol-fed rats produced fewer super- apoptosis of mature lymphocytes and the Immune System.” Alcohol’s effects oxide anions and less hydrogen per- monocytes in the blood. on the antibody-producing B cells is oxide than did macrophages from Alcohol also may reduce the ability discussed in more detail in the follow- non-alcohol-exposed rats. Further- of lymphocytes to proliferate and differ- ing section. more, the lung macrophages produced entiate adequately after they have been and secreted less nitric oxide, another activated by an antigen. Moreover, the Effects on B Cells. A characteristic molecule with characteristics and number and function of delayed-type immune-system aberration observed in functions similar to those of oxygen hypersensitivity T cells is reduced in alcoholics is the elevation of antibody radicals. The alcohol-induced decreas- alcoholics. As a result, the immune levels in the blood. Similarly, acute es in the macrophages’ production of response to certain antigens and infec- alcohol consumption in mice increased oxygen radicals and nitric oxide could tions is depressed. How alcohol affects antibody production in response to undermine the body’s defense against T-cell proliferation is not well under- certain chemical substances. Because bacteria. This mechanism could con- stood. In chronically alcohol-fed rats, antibodies are produced by B cells, tribute to the high incidence of tuber- the T cells fail to proliferate adequately these observations indicate that alcohol culosis in alcoholics. (For more in response to stimulation by IL-2. The alters either the number or function of information on the association of results of other investigations imply B cells. To date, conflicting results alcohol use and tuberculosis, see side- that decreased T-cell proliferation may exist regarding these two alternatives. bar, pp. 39Ð41.) be a consequence of the impaired Thus, clinical studies in humans found Alcohol-induced overproduction of function of accessory cells (e.g., anti- that the absolute number of B cells did oxygen radicals in the liver, in con- gen-presenting cells) after alcohol use. not differ between alcoholics and non- trast, may contribute to the develop- For example, the interaction of T cells alcoholics, but that B-cell functioning ment of alcoholic liver damage. In rats with antigen-presenting monocytes or appeared to be altered in alcoholics. In that received alcohol infusions for 1, 3, macrophages requires the presence of contrast, in mice that had been fed or 5 hours, for example, the Kupffer several proteins on the surfaces of both alcohol for 14 days, the number of B cells in the liver produced and secreted the T cells and the antigen-presenting cells in the spleen had decreased five- increased levels of superoxide anions, cells (e.g., T-cell receptors and MHC fold. Equally contradictory were the whether or not the cells were activated molecules). The production of some findings regarding B-cell functioning: by contact with pathogens. Together, of these proteins also is altered in Whereas clinical studies demonstrated these observations imply that alcohol alcohol-exposed cells. Finally, reduced elevated antibody levels in alcoholics, may have a dual negative effect on the T-cell proliferation may be attributed tissue-culture experiments to investi- body’s oxygen-radical production. to the increased production of immuno- gate these observations found that First, alcohol may inhibit oxygen- regulatory cytokines (e.g., IL-10 and alcohol inhibited the B-cells’ antibody radical and nitric oxide production in β macrophages in the lung, where these TGF- ) caused by alcohol. secretion. substances are essential for killing Overall, the effects of both acute One possible explanation for these microorganisms. Second, alcohol may and chronic alcohol exposure result in conflicting findings is that alcohol inter- increase oxygen-radical production in a weakened cell-mediated immune feres only with some aspects of B-cell the liver, where these molecules may response. Several diseases are char- functioning. For example, B cells do cause tissue damage. acterized by a reduction in the cell- not respond to all antigens in the same mediated immunity and a concomitant manner. In response to some antigens, Alcohol’s Effects on Immunity increase in the humoral immunity. B cells require the assistance of cy- Similarly, the immunological abnor- tokines secreted by T cells (i.e., T- Effects on T Cells. Alcoholics and malities observed after both chronic cellÐdependent responses), whereas in laboratory animals chronically ingest- and acute alcohol consumption appear response to other antigens, T-cell acti- ing alcohol have lower-than-normal to be consistent with a decreased cell- vation is not required (i.e., T-cellÐinde- numbers of all subpopulations of T mediated immunity characterized by pendent responses). Alcohol appears to

VOL. 21, NO. 1, 1997 35 affect these responses differently, vival of certain T-cell subpopulations. coccal pneumonia compared with the because B cells in the of alco- Although alcohol in tissue culture general population, and despite the use hol-consuming animals showed im- experiments had no effect on the abili- of , the mortality among paired proliferation during a T-cellÐ ty of T cells to produce IL-2, it likely these patients remains disturbingly dependent response but normal prolif- interferes with the T-cell response to high (15 to 77 percent). Researchers eration during a T-cellÐindependent IL-2. The potential intracellular mecha- have used mice to study some of the response. Similarly, alcoholics exhibit- nisms underlying these effects, how- mechanisms underlying the increased ed an intact T-cellÐindependent anti- ever, remain unknown. susceptibility to infections by infect- body response after administration of a Alcoholics exhibit decreased blood ing the animals with Listeria monocy- specific antigen. Thus, alcohol may levels of IFN-α, IFN-γ, and IL-2.3 In togenes, a bacterium that among other interfere with antibody production particular, the reduction of IFN-γ levels symptoms, causes liver damage in the indirectly by inhibiting the production may be a key element underlying many animals. Mice that received an alcohol- of certain T-cellÐderived cytokines of the immune alterations observed in containing diet for 7 days before be- required for B-cell function. The com- alcoholics because this cytokine, in ing infected with Listeria developed plexity of alcohol’s effects on B cells is concert with the macrophage-derived greater liver damage than control underscored further by findings that IL-12, is crucial for induction of the animals that had received no alcohol. alcohol impairs B-cell proliferation in cell-mediated immune response. Conse- Although the alcohol treatment did not response to the T-cellÐderived cytokine quently, in the absence of appropriate impair the migration of phagocytes to IL-4 but not in response to the T-cell- IFN-γ stimulation in alcoholics, a the liver, it did impair the animals’ derived cytokine IL-2. preferential induction of the humoral ability to inhibit Listeria growth. Thus, immune response could occur. The even alcohol-fed mice that should have Effects on Natural Killer Cells. NK accompanying lack of an appropriate been able to stave off the infection, cells are a type of white blood cell cell-mediated immune response would because they had previously been im- involved in the destruction of virus- make the alcoholics more susceptible munized with Listeria, had 100 times infected and cancerous cells. Conse- to infections that require a T-cell re- more Listeria organisms in their livers γ quently, NK cells play an important sponse. Furthermore, decreased IFN- than did nonalcohol-treated controls. role in preventing tumor development. levels likely contribute to additional The body’s anti-Listeria defense is Chronic alcohol consumption is asso- cytokine abnormalities (e.g., altered largely T-cell dependent and requires ciated with increased incidence of IL-12 levels), thereby further impair- interactions between specific antigens, tumors, suggesting that NK cell activ- ing the cell-mediated immune response. T cells, and phagocytic cells as well as ity may be impaired. In laboratory IFN-γ and IL-12 induction. However, animals, chronic alcohol administra- the exact roles of alcohol-induced aber- CONSEQUENCES OF ALCOHOL’S tion reduced the number and activity rations in immune-cell interactions, EFFECTS ON THE IMMUNE SYSTEM of NK cells. Tissue-culture experi- antigen-presenting cell function, and ments, in contrast, produced conflict- IFN-γ and/or IL-12 production remain ing results, demonstrating that alcohol Increased Susceptibility to to be determined. had either an inhibitory effect or no Bacterial Infections Alcohol use also impairs the body’s effect on NK cell activity. Finally, defense against pathogens infecting the acute alcohol consumption temporari- Alcoholics are considered “immuno- lungs, such as pneumonia-causing bacte- ly reduced the ability of rats to elimi- compromised hosts” because the inci- ria (e.g., pneumococci, Klebsiella pneu- nate certain tumor cells and prevent dence and severity of infections are moniae, and Legionella pneumophila) the development of tumor metastases. increased in these patients. Infections and M. tuberculosis. For example, in rats with pathogens that reside within the infected with pneumococci, the animals’ Effects on Cytokines. Cytokines pro- host’s cells and cause diseases such as susceptibility to lethal pneumonia in- duced by lymphocytes (i.e., lympho- pneumonia or tuberculosis are espe- creased if they received alcohol for 1 kines, such as IL’s and cially prevalent. Thus, alcoholics have week before the infection. Moreover, the [IFN’s]) regulate the functions of an increased incidence of pneumo- alcohol-fed rats experienced an increased immune cells as well as nonimmune spread of the pneumococci from the cells (e.g., nerve cells and cells of 3The discrepant observations that alcohol did lungs through the bloodstream compared not affect the cells’ ability to produce IL-2 in hormone-producing organs). The tissue culture experiments, whereas alcoholics with non-alcohol-treated rats and also effects of either chronic or acute alco- show decreased IL-2 levels in the blood likely failed to eliminate the pneumococci from hol use on cytokine production and can be attributed to the fact that tissue culture the blood. Other studies investigating function, however, are only partially experiments monitor the consequences of acute alcohol’s effects on the susceptibility to alcohol exposure, but the findings in alcoholics understood. IL-2 is one of the most reflect the effects of chronic alcohol exposure. infections with Klebsiella pneumoniae important T-cellÐproduced cytokines; However, this hypothesis has not been investi- and Legionella pneumophila indicated it promotes the proliferation and sur- gated in detail. that chronic alcohol treatment suppressed

36 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and Compromised Immunity

the production and/or function of neu- Current knowledge strongly sug- tant role in this process. Thus, acute trophils and macrophages. Moreover, gests that alcohol use—potentially alcohol consumption before sustaining treatment with a protein factor that stimu- both acute and chronic—can increase a traumatic injury can affect a patient’s lates neutrophil production ameliorated a person’s susceptibility to HIV infec- TNF-α production and immunosup- the alcohol-induced tion and contribute to alterations in pression after the injury as follows: by recruiting more neutrophils to the the immune system that may result in ¥ Within 0 to 3 days after the injury, lungs. an accelerated progression of the α infection. However, further research is TNF- production in the mono- cytes decreases in patients whose Increased Susceptibility to HIV needed to elucidate the mechanism by which alcohol may modulate the biol- blood alcohol levels exceed 0.1 The relationship between alcohol use ogy of HIV infection. In addition to percent at emergency-room admis- and susceptibility to infections with the its biological effects, alcohol use may sion, but increases in patients who human virus (HIV), increase the risk of HIV infection by have not consumed alcohol before which causes acquired immune defi- modifying the drinker’s behavior. For sustaining the injury. ciency syndrome (AIDS), is an actively example, factors such as increased ¥ Later during the posttrauma period evolving area of research. Although risk taking and uninhibited sexual (i.e., more than 6 days after the ample data are available on the immu- behavior, which are associated with injury), the monocytes of alcohol- nological abnormalities caused by both acute and chronic alcohol use, consuming trauma patients produce alcohol use and HIV infection, respec- can contribute to an increased risk for higher TNF-α levels than the mono- tively, knowledge concerning their HIV infection. cytes of non-alcohol-consuming combined immunosuppressive effects trauma patients. is more limited. Some researchers Consequences of Traumatic α have proposed that alcohol’s modula- Injuries ¥ The increase in TNF- production tory effects on the immune system coincides with the development of may increase the risk of initial HIV Traumatic injuries frequently are asso- posttraumatic immunosuppression, infection as well as accelerate the ciated with severe suppression of the suggesting that acute alcohol con- infection’s progression. Although this immune system, which can lead to over- sumption before sustaining major hypothesis still awaits formal confir- whelming infections and may result in injuries increases the severity of mation, several findings support alco- multiple failure and even death. the immunosuppression. Alcohol intoxication not only increas- hol’s proposed influence. For example, es the risk of sustaining traumatic one study found that HIV multiplied injuries (e.g., in motor vehicle acci- CONCLUSIONS AND FUTURE faster in blood cells isolated from binge dents) but also may exacerbate trauma- DIRECTIONS drinkers or subjects who had received induced immunosuppression. Thus, an acute alcohol dose than in cells from one study found that acutely intoxicat- Numerous research efforts have con- people who had not been exposed to ed patients (i.e., those with blood firmed that both acute and chronic alcohol (Bagasra et al. 1996). More- alcohol levels greater than 0.2 percent) alcohol use have profound regulatory over, a case report of an HIV-infected who had sustained severe abdominal effects on the immune system. Studies person demonstrated that the HIV injuries had a 2.6 times greater inci- in laboratory animals and in humans infection progressed rapidly and that dence of infections than did patients have demonstrated that even acute, the patient developed full-blown who had not consumed alcohol (Gen- moderate alcohol consumption can AIDS after initiating heavy alcohol tilello et al. 1993). Moreover, rats that impair the body’s defense against use (Fong et al. 1994). Finally, a study had received alcohol before sustaining bacteria and viruses, although these of HIV-positive intravenous drug severe burn injuries exhibited a signifi- effects are likely only transient. The users found that whereas alcohol use cantly impaired cell-mediated immunity clinical implications of such a transient did not affect the proportion in the accompanied by an increased humoral immunodepression still need to be blood of the T-cell subpopulation that immunity (i.e., elevated antibody pro- studied further. For certain types of is the target of HIV infection, alcohol duction). Such an alcohol-related mod- infections (e.g., HIV and mycobacte- use did correlate with increases in the ification of the immune system after ria), however, the failure of an appro- proportion of another T-cell subpopu- sustaining a traumatic injury could priate initial immune response to lation several years after the initial increase the patient’s risk of infections pathogens can have profound and po- infection (Crum et al. 1996). Although and prolong the trauma-related sup- tentially prolonged effects on the im- the clinical significance of this obser- pression of the immune system. mune system and the drinker’s health. vation is still unclear, the findings The mechanism underlying trauma- Researchers and clinicians are gain- suggest that alcohol consumption may induced immunosuppression has not ing further insight into the complex exacerbate HIV-induced changes in yet been identified. However, the cy- mechanisms and consequences of the immune system. tokine TNF-α clearly plays an impor- immunosuppression in chronic alco-

VOL. 21, NO. 1, 1997 37 holics. It is important, however, to BAGASRA, O.; BACHMAN, S.E.; JEW, L.; TAWA- JERRELS, T.; SAAD, A.J.; AND KRUGER, T.E. dissect the effects caused by the body’s DROS, R.; CATER, J.; BODEN, G.; RYAN, I.; AND Ethanol-induced suppression of in vivo host POMERANTS, R.J. Increased HIV type-1 replication defense mechanisms to bacterial infection. In: chronic exposure to alcohol itself and in human peripheral blood mononuclear cells Friedman, H.; Klein, T.W.; and Specter, S., eds. the effects of other alcohol-related induced by ethanol: Potential immunopathogenic Drugs of Abuse, Immunity, and AIDS. Vol. 335. immunomodulatory conditions, such as mechanisms. Journal of Infectious Diseases New York: Plenum Press, 1993. pp. 153Ð158. 173:550Ð558, 1996. malnutrition, vitamin deficiencies, and KHORUTS, A.; STAHNKE, L.; MCCLAIN, C.J.; alcoholic liver disease. Moreover, a BAUTISTA, A.P. Chronic alcohol intoxication LOGAN, G.; AND ALLEN, J.I. Circulating tumor better understanding of the specific induces hepatic injury through enhanced macro- necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. immune system alterations caused by phage inflammatory protein-2 (MIP-2) produc- tion and intracellular adhesion melocule Hepatology 13:267Ð276, 1991. chronic alcohol consumption is neces- expression in the liver. Hepatology 25:335Ð342, KRUGER, T.E., AND JERRELS, T.R. Potential role sary for designing effective therapeutic 1997. of alcohol in human immunodeficiency virus approaches to ameliorating immuno- BEN-ELIYAHU, S.; PAGE, G.G.; YIRMIYA, R.; infection. Alcohol Health & Research World 16:57Ð63, 1992. suppression in chronic alcoholics. AND TAYLOR, A.N. Acute alcohol intoxication Researchers also are investigating suppresses activity and pro- MANDREKAR, P.; CATALANO, D.; AND SZABO, G. the mechanisms underlying the differ- motes tumor metastasis. Nature Medicine 2: Human monocyte IL-10 production is increased ential effects of chronic and acute 457Ð460, 1996. by acute ethanol treatment. Cytokines 8:567Ð 577, 1996. alcohol use on the immune system. CRUM, R.M.; DALAI, N.; COHN, S.; CELENTANO, For example, the increased levels of D.D.; AND VLAHOV, D. Alcohol use and T NELSON, S.; SHELLITO, J.; MASON, C.; AND SUM- subsets among injection drug users MER, W. Alcohol and bacterial pneumonia. Al- inflammatory cytokines observed in with HIV-1 infection: A prospective analysis. cohol Health & Research World 16:73Ð86, 1992. alcoholics contrast with the decreased : Clinical and Experimental inflammatory response seen after Research 20:364Ð371, 1996. ROSELLE, G.A. Alcohol and the immune system. Alcohol Health & Research World 16:16Ð22, acute alcohol treatment. Finally, addi- DAVIS, C.C.; MELLENCAMP, M.; AND PREHEIM, 1992. tional research is needed to delineate L. A model of pneumococcal pneumonia in some of the intracellular signaling chronically intoxicated rats. Journal of Infec- SAAD, A.J.; DOMIATI-SAAD, R.; AND JERRELS, T. tious Diseases 163:799Ð805, 1991. Ethanol ingestion increases susceptibility of mice events in immune cells that are affect- to Listeria monocytogenes. Alcoholism: Clinical ed by acute and chronic alcohol use in DEVIERE, J.; CONTENT, J.; DENYS, C.; VANDEN- and Experimental Research 17:75Ð85, 1993. BUSSCHE, L.; SCHANDENE, J.; WYBRAN, E., AND order to better understand alcohol’s SPITZER, J., AND BAUTISTA, A. Alcohol, cy- DUPONT, E. High IL-6 levels and in- tokines and immunodeficiency. In: Friedman, regulatory effects on the complex creased production by leukocytes in alcoholic H.; Klein, T.W.; and Specter, S., eds. Drugs of interactions of the immune system. liver cirrhosis. Correlation with IgA serum Abuse, Immunity, and AIDS. New York: Ple- levels and production. Clinical and num Press, 1993. pp. 159Ð164. Experimental Immunology 77:221Ð225, 1989. EDITORIAL NOTE SZABO, G.; MANDREKAR, P.; AND CATALANO, D. FONG, I.W.; READ, S.; WAINBERG, M.A.; CHIA, Inhibition of -induced T-cell W.K.; AND MAJOR, C. Alcoholism and rapid This article is accompanied by a proliferation and monocyte IL-1β, TNF and IL- progression to AIDS after seroconversion. 6 production by acute ethanol. Journal of Leuk- “Suggested Reading” list that in- Clinics of Infectious Diseases 19:337Ð338, 1994. ocyte Biology 58:342Ð350, 1995. cludes only key references. A com- GENTILELLO, L.M.; COBEAN, R.A.; WALKER, plete bibliography of sources SZABO, G.; MANDREKAR, P.; VERMA, B.; AND A.P.; MOORE, E.E.; WERTZ, M.J.; AND CATALANO, D. Acute ethanol uptake prior to consulted is available from the au- DELLINGER, E.P. Acute ethanol intoxication injury modulates monocyte TNFα production thor. increases the risk of infections following pene- and mononuclear cell apoptosis. In: Faist, E., ed. trating abdominal trauma. Journal of Trauma Immune Consequences of Trauma and . 34:669Ð675, 1993. Berlin: Springer-Verlag, 1996. pp 252Ð260.

SUGGESTED READING JERRELS, T., AND SIBLEY, D. Effects of ethanol VICENTE-GUTIERREZ, M.M.; RUIZ, A.D.; on T-cell-mediated immunity to infectious EXTREMERA, B.G.; GARCIA, J.M.B.; AND GEA, ALDO-BENSON, M.; PRATT, L.; AND HARDWICK, agents. In: Friedman, H.; Klein, T.W.; and F.G. Low serum levels of alpha-interferon, J. Alcohol can inhibit effect of IL-4 on activated Specter, S., eds. Drugs of Abuse, Immunity and gamma-interferon, and interleukin-2 in alcoholic murine B cells. Immunology Research 11:117Ð Infections. Boca Raton: CRC Press, 1996. pp. cirrhosis. Digestive Disease Sciences 36:1209Ð 124, 1992. 129Ð141. 1212, 1991.

38 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and Compromised Immunity

ALCOHOL AND SUSCEPTIBILITY TO TUBERCULOSIS

Worldwide, tuberculosis (TB) is the leading cause of death Because alcohol use significantly inhibits cell-mediated from a single infectious agent (Flynn and Bloom 1996). immunity, it compromises the body’s immune defense. Mycobacterium tuberculosis, the agent responsible for TB, Thus, alcoholism—along with other diseases associated is transmitted when a person inhales microscopic airborne with impaired cell-mediated immunity (e.g., HIV infec- particles containing the organism (i.e., “droplet nuclei”) tion)—increases a person’s susceptibility to active TB coughed up by someone with active TB disease, although infection as well as reactivation of latent disease (Flynn prolonged exposure usually is necessary before an infec- and Bloom 1996). Researchers do not know, however, tion becomes established. Initially M. tuberculosis attacks whether alcohol consumption itself or the liver damage and the lung, where immune cells (i.e., macrophages and lym- malnutrition often associated with alcoholism are primarily phocytes) battle the infection. In the absence of adequate responsible for the impaired immunity of alcoholics. immunity, however, the bacteria ingested by macrophages Investigators studying mechanisms by which alcohol continue to multiply within these immune cells, and char- predisposes people to TB recently have focused special acteristic lesions called tubercles eventually form in the lungs. attention on the specific immune system components Among other symptoms, people with active TB develop a participating in the body’s defense against M. tuberculosis bloody cough, fatigue, and difficulty breathing. TB can and related mycobacteria. Alcohol use has been found to affect any or develop into systemic infection hinder the body’s antimycobacterial defense on multiple (i.e., miliary TB) when infected cells spread from the lungs levels, including through impaired macrophage response, and disseminate through the bloodstream. No effective altered levels of the proteins that act as intercellular medi- vaccination against TB currently exists, but 6 to 9 months ators (i.e., cytokines), and a disturbed balance between the of treatment with multiple antituberculous drugs will cure two basic types of acquired immunity: cell-mediated im- most TB patients who complete the course of . munity and immunity provided by circulating antibodies Sociological studies show that TB is more prevalent in (i.e., humoral immunity). Each of these interrelated conse- low-income, densely populated housing areas—settings quences is discussed in the sections that follow. often associated with high rates of alcoholism.1 Numerous studies also have noted a direct association Impaired Macrophage Response. Macrophage activation between alcoholism and pulmonary tuberculosis is considered essential for local containment and destruc- (Jacobson 1992). Such apparent susceptibility to TB tion of mycobacteria (including M. tuberculosis) and infection among alcoholics, especially those who are other invasive microorganisms. Thus, macrophage activi- homeless or indigent, can be attributed both to biological ty is the hallmark of resistance to TB (Flynn and Bloom and to social and behavioral factors. 1996). These immune system cells (along with the mono- cytes that give rise to them) play a key role in directly Biological Factors “presenting” the chemical identifiers that stimulate an Although approximately one-third of the world’s popula- immune response (i.e., the antigens) to lymphocytes in tion is infected with M. tuberculosis, only about 10 percent the body’s lymph tissue. In response to antigen presenta- will experience either acute or reactivated disease (Flynn tion, certain lymphocytes (i.e., T lymphocytes) develop and Bloom 1996). Clearly, the body’s immune system is into T cells that specifically target the M. tuberculosis quite capable of controlling M. tuberculosis in most cases. organism for destruction. These T cells rapidly multiply Any illness or condition associated with an impaired im- and circulate throughout the body. Evidence from several mune system, however, can increase the likelihood of laboratories suggests that activation of two types of T developing active TB. In particular, numerous animal cells in particular (i.e., CD4 and CD8 T cells) is impor- studies have confirmed that the body’s control of M. tuber- tant in the control of mycobacterial infection (Flynn et al. culosis infection resides in its ability to mobilize macro- 1992; Kaufmann and Flesch 1986; Leveton et al. 1989; phages and lymphocytes against invading organisms (i.e., Orme and Collins 1983, 1984; Flory et al. 1992). cell-mediated immunity) (Dunlap and Briles 1993). Although alcohol likely affects many immune system cells, macrophages and monocytes appear to be particularly 1The terms “alcoholism” and “alcoholic” as used in this article are sensitive to its influences. Both acute and chronic alcohol use summary terms for the diagnoses of alcohol abuse and alcoholism. may decrease the activation of antigen-specific T cells by 2Compared with M. tuberculosis, MAC is a less invasive infectious inhibiting the macrophages’ capacity to present mycobacterial agent, but it has been associated with both pulmonary and disseminated antigen to lymphocytes (Szabo et al. 1993). Bermudez and disease in people with compromised immune systems (e.g., alcoholics Young (1991) have shown that alcohol also enhances the or people with AIDS), just as TB has. The pathology and cell-mediated survival of another pathogen (i.e., the Mycobacterium avium immune mechanisms involved in the body’s defense against MAC are 2 similar to those seen in M. tuberculosis infection, making research on complex, or MAC ) within blood-derived macrophages in this agent relevant to an understanding of TB control. people and liver macrophages (i.e., Kupffer cells) in mice.

VOL. 21, NO. 1, 1997 39 The same study demonstrated an increase in MAC colony 10). IL-12 enhances the activity of CD4 and CD8 T cells, counts in the blood, liver, and spleen of alcohol-fed mice as well as natural killer cells, and triggers a cell-mediated compared with controls, suggesting that alcohol use prior to immune response; elevated levels of IL-10, however, and during MAC infection contributes to dissemination of inhibit production of IL-12 and other inflammatory cy- the disease in the body. tokines. In recent studies of isolated human monocytes In addition to decreasing the antimycobacterial activi- exposed to alcohol, researchers have observed elevated ty of macrophages, alcohol consumption also reduces IL-10 levels, inhibition of IL-12, increased production of macrophage response to immune system modifiers. For other mediators that check the immune system (e.g., example, the cytokines known as tumor necrosis factor transforming growth factor beta [TGF-β]), and a reduced alpha (TNF-α) and -macrophage colony- antigen-presenting capacity (Szabo et al. 1993, 1996; stimulating factor (GM-CSF) both have been shown to Mandrekar et al. 1996). All of these effects imply that induce macrophages to inhibit the growth of and destroy acute alcohol consumption impairs a cell-mediated (i.e., mycobacteria. In vitro studies suggest that alcohol im- Th1-type) immune response and consequently tilts the pedes the protective effect exerted by these cytokines, balance of the immune system toward humoral (i.e., Th2- however (Bermudez and Young 1991). type) immune functions. Given the importance of cell- mediated immunity in overcoming TB infection, the Altered Cytokine Levels. TNF-α, one of the inflammatory implications of this shift can be significant for alcoholics mediators derived primarily from macrophages, plays a exposed to M. tuberculosis. major role in antimycobacterial defense (Nelson et al. 1995; Researchers also have found, however, that the cy- Flynn and Bloom 1996). This cytokine directly inhibits tokine gamma-interferon (IFN-γ) plays a critical role in mycobacterial growth in vitro, recruits additional inflamma- determining whether a Th1- or Th2-type response will tory cells, and induces the action of other antimycobacterial dominate in alcohol-exposed monocytes. Recent studies mediators (e.g., nitric oxide and reactive oxygen radicals). showed that the presence of IFN-γ decreased alcohol- One of the most dramatic effects of both acute and induced IL-10 production, thus canceling IL-10’s inhibi- chronic alcohol use is the impaired capacity of monocytes tion of IL-12 and thereby augmenting cell-mediated (i.e., to produce cytokines that trigger inflammation, particularly Th1-type) immunity (Mandrekar et al. 1996; Szabo et al. TNF-α, in response to bacterial or mycobacterial infection. 1996). This finding supports the demonstration by Flynn In a study with rats, Nelson and colleagues (1989) found and Bloom (1996) that IFN-γ is essential to resistance that the immune cells first to be exposed to mycobacteria against TB in mice. Vicente-Gutierrez and colleagues γ (i.e., macrophages in the alveoli of the lungs) showed a (1991) have reported decreased IFN- in chronic alco- γ reduced capacity to manufacture TNF-α following both holics, indicating that suppressed IFN- levels in alco- chronic and acute alcohol consumption, an effect that holics likely contribute to an impaired cell-mediated likely would contribute to a compromised immune defense immune response during mycobacterial infection. against TB. Of interest, Denis (1991) found that TNF-α Taken together, both acute and chronic alcohol use had a beneficial effect on survival when it was infused into have been shown to predispose the body to compromised mice inoculated with M. tuberculosis, suggesting that defense against mycobacteria. Although researchers still alcohol’s negative effect on the antimycobacterial activity need to refine our understanding of the exact mechanisms of macrophages potentially could be overcome. by which alcohol use decreases antimycobacterial defense, the immunosuppressive effects of alcohol on monocyte and Disturbed Cell-Mediated and Humoral Immunity Bal- macrophage function, cytokine production, and antigen- ance. Both acute and chronic alcohol use are associated specific T-cell activation appear to be key factors in the with a shift toward the predominance of humoral immune increased susceptibility to TB following alcohol use. functions at the expense of cell-mediated functions, as indicated by increased levels of circulating antibodies and Social and Behavioral Factors decreased T-cell activity. Specifically, acute and chronic For alcoholics, especially those who are indigent or alcohol use alter the profile of the T-cell population so homeless, several social and behavioral factors converge that the type of cells known as T-helper-2 (Th2), which to increase their vulnerability to TB and to hinder their are associated with humoral immunity, dominate over recovery from the disease. those known as T-helper-1 (Th1), which are associated with cell-mediated immunity. One recent hypothesis High-Risk Living Conditions. Typically, indigent and suggests that this shift comes about through alcohol’s homeless alcoholics dwell in crowded and impoverished effects on monocytes. Monocytes play a pivotal role in living conditions. Such an environment significantly in- supporting a Th1 immune response in two ways: through creases their chances for repeatedly inhaling M. tuberculo- their capacity to present antigen to activate T cells and sis droplet nuclei. With prolonged exposure, a person is through their manufacture of the important cytokines more likely to acquire an active TB infection and subse- known as interleukin-12 (IL-12) and interleukin-10 (IL- quently spread the disease by coughing up more infectious

40 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and Compromised Immunity

droplets for others to inhale. TB outbreaks have occurred REFERENCES in urban homeless shelters and other densely populated BERMUDEZ, L.E., AND YOUNG, L.S. Ethanol augments intracellular survival residential settings, such as prisons and nursing homes. of Mycobacterium avium complex and impairs macrophage responses to Kline and colleagues (1995) even reported an outbreak cytokines. Journal of Infectious Diseases 163(6):1286Ð1292, 1991. among regular patrons of a neighborhood bar and specu- DENIS, M. Involvement of cytokines in determining resistance and lated that heavy alcohol use and a highly infective source acquired immunity in murine tuberculosis. Journal of Leukocyte could have been contributing factors. Biology 50(5):495Ð501, 1991.

DUNLAP, N.E., AND BRILES, D.E. Immunology of tuberculosis. Medical Behavioral Issues. The chaotic lifestyles of most indigent Clinics of North America 77(6):1235Ð1251, 1993. alcoholics tend to delay their seeking medical attention FLORY, C.; HUBBARD, R.; AND COLLINS, F. Effects of in vivo T lympho- until their illness is fairly severe. Consequently, they cyte subset depletion on mycobacterial infections in mice. Journal of often show up at a hospital or clinic with extensive TB Leukocyte Biology 51:225Ð229, 1992. infection and tissue destruction. Nevertheless, unless their FLYNN, J.L., AND BLOOM, B.R. Role of T1 and T2 cytokines in the illness is far advanced, alcoholics theoretically should response to Mycobacterium tuberculosis. Annals of the New York respond just as well as nonalcoholics to medical therapy. Academy of Sciences 795:137Ð146, 1996. Indigent and homeless alcoholics actually have a poorer FLYNN, J.L.; GOLDSTEIN, M.M.; TRIEBOLD, K.J.; KOLLER, B.; AND BLOOM, prognosis than others with TB, however. The primary B.R. Major histocompatibility complex class I-restricted T cells are re- reason is not a worse response to medications but a rela- quired for resistance to Mycobacterium tuberculosis infection. Proceedings tive lack of cooperation in taking them. The same disor- of the National Academy of Sciences USA 89:12013Ð12017, 1992.

ganized life circumstances that delay treatment seeking JACOBSON, J.M. Alcoholism and tuberculosis. Alcohol Health & also impede taking regular doses of medication. In addi- Research World 16(1):39Ð45, 1992.

tion, the treatments for TB involve drugs that are poten- KAUFMANN, S.H.E., AND FLESCH, I. Function and antigen recognition tially toxic to the liver and the nervous system, and pattern of L3T4+ T cell clones from Mycobacterium tuberculosis- alcohol enhances their toxicity. Rather than stop drinking, immune mice. Infection and Immunity 54:291Ð296, 1986.

alcoholics may avoid treatment for TB. KLINE, S.E.; HEDEMARK, L.L.; AND DAVIES, S.F. Outbreak of tuberculo- Standard drug therapy for TB currently involves 9 sis among regular patrons of a neighborhood bar. New England Journal months of taking the medications isoniazid and rifampin of Medicine 333(4):222Ð227, 1995. or 6 months of taking isoniazid, rifampin, and pyrazi- LEVETON, C.; BARNASS, S.; CHAMPION, B.; LUCAS, S.; DE SOUZA, B.; NICOL, M.; namide. After an initial phase of daily medication, patients BANERJEE, D.; AND ROOK, G. T-cell mediated protection of mice against virulent can receive drugs twice weekly without compromising Mycobacterium tuberculosis. Infection and Immunity 57(2):390Ð395, 1989. effectiveness. (The slow growth cycle of M. tuberculosis MANDREKAR, P.; CATALANO, D.; GIROUARD, L.; AND SZABO, G. Human necessitates a long treatment duration, and multiple drugs monocyte IL-10 production is increased by acute ethanol treatment. thwart the organism’s ability to develop resistance.) Cytokine 8(7):567Ð577, 1996. Because homeless alcoholics frequently have difficulty NELSON, S.; BAGBY, G.J.; BAINTON, B.G.; AND SUMMER, W.R. The effects adapting to hospitalization, outpatient care is the usual of acute and chronic alcoholism on tumor necrosis factor and the inflam- approach to managing their illness. Even so, these patients matory response. Journal of Infectious Diseases 160(3):422Ð429, 1989. may not comply well with treatment, either by failing to NELSON, S.; MASON, C.; BAGBY, G.; AND SUMMER, W. Alcohol, tumor keep their medical appointments consistently or by not necrosis factor, and tuberculosis. Alcoholism: Clinical and completing therapy. Impoverished alcoholics thus are Experimental Research 19(1):17Ð24, 1995. prone to reactivation of TB, and if their medication use is ORME, I., AND COLLINS, F. Protection against Mycobacterium tuberculo- erratic, a strain of M. tuberculosis resistant to standard sis infection by adoptive immunotherapy. Journal of Experimental medication is more likely to develop. Contagious alco- Medicine 158:74Ð83, 1983. holics then spread resistant TB strains to others. ORME, I., AND COLLINS, F. Adoptive protection of the Mycobacteria Alcoholics may be especially unlikely to cooperate tuberculosis-infected lung. Cellular Immunology 84:113Ð120, 1984. with treatment if they perceive medical staff as a threat to SZABO, G.; VERMA, B.; AND CATALANO, D. Selective inhibition of their drinking—a likely scenario given the dangers of antigen-specific T lymphocyte proliferation by acute ethanol exposure: combining TB medication with alcohol. Caregivers The role of impaired monocyte capacity and medi- ator production. Journal of Leukocyte Biology 54(6):534Ð544, 1993. should bear in mind that TB is a serious public health hazard and give first priority to resolving a patient’s TB SZABO, G.; GIROUARD, L.; MANDREKAR, P.; AND CATALANO, D. Acute ethanol treatment augments interleukin-12 production in activated over addressing his or her alcoholism. By providing alco- human monocytes. Annals of the New York Academy of Sciences holic TB patients with friendly, nonthreatening support, 795:422Ð425, 1996. caregivers may improve the chances for complete TB VICENTE-GUTIERREZ, M.M.; RUIZ, A.D.; EXTREMERA, B.G.; GARCIA, treatment and, possibly, succeed in helping the patient J.M.B.; AND GEA, F.G. Low serum levels of alpha-interferon, gamma- accept the need for alcoholism treatment as well. interferon, and interleukin-2 in alcoholic cirrhosis. Digestive Diseases —Gyongyi Szabo and Sciences 36(9):1209Ð1212, 1991.

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