FAKTOR RISIKO ALKOHOL DAN TB

7/23/2019 FAKTOR RISIKO ALKOHOL DAN TB

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The immune system serves as thebodys defense against infectionsby microorganisms; damage

caused by other foreign substances;and the uncontrolled, tumorous growthof the bodys own cells. Impairment ofthis system can increase a personsrisk for developing various illnesses,

including infectious diseases, such astuberculosis, and certain types of can-cer. Alcohol can modulate this de-fense, and clinicians have known for along time that chronic alcohol abusershave an impaired immune system.This impairment manifests itself inseveral ways. For example, alcoholicsare prone to infections by variousdisease-causing microorganisms (i.e.,pathogens); have a decreased ability tofight these infections; and have an

increased risk of developing tumors,particularly in the head, neck, andupper gastrointestinal tract. Althoughalcohol-induced malnutritioninclud-ing vitamin deficienciesand ad-vanced liver cirrhosis likely contributeto some abnormalities in the immunesystem of alcoholics, alcohol itself

also is a potent modulator of immunefunctions. Interestingly, not onlychronic alcohol abuse but also single-episode (i.e., acute) and/or moderatealcohol consumption can affect theimmune system.

This article briefly reviews themain features and components of theimmune system and summarizes someof the consequences and mechanismsof alcohol use on the bodys defenseagainst pathogens.

THE IMMUNE SYSTEMANOVERVIEW

The immune system has two mainarms: innate, or nonspecific, immunity

and acquired, or specific, immunity.

Innate immunity exists before thebody is exposed to a pathogen for the

first time. Moreover, this system doesnot respond to specific pathogens butinstead responds to any pathogen it

encounters. For example, the cells

involved in innate immunity immedi-ately attack any kind of bacterium or

30 ALCOHOL HEALTH & RESEARCH WORLD

Alcohols Contribution to

Compromised ImmunityGYONGYI SZABO, M.D., PH.D.

Alcoholics frequently suffer from infectious diseases and have increased rates ofsome cancers, indicating that alcohol impairs the immune system, which protects thebody against this type of damage. Alcohol interferes with the functions of many ofthe cells and molecules that are part of the immune system. For example, alcoholinhibits the functions of the cells that ingest and destroy invading microorganisms

(i.e., neutrophils, monocytes, and macrophages). Both acute and chronic alcoholexposure also alter the production of signaling molecules that help coordinate theimmune response (i.e., cytokines). Finally, alcohol adversely affects the functions ofthe cells that mediate the immune response against specific microorganisms andlong-term immunity (i.e., T cells and B cells). As a result, alcoholics have anincreased susceptibility to diseases caused by bacterial infections, such astuberculosis and pneumonia. Alcoholics also may be more susceptible to infectionsfrom the virus that causes AIDS. In addition, alcohol intoxication can exacerbate theimmune suppression that occurs after traumatic injuries. KEY WORDS: immune system;immune disorder; immune response; AODE (alcohol and other drug effects); cytokines;inflammation; oxygen radicals; bacterial disease; HIV infection; trauma; injury; pathologicprocess; literature review

GYONGYISZABO, M.D., PH.D., is aresearch associate professor of medi-cine in the Department of Medicine,University of Massachusetts MedicalCenter, Worcester, Massachusetts.


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virus that enters the body, whether it isthe first or second infection by thatorganism. Acquired immunity, incontrast, is activated only after thebody is exposed to a pathogen for thefirst time. In addition, the acquired

response is specific to one particularpathogen. For example, whenMyco-bacterium tuberculosis, the bacteriumthat causes tuberculosis, enters thebody, the contact with that pathogenactivates cells involved in acquiredimmunity. These activated cells attackonlyM. tuberculosis and no otherbacteria or viruses. The activated cellsalso generate a kind of immune mem-orythat allows the body to fight asecond infection by the same pathogeneven faster and more efficiently.

The elements of innate immunityinclude white blood cells that ingest anddestroy microorganisms (i.e., phago-cytes); certain proteins that circulate inthe blood, called the complement1

system; and signaling molecules (i.e.,cytokines) that are produced and secret-ed by some of the phagocytes. Severaldifferent types of phagocytes exist, withspecific functions as follows:

Neutrophils ingest and thereby de-stroy pathogens, primarily invading

bacteria.

Monocytes that circulate in theblood or that have entered thetissues (i.e., macrophages) ingestand destroy a variety of foreignsubstances and microorganisms.Monocytes also exhibit pathogen-derived proteins and other mole-cules (i.e., antigens) on their surfacesin order to activate other cells inthe immune system. Finally, mono-cytes and macrophages secrete

cytokines that help regulate im-mune system activity.

Natural killer (NK) cells recognizeand eliminate cells in the body thathave been infected by parasites orthat have turned into cancer cells.

The elements of acquired immunityinclude numerous cell types and mole-

cules that function cooperatively tomount a complex host defense andthereby amplify and focus the protectionoffered by the innate immunity. Themost important cells involved in ac-quired immunity are T lymphocytes, or

T cells, and B lymphocytes, or B cells.These cells circulate in the blood orreside in special lymphoid tissues (e.g.,the spleen, lymph nodes, and tonsils),where they can encounter antigens andinitiate an immune response.

T cells and B cells are the corner-stones of two types of immune re-sponses, the cell-mediated immunityand the antibody-mediated (i.e., hu-moral) immunity. The cell-mediatedimmunity relies primarily on T cellsthat are activated by exposure to anti-

gen-presenting cells (e.g., monocytes,macrophages, and B cells). Each anti-gen-presenting cell displays only oneantigen (e.g., a viral protein) on itssurface and thus stimulates only Tcells that recognize this specific anti-gen. The activated T cell then canbind to other cells carrying the sameantigen (e.g., virus-infected cells) andinitiate their destruction. Several sub-populations of T cells have specificfunctions in the complex chain ofevents occurring during an immuneresponse:

Helper T cells produce and secretecytokines that stimulate the activityof other immune cells.

Cytotoxic T cells recognize anti-gens on the surface of virus-infect-ed or transplanted cells and destroythese cells.

Suppressor T cells inhibit otherimmune responses, thereby pre-venting overreaction of the im-

mune system.

Delayed-type hypersensitivity Tcells produce cytokines that inducea localized inflammatory responseand attract macrophages and cyto-toxic T cells to that site to elimi-nate the antigen.

The B cells produce the humoralimmunity. These cells carry immuneproteins (i.e., antibodies, or immuno-globulins) on their surface that recog-

nize and bind to antigens. Like T cells,each B cell also recognizes only onespecific antigen and becomes activatedwhen it comes into contact with it.Most activated B cells develop into so-called plasma cells, which secrete their

antibodies into the blood or lymph.There the antibodies can bind to theirtarget antigens (e.g., a virus or a virus-infected cell) and thus mark them fordestruction. Other B cells becomememory cells, which help the bodyfight a second infection by the samepathogen more expeditiously.

The T-cell and B-cell responses arenot independent of each other, however,but are intricately intertwined. Thus, Bcells that have bound an antigen serveas antigen-presenting cells that canactivate a T-cell response. Moreover, Bcells and T cells communicate with eachother and with other immune cells bysecreting numerous cytokines that caninfluence various components of boththe nonspecific and specific immuneresponses. For example, some T cellsproduce cytokines that stimulate theirown activity or that of other T cells.Other subgroups of T cells secrete cy-tokines that inhibit the cell-mediatedand humoral immunity and thus prevent

an excessive reaction of the immunesystem. Finally, some T-cellderivedcytokines enhance B-cell multiplication,differentiation, and antibody production.The largest family of cytokines are theinterleukins (ILs), which are producedin various cell types and have numerousfunctions (see table).

The following example may helpillustrate some of the complex interac-tions that take place during an immuneresponse. When a person sustains asmall injury, such as a cut, bacteria can

enter the body and the bloodstreamthrough the wound. Phagocytes (e.g.,monocytes and neutrophils) patrollingthe blood encounter some of thesebacteria; identify them as foreign tothe body; and engulf, ingest, and de-stroy them. During the intracellularbreakdown of the ingested bacteria,the phagocytes generate small proteinsor protein fragments that serve asantigens. The phagocytes display theseantigens on their cell surface, together

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Alcohol and Compromised Immunity

1For a definition of this and other technicalterms used throughout this article, see thecentral glossary, pp. 9396.


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Important Cytokines of the Immune System

Cytokine Primary Source Principal Functions

Inflammatory cytokines

Interferon alpha (IFN-)

Interleukin 1 (IL-1)


Tumor necrosis factor alpha(TNF-)

Immunoregulatory cytokines



Transforming growth factor beta(TGF-)

Chemokines


Lymphokines

Interferon gamma (IFN-)



Macrophages

Macrophages and other cells

Macrophages, T cells, and other cells

Macrophages, T cells, natural killer (NK)cells, and other cells

Macrophages and T cells

Monocytes and macrophages

Macrophages and T cells

Macrophages

T cells

T cells

A subtype of T cells (i.e., CD4 T cells)

Induces protection against viral infections;activates macrophages; and inhibits the growthof various cell types

Produces inflammatory responses; inducesfever; stimulates proliferation of helper T cells;and promotes B-cell growth and differentiation

Promotes maturation of stimulated B cells toantibody-secreting plasma cells; acts with othercytokines to stimulate immature and mature Tcells; and stimulates production of complementfactors and other mediators of inflammatoryresponses

Promotes inflammatory responses; stimulatesneutrophils and macrophages; induces fever;and induces macrophages to produce IL-1,IL-6, and TNF-

Inhibits T-cell proliferation; reduces productionof inflammatory cytokines; and promotes B-cellproliferation and antibody secretion

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

Inhibits T-cell proliferation; reduces productionof inflammatory cytokines; augments B-cellproliferation and antibody secretion; andpromotes collagen production

Attracts neutrophils to the site of an infection

Induces protection against viral infection;stimulates macrophages and neutrophils;

enhances expression of major histocom-patibility complex (MHC) proteins on manycells; and promotes B-cell and T-celldifferentiation

Stimulates proliferation of T cells; enhancesactivity of NK cells; and stimulates B-cellproliferation and antibody production

Stimulates T-cell growth; induces B-cellactivation and growth; and modulates antibodyproduction by B cells


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with certain of their own proteinsknown as major histocompatibilitycomplex (MHC) proteins. In additionto the phagocytes, proteins of the com-plement system also recognize the in-vading bacteria and bind to proteins on

the bacterial surface. This binding trig-gers several biochemical processesthat eventually lead to the destructionof the bacteria.

T cells circulating in the bloodrecognize phagocytes simultaneouslydisplaying antigens and MHC proteins.The T cells bind to the phagocyte-bound antigens through the help ofdocking molecules, called T-cell re-ceptors. The activated T cells multiplyand begin secreting cytokines, which,in turn, activate cytotoxic T cells that

can then recognize, bind to, and de-stroy cells infected by the invadingbacteria.

Parallel to the T-cell response, theB cells mount another line of defenseagainst the invading bacteria. Thus,antibodies on the B-cell surface recog-nize and bind to antigens on the bacte-rial surface. This binding activates theB cells, which then differentiate intoplasma cells that secrete large amountsof antibodies. The antibodies are dis-tributed throughout the bloodstreamand bind to the bacteria wherever theyencounter them, aided by proteins ofthe complement system. The antibody-covered bacteria clump together andbecome new targets for monocytes andother phagocytes.

ALCOHOLS EFFECTS ON THEIMMUNE DEFENSE

The bodys response to an invadingpathogen can be divided into two

phases. The first phase is an inflam-matory reaction, which protects thebody from the immediate effects ofthe infection. The inflammatory re-sponse primarily involves phagocyticcells that help eliminate the pathogen,cytokines secreted mainly by thesephagocytes, and other molecules (e.g.,oxygen radicals) that assist in killingthe pathogen. The second phase, thedevelopment of immunity to thepathogen, is mediated by T cells and

B cells. Alcohol can interfere withboth phases of the immune response.

Alcohols Effects on theInflammatory Response

Effects on Phagocytic Cells. Duringan inflammatory response, chemicalsubstances released by cells at the siteof the infection induce phagocytes tomigrate from their normal locationsin the bloodstream or the tissues tothe site of the inflammation. Thisprocess is called chemotaxis. Varioussubstances can serve as chemotacticagents, including activated compo-nents of the complement system, agroup of white blood cell-derivedproteins called leukotrienes, and otherproteins produced by immune cells(i.e., chemokines, such as interleukin-8 [IL-8]). The neutrophils and mono-cytes recruited from the bloodstreammust adhere to and migrate throughthe cell layer lining the blood vesselsat the site of the infection, ingest themicroorganisms, and destroy the in-gested pathogens using specific en-zymes or toxic, oxygen-derived freeradicals.

Alcohol can affect this sequence of

events at several levels. Alcoholseffects on phagocyte adhesion to the

blood-vessel walls and chemotaxiswere studied in chronically alcohol-fed rats. Neutrophils from these ani-mals exhibited increased levels ofCD18 molecules on their surface,which are required for adhesion.Furthermore, chemokines (e.g., IL-8)secreted by macrophages residing inthe liver (i.e., Kupffer cells) of thealcohol-fed rats increased the chemo-taxis of normal neutrophils. Increased

infiltration of neutrophils into theliver, in turn, can lead to liver injury.Thus, an alcohol-induced increase inchemokine production by Kupffercells may lead to neutrophil accumu-lation and thus to liver damage (e.g.,alcoholic hepatitis). This hypothesis isconsistent with observations that inpatients with acute alcoholic hepatitis,IL-8 levels in the blood are elevatedand may be associated with neutrophilaccumulation in the liver.

Increased neutrophil chemotaxiseven occurred in rats that received aone-time alcohol injection. In contrast,Kupffer cell chemotaxis decreasedunder the same conditions. Theseresults suggest that alcohol can differ-

entially affect the functions of variousphagocytic cell types. Studies withcultured human cells, however,demonstrated decreased neutrophilchemotaxis after the cells were ex-posed to alcohol.

Chronic as well as acute alcoholconsumption also reduces the abilityof phagocytes to ingest and breakdown pathogenic bacteria. For exam-ple, cultured human monocytes ex-posed to alcohol showed reducedphagocytic functions; moreover, thecells produced less of a receptor pro-tein that is required for the ingestionof antibody-coated particles. In mice,both short-term and long-term alcoholfeeding reduced the phagocytic abilityof macrophages residing in the mem-brane lining the abdominal cavity.Thus, abnormal neutrophil adherenceand chemotaxis, as well as reducedphagocytic function of macrophages,may contribute to the impaired de-fense against microorganisms ob-

served after alcohol consumption.

Effects on Inflammatory Cytokines.Phagocyte contact with pathogensinduces the release of cytokines by thephagocytes that help initiate andmaintain the inflammatory responseand thus play a pivotal role in thebodys immune defense. The mostcommon inflammatory cytokinestumor necrosis factor alpha (TNF-),IL-1, and IL-6are primarily pro-duced by monocytes and macrophages

(see figure). During an overwhelminginflammatory response, however,neutrophils, lymphocytes, and othertissue cells also can be sources of in-flammatory cytokines. Excessive lev-els of these cytokines may causetissue damage, whereas reduced levelsmay result in an insufficient immuneresponse.

In chronic alcohol abusers, particu-larly those with alcoholic liver dis-ease, the levels of TNF-, IL-1, and

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IL-6 in the blood are significantlyelevated. These increased cytokinelevels may contribute to most of thesigns and symptoms observed in pa-tients with alcoholic hepatitis (e.g.,generally increased metabolism, fever,weight loss, elevated levels of pro-teins produced in the liver, and mark-ers of malnutrition). It is unknown,however, which cells cause the eleva-ted inflammatory cytokine productionin alcoholics.

Acute, moderate alcohol consump-tion, in contrast, transiently reduces

the pathogen-induced production ofinflammatory cytokines. For example,cultured human monocytes exposed toalcohol before being stimulated withvarious bacterial antigens producedlower-than-normal levels of TNF-,IL-1, and IL-6. Similarly, the TNF-levels produced in response to a chal-lenge with a bacterial antigen weredecreased in mice that had received asingle dose of alcohol. Consideringthe pivotal role of TNF- in the de-

fense against microorganisms, im-paired inflammatory cytokine produc-tion after acute alcohol exposuresignificantly compromises the bodysdefense system.

Effects on ImmunoregulatoryCytokines. The initial inflammatoryresponse to pathogens normally isturned off by regulatory cytokineswhose production typically is inducedin a later phase of the infection. Themost studied immunoregulatory cy-tokines are IL-10 and transforming

growth factor beta (TGF-), both ofwhich are produced by macrophagesand T cells. IL-10 promotes humoralimmunity and inhibits cell-mediatedimmunity by reducing the productionof several cytokines, including inflam-matory cytokines, and by preventingthe multiplication (i.e., proliferation)of T cells. Acute alcohol exposureincreases IL-10 production in culturedhuman monocytes both in the absenceand presence of stimulation by bacte-

rial antigens and thus may interferewith the normal interaction of the cell-mediated and humoral immunities.

The other cytokine controllinginflammatory reactions and T-cellproliferation is TGF-. In experiments

using cultured monocytes, physio-logically relevant alcohol concentra-tions2 activated both the baseline andthe bacterial antigen-induced TGF-production. Elevated TGF- levelsmay have multiple implications forimmune-system functioning, includ-ing inhibition of inflammatory cyto-kine production by monocytes andother cells, inhibition of T-cell prolif-eration, and augmentation of thehumoral immune response. As a re-

sult, the drinker becomes more sus-ceptible to infections and exhibitsdecreased immune system activity ineliminating infections. In addition,elevated TGF- levels promote colla-gen production. Collagen moleculesnormally form the fibers making uptendons and ligaments. However,excessive collagen production result-ing from alcohol-induced TGF- mayresult in abnormal collagen depositsin the liver that have been implicatedin the development of some types of

alcoholic liver disease.Alcohol also increases the produc-

tion of nonprotein regulatorymolecules that inhibit the antigen-presenting capacity of monocytes,inflammatory cytokine production,and T-cell proliferation.

By increasing the levels of thesesubstances as well as of IL-10 andTGF-, alcohol can interfere withthe bodys normal defense againstinvading microorganisms in two

ways: by reducing inflammatory-cytokine production and by inhibit-ing T-cell proliferation.


Immunoregulatory

cytokines

(e.g., TGF-, IL-10)

Chemokines

(e.g., IL-8)

Antibacterial compounds

(e.g., oxygen radicals, nitric oxide)

Other factors (e.g., proteins

involved in blood clotting,

proteins stimulating the

growth of other cells)

T-cell

activating

cytokines

(e.g., IL-12)

Inflammatory

cytokines

(e.g., TNF-,

IL-1, IL-6)

Monocyte/macrophage-derived substances potentially affected by alcohol. Mono-

cytes and macrophages produce numerous substances that initiate and regulate

inflammatory reactions; attract other immune cells (i.e., chemokines); stimulate T

cells; help in the elimination of pathogens, such as bacteria; and perform other

functions throughout the body. Alcohol may interfere with the production and se-

cretion of all these substances, thereby impairing the bodys immune response.

IL = interleukin; TGF- = transforming growth factor beta; TNF- = tumor necrosis factor alpha.

2The alcohol concentrations used in theseexperiments were 10 to 100 millimoles per liter(mmol/L). Concentrations of 25 mmol/Lapproximate blood alcohol levels of 0.1 per-cent, the legal limit for driving in many States.Concentrations of 100 mmol/L correspond toblood alcohol levels of approximately 0.4percent, which are sometimes seen in alco-holics after acute alcohol consumption.


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Effects on Oxygen-Radical Production.Oxygen radicals (e.g., superoxide anionsand hydrogen peroxide) are unstableoxygen-containing molecules thatreadily interact with other moleculesin a cell. Oxygen radicals produced by

macrophages and other phagocytesplay a crucial role in destroying micro-organisms, especially in the lungs.Researchers found that macrophagesin the lungs of acutely or chronicallyalcohol-fed rats produced fewer super-oxide anions and less hydrogen per-oxide than did macrophages fromnon-alcohol-exposed rats. Further-more, the lung macrophages producedand secreted less nitric oxide, anothermolecule with characteristics andfunctions similar to those of oxygen

radicals. The alcohol-induced decreas-es in the macrophagesproduction ofoxygen radicals and nitric oxide couldundermine the bodys defense againstbacteria. This mechanism could con-tribute to the high incidence of tuber-culosis in alcoholics. (For moreinformation on the association ofalcohol use and tuberculosis, see side-bar, pp. 3941.)

Alcohol-induced overproduction ofoxygen radicals in the liver, in con-trast, may contribute to the develop-ment of alcoholic liver damage. In ratsthat received alcohol infusions for 1, 3,or 5 hours, for example, the Kupffercells in the liver produced and secretedincreased levels of superoxide anions,whether or not the cells were activatedby contact with pathogens. Together,these observations imply that alcoholmay have a dual negative effect on thebodys oxygen-radical production.First, alcohol may inhibit oxygen-radical and nitric oxide production in

macrophages in the lung, where thesesubstances are essential for killingmicroorganisms. Second, alcohol mayincrease oxygen-radical production inthe liver, where these molecules maycause tissue damage.

Alcohols Effects on Immunity

Effects on T Cells. Alcoholics andlaboratory animals chronically ingest-ing alcohol have lower-than-normalnumbers of all subpopulations of T

cells in the blood, in the thymusthegland where T cells matureand inthe spleen, where immune reactionsare initiated. The mechanism underly-ing the alcohol-induced decrease in T-cell numbers still is unknown. Some

researchers have suggested that acutealcohol exposure induces programmedcell death, or apoptosis, in immature Tcells in the thymus. Acute alcoholexposure also results in increasedapoptosis of mature lymphocytes andmonocytes in the blood.

Alcohol also may reduce the abilityof lymphocytes to proliferate and differ-entiate adequately after they have beenactivated by an antigen. Moreover, thenumber and function of delayed-typehypersensitivity T cells is reduced inalcoholics. As a result, the immuneresponse to certain antigens and infec-tions is depressed. How alcohol affectsT-cell proliferation is not well under-stood. In chronically alcohol-fed rats,the T cells fail to proliferate adequatelyin response to stimulation by IL-2. Theresults of other investigations implythat decreased T-cell proliferation maybe a consequence of the impairedfunction of accessory cells (e.g., anti-gen-presenting cells) after alcohol use.

For example, the interaction of T cellswith antigen-presenting monocytes ormacrophages requires the presence ofseveral proteins on the surfaces of boththe T cells and the antigen-presentingcells (e.g., T-cell receptors and MHCmolecules). The production of someof these proteins also is altered inalcohol-exposed cells. Finally, reducedT-cell proliferation may be attributedto the increased production of immuno-regulatory cytokines (e.g., IL-10 andTGF-) caused by alcohol.

Overall, the effects of both acuteand chronic alcohol exposure result ina weakened cell-mediated immuneresponse. Several diseases are char-acterized by a reduction in the cell-mediated immunity and a concomitantincrease in the humoral immunity.Similarly, the immunological abnor-malities observed after both chronicand acute alcohol consumption appearto be consistent with a decreased cell-mediated immunity characterized by

reduced T-cell proliferation, accom-panied by an enhanced humoral im-munity marked by increased antibodylevels. This shift in the immune re-sponse likely impairs the bodys defenseagainst bacterial infections requiring a

predominantly cell-mediated immuneresponse, such as infections withM.tuberculosis orListeria monocytogenes,which are discussed in the sectionConsequences of Alcohols Effects onthe Immune System.Alcohols effectson the antibody-producing B cells isdiscussed in more detail in the follow-ing section.

Effects on B Cells. A characteristicimmune-system aberration observed inalcoholics is the elevation of antibodylevels in the blood. Similarly, acutealcohol consumption in mice increasedantibody production in response tocertain chemical substances. Becauseantibodies are produced by B cells,these observations indicate that alcoholalters either the number or function ofB cells. To date, conflicting resultsexist regarding these two alternatives.Thus, clinical studies in humans foundthat the absolute number of B cells didnot differ between alcoholics and non-

alcoholics, but that B-cell functioningappeared to be altered in alcoholics. Incontrast, in mice that had been fedalcohol for 14 days, the number of Bcells in the spleen had decreased five-fold. Equally contradictory were thefindings regarding B-cell functioning:Whereas clinical studies demonstratedelevated antibody levels in alcoholics,tissue-culture experiments to investi-gate these observations found thatalcohol inhibited the B-cellsantibodysecretion.

One possible explanation for theseconflicting findings is that alcohol inter-feres only with some aspects of B-cellfunctioning. For example, B cells donot respond to all antigens in the samemanner. In response to some antigens,B cells require the assistance of cy-tokines secreted by T cells (i.e., T-celldependent responses), whereas inresponse to other antigens, T-cell acti-vation is not required (i.e., T-cellinde-pendent responses). Alcohol appears to

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affect these responses differently,because B cells in the spleens of alco-hol-consuming animals showed im-paired proliferation during a T-celldependent response but normal prolif-eration during a T-cellindependent

response. Similarly, alcoholics exhibit-ed an intact T-cellindependent anti-body response after administration of aspecific antigen. Thus, alcohol mayinterfere with antibody productionindirectly by inhibiting the productionof certain T-cellderived cytokinesrequired for B-cell function. The com-plexity of alcohols effects on B cells isunderscored further by findings thatalcohol impairs B-cell proliferation inresponse to the T-cellderived cytokineIL-4 but not in response to the T-cell-derived cytokine IL-2.

Effects on Natural Killer Cells. NKcells are a type of white blood cellinvolved in the destruction of virus-infected and cancerous cells. Conse-quently, NK cells play an importantrole in preventing tumor development.Chronic alcohol consumption is asso-ciated with increased incidence oftumors, suggesting that NK cell activ-ity may be impaired. In laboratory

animals, chronic alcohol administra-tion reduced the number and activityof NK cells. Tissue-culture experi-ments, in contrast, produced conflict-ing results, demonstrating that alcoholhad either an inhibitory effect or noeffect on NK cell activity. Finally,acute alcohol consumption temporari-ly reduced the ability of rats to elimi-nate certain tumor cells and preventthe development of tumor metastases.

Effects on Cytokines. Cytokines pro-

duced by lymphocytes (i.e., lympho-kines, such as ILs and interferons[IFNs]) regulate the functions ofimmune cells as well as nonimmunecells (e.g., nerve cells and cells ofhormone-producing organs). Theeffects of either chronic or acute alco-hol use on cytokine production andfunction, however, are only partiallyunderstood. IL-2 is one of the mostimportant T-cellproduced cytokines;it promotes the proliferation and sur-

vival of certain T-cell subpopulations.Although alcohol in tissue cultureexperiments had no effect on the abili-ty of T cells to produce IL-2, it likelyinterferes with the T-cell response toIL-2. The potential intracellular mecha-

nisms underlying these effects, how-ever, remain unknown.

Alcoholics exhibit decreased bloodlevels of IFN-, IFN-, and IL-2.3 Inparticular, the reduction of IFN-levelsmay be a key element underlying manyof the immune alterations observed inalcoholics because this cytokine, inconcert with the macrophage-derivedIL-12, is crucial for induction of thecell-mediated immune response. Conse-quently, in the absence of appropriateIFN-stimulation in alcoholics, a

preferential induction of the humoralimmune response could occur. Theaccompanying lack of an appropriatecell-mediated immune response wouldmake the alcoholics more susceptibleto infections that require a T-cell re-sponse. Furthermore, decreased IFN-levels likely contribute to additionalcytokine abnormalities (e.g., alteredIL-12 levels), thereby further impair-ing the cell-mediated immune response.

CONSEQUENCES OF ALCOHOLSEFFECTS ON THE IMMUNE SYSTEM

Increased Susceptibility toBacterial Infections

Alcoholics are considered immuno-compromised hostsbecause the inci-dence and severity of infections areincreased in these patients. Infectionswith pathogens that reside within thehosts cells and cause diseases such as

pneumonia or tuberculosis are espe-cially prevalent. Thus, alcoholics havean increased incidence of pneumo-

coccal pneumonia compared with thegeneral population, and despite the useof antibiotics, the mortality amongthese patients remains disturbinglyhigh (15 to 77 percent). Researchershave used mice to study some of the

mechanisms underlying the increasedsusceptibility to infections by infect-ing the animals withListeria monocy-togenes, a bacterium that among othersymptoms, causes liver damage in theanimals. Mice that received an alcohol-containing diet for 7 days before be-ing infected withListeria developedgreater liver damage than controlanimals that had received no alcohol.Although the alcohol treatment did notimpair the migration of phagocytes tothe liver, it did impair the animalsability to inhibitListeria growth. Thuseven alcohol-fed mice that should havebeen able to stave off the infection,because they had previously been im-munized withListeria, had 100 timesmoreListeria organisms in their liversthan did nonalcohol-treated controls.The bodys anti-Listeria defense islargely T-cell dependent and requiresinteractions between specific antigensT cells, and phagocytic cells as well asIFN-and IL-12 induction. However,

the exact roles of alcohol-induced aber-rations in immune-cell interactions,antigen-presenting cell function, andIFN-and/or IL-12 production remainto be determined.

Alcohol use also impairs the bodysdefense against pathogens infecting thelungs, such as pneumonia-causing bacte-ria (e.g., pneumococci, Klebsiella pneu-moniae, andLegionella pneumophila)andM. tuberculosis. For example, in ratsinfected with pneumococci, the animalssusceptibility to lethal pneumonia in-

creased if they received alcohol for 1week before the infection. Moreover, thealcohol-fed rats experienced an increasedspread of the pneumococci from thelungs through the bloodstream comparedwith non-alcohol-treated rats and alsofailed to eliminate the pneumococci fromthe blood. Other studies investigatingalcohols effects on the susceptibility toinfections with Klebsiella pneumoniaeandLegionella pneumophila indicatedthat chronic alcohol treatment suppressed


3The discrepant observations that alcohol didnot affect the cellsability to produce IL-2 intissue culture experiments, whereas alcoholicsshow decreased IL-2 levels in the blood likelycan be attributed to the fact that tissue cultureexperiments monitor the consequences of acutealcohol exposure, but the findings in alcoholicsreflect the effects of chronic alcohol exposure.However, this hypothesis has not been investi-gated in detail.


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the production and/or function of neu-trophils and macrophages. Moreover,treatment with a protein factor that stimu-lates neutrophil production amelioratedthe alcohol-induced immunosuppressionby recruiting more neutrophils to the

lungs.

Increased Susceptibility to HIV

The relationship between alcohol useand susceptibility to infections with thehuman immunodeficiency virus (HIV),which causes acquired immune defi-ciency syndrome (AIDS), is an activelyevolving area of research. Althoughample data are available on the immu-nological abnormalities caused byalcohol use and HIV infection, respec-

tively, knowledge concerning theircombined immunosuppressive effectsis more limited. Some researchershave proposed that alcohols modula-tory effects on the immune systemmay increase the risk of initial HIVinfection as well as accelerate theinfections progression. Although thishypothesis still awaits formal confir-mation, several findings support alco-hols proposed influence. For example,one study found that HIV multiplied

faster in blood cells isolated from bingedrinkers or subjects who had receivedan acute alcohol dose than in cells frompeople who had not been exposed toalcohol (Bagasra et al. 1996). More-over, a case report of an HIV-infectedperson demonstrated that the HIVinfection progressed rapidly and thatthe patient developed full-blownAIDS after initiating heavy alcoholuse (Fong et al. 1994). Finally, a studyof HIV-positive intravenous drugusers found that whereas alcohol use

did not affect the proportion in theblood of the T-cell subpopulation thatis the target of HIV infection, alcoholuse did correlate with increases in theproportion of another T-cell subpopu-lation several years after the initialinfection (Crum et al. 1996). Althoughthe clinical significance of this obser-vation is still unclear, the findingssuggest that alcohol consumption mayexacerbate HIV-induced changes inthe immune system.

Current knowledge strongly sug-gests that alcohol usepotentiallyboth acute and chroniccan increasea persons susceptibility to HIV infec-tion and contribute to alterations inthe immune system that may result in

an accelerated progression of theinfection. However, further research isneeded to elucidate the mechanism bywhich alcohol may modulate the biol-ogy of HIV infection. In addition toits biological effects, alcohol use mayincrease the risk of HIV infection bymodifying the drinkers behavior. Forexample, factors such as increasedrisk taking and uninhibited sexualbehavior, which are associated withboth acute and chronic alcohol use,can contribute to an increased risk for

HIV infection.

Consequences of TraumaticInjuries

Traumatic injuries frequently are asso-ciated with severe suppression of theimmune system, which can lead to over-whelming infections and may result inmultiple organ failure and even death.Alcohol intoxication not only increas-es the risk of sustaining traumaticinjuries (e.g., in motor vehicle acci-

dents) but also may exacerbate trauma-induced immunosuppression. Thus,one study found that acutely intoxicat-ed patients (i.e., those with bloodalcohol levels greater than 0.2 percent)who had sustained severe abdominalinjuries had a 2.6 times greater inci-dence of infections than did patientswho had not consumed alcohol (Gen-tilello et al. 1993). Moreover, rats thathad received alcohol before sustainingsevere burn injuries exhibited a signifi-cantly impaired cell-mediated immunity

accompanied by an increased humoralimmunity (i.e., elevated antibody pro-duction). Such an alcohol-related mod-ification of the immune system aftersustaining a traumatic injury couldincrease the patients risk of infectionsand prolong the trauma-related sup-pression of the immune system.

The mechanism underlying trauma-induced immunosuppression has notyet been identified. However, the cy-tokine TNF- clearly plays an impor-

tant role in this process. Thus, acutealcohol consumption before sustaininga traumatic injury can affect a patientsTNF- production and immunosup-pression after the injury as follows:

Within 0 to 3 days after the injury,TNF- production in the mono-cytes decreases in patients whoseblood alcohol levels exceed 0.1percent at emergency-room admis-sion, but increases in patients whohave not consumed alcohol beforesustaining the injury.

Later during the posttrauma period(i.e., more than 6 days after theinjury), the monocytes of alcohol-consuming trauma patients producehigher TNF- levels than the mono-cytes of non-alcohol-consumingtrauma patients.

The increase in TNF- productioncoincides with the development ofposttraumatic immunosuppression,suggesting that acute alcohol con-sumption before sustaining majorinjuries increases the severity ofthe immunosuppression.

CONCLUSIONS AND FUTURE

DIRECTIONS

Numerous research efforts have con-firmed that both acute and chronicalcohol use have profound regulatoryeffects on the immune system. Studiesin laboratory animals and in humanshave demonstrated that even acute,moderate alcohol consumption canimpair the bodys defense againstbacteria and viruses, although theseeffects are likely only transient. Theclinical implications of such a transient

immunodepression still need to bestudied further. For certain types ofinfections (e.g., HIV and mycobacte-ria), however, the failure of an appro-priate initial immune response topathogens can have profound and po-tentially prolonged effects on the im-mune system and the drinkers health.

Researchers and clinicians are gain-ing further insight into the complexmechanisms and consequences ofimmunosuppression in chronic alco-

VOL. 21, NO. 1, 1997 37



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holics. It is important, however, to

dissect the effects caused by the bodyschronic exposure to alcohol itself and

the effects of other alcohol-related

immunomodulatory conditions, such asmalnutrition, vitamin deficiencies, and

alcoholic liver disease. Moreover, abetter understanding of the specific

immune system alterations caused by

chronic alcohol consumption is neces-sary for designing effective therapeutic

approaches to ameliorating immuno-

suppression in chronic alcoholics.Researchers also are investigating

the mechanisms underlying the differ-ential effects of chronic and acute

alcohol use on the immune system.

For example, the increased levels of

inflammatory cytokines observed inalcoholics contrast with the decreased

inflammatory response seen afteracute alcohol treatment. Finally, addi-

tional research is needed to delineatesome of the intracellular signaling

events in immune cells that are affect-

ed by acute and chronic alcohol use inorder to better understand alcohols

regulatory effects on the complex

interactions of the immune system.

EDITORIAL NOTE

This article is accompanied by a

Suggested Readinglist that in-

cludes only key references. A com-plete bibliography of sources

consulted is available from the au-

thor.

SUGGESTED READING

ALDO-BENSON, M.; PRATT, L.; AND HARDWICK,

J. Alcohol can inhibit effect of IL-4 on activatedmurine B cells.Immunology Research 11:117

124, 1992.

BAGASRA, O.; BACHMAN, S.E.; JEW, L.; TAWA-

DROS, R.; CATER, J.; BODEN, G.; RYAN, I.; AND

POMERANTS, R.J. Increased HIV type-1 replication

in human peripheral blood mononuclear cells

induced by ethanol: Potential immunopathogenic

mechanisms.Journal of Infectious Diseases

173:550558, 1996.

BAUTISTA, A.P. Chronic alcohol intoxication

induces hepatic injury through enhanced macro-

phage inflammatory protein-2 (MIP-2) produc-

tion and intracellular adhesion melocule

expression in the liver.Hepatology 25:335342,

1997.

BEN-ELIYAHU, S.; PAGE, G.G.; YIRMIYA, R.;

AND TAYLOR, A.N. Acute alcohol intoxication

suppresses natural killer cell activity and pro-

motes tumor metastasis.Nature Medicine 2:

457460, 1996.

CRUM, R.M.; DALAI, N.; COHN, S.; CELENTANO,

D.D.; AND VLAHOV, D. Alcohol use and T

lymphocyte subsets among injection drug users

with HIV-1 infection: A prospective analysis.

Alcoholism: Clinical and Experimental

Research 20:364371, 1996.

DAVIS, C.C.; MELLENCAMP, M.; AND PREHEIM,

L. A model of pneumococcal pneumonia in

chronically intoxicated rats.Journal of Infec-

tious Diseases 163:799805, 1991.

DEVIERE, J.; CONTENT, J.; DENYS, C.; VANDEN-

BUSSCHE, L.; SCHANDENE, J.; WYBRAN, E., AND

DUPONT, E. High IL-6 serum levels and in-

creased production by leukocytes in alcoholic

liver cirrhosis. Correlation with IgA serum

levels and lymphokine production. Clinical and

Experimental Immunology 77:221225, 1989.

FONG, I.W.; READ, S.; WAINBERG, M.A.; CHIA,

W.K.; AND MAJOR, C. Alcoholism and rapid

progression to AIDS after seroconversion.

Clinics of Infectious Diseases 19:337338, 1994.

GENTILELLO, L.M.; COBEAN, R.A.; WALKER,

A.P.; MOORE, E.E.; WERTZ, M.J.; AND

DELLINGER, E.P. Acute ethanol intoxication

increases the risk of infections following pene-

trating abdominal trauma.Journal of Trauma

34:669675, 1993.

JERRELS, T., AND SIBLEY, D. Effects of ethanol

on T-cell-mediated immunity to infectious

agents. In: Friedman, H.; Klein, T.W.; and

Specter, S., eds.Drugs of Abuse, Immunity andInfections. Boca Raton: CRC Press, 1996. pp.

129141.

JERRELS, T.; SAAD, A.J.; AND KRUGER, T.E.Ethanol-induced suppression of in vivo hostdefense mechanisms to bacterial infection. In:Friedman, H.; Klein, T.W.; and Specter, S., eds

Drugs of Abuse, Immunity, and AIDS. Vol. 335New York: Plenum Press, 1993. pp. 153158.

KHORUTS, A.; STAHNKE, L.; MCCLAIN, C.J.;

LOGAN, G.; AND ALLEN, J.I. Circulating tumornecrosis factor, interleukin-1 and interleukin-6concentrations in chronic alcoholic patients.

Hepatology 13:267276, 1991.

KRUGER, T.E., AND JERRELS, T.R. Potential roleof alcohol in human immunodeficiency virusinfection.Alcohol Health & Research World16:5763, 1992.

MANDREKAR, P.; CATALANO, D.; AND SZABO, G.Human monocyte IL-10 production is increasedby acute ethanol treatment. Cytokines 8:567577, 1996.

NELSON, S.; SHELLITO, J.; MASON, C.; AND SUM-MER

, W. Alcohol and bacterial pneumonia.Al-cohol Health & Research World16:7386, 1992

ROSELLE, G.A. Alcohol and the immune systemAlcohol Health & Research World 16:1622,1992.

SAAD, A.J.; DOMIATI-SAAD, R.; AND JERRELS, T.Ethanol ingestion increases susceptibility of micetoListeria monocytogenes. Alcoholism: Clinicaland Experimental Research 17:7585, 1993.

SPITZER, J., AND BAUTISTA, A. Alcohol, cy-tokines and immunodeficiency. In: Friedman,H.; Klein, T.W.; and Specter, S., eds.Drugs of

Abuse, Immunity, and AIDS. New York: Ple-num Press, 1993. pp. 159164.

SZABO, G.; MANDREKAR, P.; AND CATALANO, D.Inhibition of superantigen-induced T-cellproliferation and monocyte IL-1, TNF and IL-6 production by acute ethanol.Journal of Leuk-ocyte Biology 58:342350, 1995.

SZABO, G.; MANDREKAR, P.; VERMA, B.; ANDCATALANO, D. Acute ethanol uptake prior toinjury modulates monocyte TNF productionand mononuclear cell apoptosis. In: Faist, E., ed

Immune Consequences of Trauma and Sepsis.

Berlin: Springer-Verlag, 1996. pp 252260.

VICENTE-GUTIERREZ, M.M.; RUIZ, A.D.;EXTREMERA, B.G.; GARCIA, J.M.B.; AND GEA,F.G. Low serum levels of alpha-interferon,

gamma-interferon, and interleukin-2 in alcoholiccirrhosis.Digestive Disease Sciences 36:12091212, 1991.



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Worldwide, tuberculosis (TB) is the leading cause of deathfrom a single infectious agent (Flynn and Bloom 1996).

Mycobacterium tuberculosis, the agent responsible for TB,is transmitted when a person inhales microscopic airborneparticles containing the organism (i.e., droplet nuclei)coughed up by someone with active TB disease, althoughprolonged exposure usually is necessary before an infec-tion becomes established. InitiallyM. tuberculosis attacksthe lung, where immune cells (i.e., macrophages and lym-phocytes) battle the infection. In the absence of adequateimmunity, however, the bacteria ingested by macrophagescontinue to multiply within these immune cells, and char-acteristic lesions called tubercles eventually form in the lungs.Among other symptoms, people with active TB develop abloody cough, fatigue, and difficulty breathing. TB can

affect any organ system or develop into systemic infection(i.e., miliary TB) when infected cells spread from the lungsand disseminate through the bloodstream. No effectivevaccination against TB currently exists, but 6 to 9 monthsof treatment with multiple antituberculous drugs will curemost TB patients who complete the course of therapy.

Sociological studies show that TB is more prevalent inlow-income, densely populated housing areassettingsoften associated with high rates of alcoholism.1

Numerous studies also have noted a direct associationbetween alcoholism and pulmonary tuberculosis(Jacobson 1992). Such apparent susceptibility to TBinfection among alcoholics, especially those who arehomeless or indigent, can be attributed both to biologicaland to social and behavioral factors.

Biological Factors

Although approximately one-third of the worlds popula-tion is infected withM. tuberculosis, only about 10 percentwill experience either acute or reactivated disease (Flynnand Bloom 1996). Clearly, the bodys immune system isquite capable of controllingM. tuberculosis in most cases.Any illness or condition associated with an impaired im-mune system, however, can increase the likelihood ofdeveloping active TB. In particular, numerous animalstudies have confirmed that the bodys control ofM. tuber-

culosis infection resides in its ability to mobilize macro-phages and lymphocytes against invading organisms (i.e.,cell-mediated immunity) (Dunlap and Briles 1993).

Because alcohol use significantly inhibits cell-mediatedimmunity, it compromises the bodys immune defense.

Thus, alcoholism

along with other diseases associatedwith impaired cell-mediated immunity (e.g., HIV infec-tion)increases a persons susceptibility to active TBinfection as well as reactivation of latent disease (Flynnand Bloom 1996). Researchers do not know, however,whether alcohol consumption itself or the liver damage andmalnutrition often associated with alcoholism are primarilyresponsible for the impaired immunity of alcoholics.

Investigators studying mechanisms by which alcoholpredisposes people to TB recently have focused specialattention on the specific immune system componentsparticipating in the bodys defense againstM. tuberculosisand related mycobacteria. Alcohol use has been found to

hinder the bodys antimycobacterial defense on multiplelevels, including through impaired macrophage response,

altered levels of the proteins that act as intercellular medi-ators (i.e., cytokines), and a disturbed balance between thetwo basic types of acquired immunity: cell-mediated im-munity and immunity provided by circulating antibodies(i.e., humoral immunity). Each of these interrelated conse-quences is discussed in the sections that follow.

Impaired Macrophage Response. Macrophage activationis considered essential for local containment and destruc-tion of mycobacteria (includingM. tuberculosis) andother invasive microorganisms. Thus, macrophage activi-

ty is the hallmark of resistance to TB (Flynn and Bloom1996). These immune system cells (along with the mono-cytes that give rise to them) play a key role in directlypresentingthe chemical identifiers that stimulate animmune response (i.e., the antigens) to lymphocytes inthe bodys lymph tissue. In response to antigen presenta-tion, certain lymphocytes (i.e., T lymphocytes) developinto T cells that specifically target theM. tuberculosisorganism for destruction. These T cells rapidly multiplyand circulate throughout the body. Evidence from severallaboratories suggests that activation of two types of Tcells in particular (i.e., CD4 and CD8 T cells) is impor-tant in the control of mycobacterial infection (Flynn et al.

1992; Kaufmann and Flesch 1986; Leveton et al. 1989;Orme and Collins 1983, 1984; Flory et al. 1992).Although alcohol likely affects many immune system

cells, macrophages and monocytes appear to be particularlysensitive to its influences. Both acute and chronic alcohol usemay decrease the activation of antigen-specific T cells byinhibiting the macrophagescapacity to present mycobacterialantigen to lymphocytes (Szabo et al. 1993). Bermudez andYoung (1991) have shown that alcohol also enhances thesurvival of another pathogen (i.e., theMycobacterium aviumcomplex, or MAC2) within blood-derived macrophages inpeople and liver macrophages (i.e., Kupffer cells) in mice.

VOL. 21, NO. 1, 1997 39

ALCOHOL AND SUSCEPTIBILITY TO TUBERCULOSIS

1The terms alcoholismand alcoholicas used in this article aresummary terms for the diagnoses of alcohol abuse and alcoholism.

2Compared withM. tuberculosis, MAC is a less invasive infectiousagent, but it has been associated with both pulmonary and disseminateddisease in people with compromised immune systems (e.g., alcoholicsor people with AIDS), just as TB has. The pathology and cell-mediatedimmune mechanisms involved in the bodys defense against MAC aresimilar to those seen inM. tuberculosis infection, making research onthis agent relevant to an understanding of TB control.



11/12

The same study demonstrated an increase in MAC colonycounts in the blood, liver, and spleen of alcohol-fed micecompared with controls, suggesting that alcohol use prior toand during MAC infection contributes to dissemination ofthe disease in the body.

In addition to decreasing the antimycobacterial activi-ty of macrophages, alcohol consumption also reducesmacrophage response to immune system modifiers. Forexample, the cytokines known as tumor necrosis factoralpha (TNF-) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both have been shown toinduce macrophages to inhibit the growth of and destroymycobacteria. In vitro studies suggest that alcohol im-pedes the protective effect exerted by these cytokines,however (Bermudez and Young 1991).

Altered Cytokine Levels. TNF-, one of the inflammatorymediators derived primarily from macrophages, plays a

major role in antimycobacterial defense (Nelson et al. 1995;Flynn and Bloom 1996). This cytokine directly inhibitsmycobacterial growth in vitro, recruits additional inflamma-tory cells, and induces the action of other antimycobacterialmediators (e.g., nitric oxide and reactive oxygen radicals).

One of the most dramatic effects of both acute andchronic alcohol use is the impaired capacity of monocytesto produce cytokines that trigger inflammation, particularlyTNF-, in response to bacterial or mycobacterial infection.In a study with rats, Nelson and colleagues (1989) foundthat the immune cells first to be exposed to mycobacteria(i.e., macrophages in the alveoli of the lungs) showed areduced capacity to manufacture TNF- following both

chronic and acute alcohol consumption, an effect thatlikely would contribute to a compromised immune defenseagainst TB. Of interest, Denis (1991) found that TNF-had a beneficial effect on survival when it was infused intomice inoculated withM. tuberculosis, suggesting thatalcohols negative effect on the antimycobacterial activityof macrophages potentially could be overcome.

Disturbed Cell-Mediated and Humoral Immunity Bal-ance. Both acute and chronic alcohol use are associatedwith a shift toward the predominance of humoral immunefunctions at the expense of cell-mediated functions, asindicated by increased levels of circulating antibodies and

decreased T-cell activity. Specifically, acute and chronicalcohol use alter the profile of the T-cell population sothat the type of cells known as T-helper-2 (Th2), whichare associated with humoral immunity, dominate overthose known as T-helper-1 (Th1), which are associatedwith cell-mediated immunity. One recent hypothesissuggests that this shift comes about through alcoholseffects on monocytes. Monocytes play a pivotal role insupporting a Th1 immune response in two ways: throughtheir capacity to present antigen to activate T cells andthrough their manufacture of the important cytokinesknown as interleukin-12 (IL-12) and interleukin-10 (IL-

10). IL-12 enhances the activity of CD4 and CD8 T cells,as well as natural killer cells, and triggers a cell-mediatedimmune response; elevated levels of IL-10, however,inhibit production of IL-12 and other inflammatory cy-tokines. In recent studies of isolated human monocytes

exposed to alcohol, researchers have observed elevatedIL-10 levels, inhibition of IL-12, increased production ofother mediators that check the immune system (e.g.,transforming growth factor beta [TGF-]), and a reducedantigen-presenting capacity (Szabo et al. 1993, 1996;Mandrekar et al. 1996). All of these effects imply thatacute alcohol consumption impairs a cell-mediated (i.e.,Th1-type) immune response and consequently tilts thebalance of the immune system toward humoral (i.e., Th2-type) immune functions. Given the importance of cell-mediated immunity in overcoming TB infection, theimplications of this shift can be significant for alcoholicsexposed toM. tuberculosis.

Researchers also have found, however, that the cy-tokine gamma-interferon (IFN-) plays a critical role indetermining whether a Th1- or Th2-type response willdominate in alcohol-exposed monocytes. Recent studiesshowed that the presence of IFN-decreased alcohol-induced IL-10 production, thus canceling IL-10s inhibi-tion of IL-12 and thereby augmenting cell-mediated (i.e.,Th1-type) immunity (Mandrekar et al. 1996; Szabo et al.1996). This finding supports the demonstration by Flynnand Bloom (1996) that IFN-is essential to resistanceagainst TB in mice. Vicente-Gutierrez and colleagues(1991) have reported decreased IFN-in chronic alco-holics, indicating that suppressed IFN-levels in alco-

holics likely contribute to an impaired cell-mediatedimmune response during mycobacterial infection.Taken together, both acute and chronic alcohol use

have been shown to predispose the body to compromiseddefense against mycobacteria. Although researchers stillneed to refine our understanding of the exact mechanismsby which alcohol use decreases antimycobacterial defense,the immunosuppressive effects of alcohol on monocyte andmacrophage function, cytokine production, and antigen-specific T-cell activation appear to be key factors in theincreased susceptibility to TB following alcohol use.

Social and Behavioral Factors

For alcoholics, especially those who are indigent orhomeless, several social and behavioral factors convergeto increase their vulnerability to TB and to hinder theirrecovery from the disease.

High-Risk Living Conditions. Typically, indigent andhomeless alcoholics dwell in crowded and impoverishedliving conditions. Such an environment significantly in-creases their chances for repeatedly inhalingM. tuberculo-sis droplet nuclei. With prolonged exposure, a person ismore likely to acquire an active TB infection and subse-quently spread the disease by coughing up more infectious



12/12

droplets for others to inhale. TB outbreaks have occurredin urban homeless shelters and other densely populatedresidential settings, such as prisons and nursing homes.Kline and colleagues (1995) even reported an outbreakamong regular patrons of a neighborhood bar and specu-

lated that heavy alcohol use and a highly infective sourcecould have been contributing factors.

Behavioral Issues. The chaotic lifestyles of most indigentalcoholics tend to delay their seeking medical attentionuntil their illness is fairly severe. Consequently, theyoften show up at a hospital or clinic with extensive TBinfection and tissue destruction. Nevertheless, unless theirillness is far advanced, alcoholics theoretically shouldrespond just as well as nonalcoholics to medical therapy.Indigent and homeless alcoholics actually have a poorerprognosis than others with TB, however. The primaryreason is not a worse response to medications but a rela-

tive lack of cooperation in taking them. The same disor-ganized life circumstances that delay treatment seekingalso impede taking regular doses of medication. In addi-tion, the treatments for TB involve drugs that are poten-tially toxic to the liver and the nervous system, andalcohol enhances their toxicity. Rather than stop drinking,alcoholics may avoid treatment for TB.

Standard drug therapy for TB currently involves 9months of taking the medications isoniazid and rifampinor 6 months of taking isoniazid, rifampin, and pyrazi-namide. After an initial phase of daily medication, patientscan receive drugs twice weekly without compromisingeffectiveness. (The slow growth cycle ofM. tuberculosisnecessitates a long treatment duration, and multiple drugsthwart the organisms ability to develop resistance.)Because homeless alcoholics frequently have difficultyadapting to hospitalization, outpatient care is the usualapproach to managing their illness. Even so, these patientsmay not comply well with treatment, either by failing tokeep their medical appointments consistently or by notcompleting therapy. Impoverished alcoholics thus areprone to reactivation of TB, and if their medication use iserratic, a strain ofM. tuberculosis resistant to standardmedication is more likely to develop. Contagious alco-holics then spread resistant TB strains to others.

Alcoholics may be especially unlikely to cooperatewith treatment if they perceive medical staff as a threat totheir drinkinga likely scenario given the dangers ofcombining TB medication with alcohol. Caregiversshould bear in mind that TB is a serious public healthhazard and give first priority to resolving a patients TBover addressing his or her alcoholism. By providing alco-holic TB patients with friendly, nonthreatening support,caregivers may improve the chances for complete TBtreatment and, possibly, succeed in helping the patientaccept the need for alcoholism treatment as well.

Gyongyi Szabo

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KLINE, S.E.; HEDEMARK, L.L.; AND DAVIES, S.F. Outbreak of tuberculo-sis among regular patrons of a neighborhood bar.New England Journalof Medicine 333(4):222227, 1995.

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SZABO, G.; GIROUARD, L.; MANDREKAR, P.; AND CATALANO, D. Acuteethanol treatment augments interleukin-12 production in activatedhuman monocytes.Annals of the New York Academy of Sciences795:422425, 1996.

VICENTE-GUTIERREZ, M.M.; RUIZ, A.D.; EXTREMERA, B.G.; GARCIA,J.M.B.; AND GEA, F.G. Low serum levels of alpha-interferon, gamma-interferon, and interleukin-2 in alcoholic cirrhosis.Digestive Diseasesand Sciences 36(9):12091212, 1991.


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FAKTOR RISIKO ALKOHOL DAN TB

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