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PERSPECTIVES

billion per year (of which more than US $30 billion is for the direct costs of medical care).

In many wealthy countries, with technol- ogy and resources in place to mitigate some of the harmful effects caused by alcohol, alco- hol consumption has been on the decline. By contrast, drinking is clearly on the rise in poor and developing countries, and in the countries of Central and Eastern Europe. This trend is of substantial concern from a world health perspective because public health mea- sures and infrastructures either do not exist or are insufficient in these countries5. In parts

of Central and Eastern Europe, alcohol use is contributing to fluctuations in male life expectancy6. Specifically, a decline of 6.2 years was observed in male life expectancy in Russia from 1990 to 1994 (REF. 6). This trend almost completely reversed by 1998 and was associated with a 19% reduction in average daily alcohol consumption; this decline might be due to less economic stress6.

Economic development and religion seem to be the most influential determinants of national alcohol consumption, and define patterns and levels of drinking. For example, South Africa ranked 45th in per-capita adult alcohol consumption in 1996 (REF. 1). However, because most black South African adults do not drink at all, the average yearly consumption of alcohol among those who do drink is almost three times what the statistics would initially suggest. Although women in most nations tend to drink less than men, the differences are far greater in developing

Impaired health caused by alcohol abuse has been known throughout recorded history. Over the past century, alcohol abuse has been clearly linked to host susceptibility to infectious disease, particularly bacterial pneumonia. Recently, both acute and chronic alcohol intake have been shown to result in specific defects in innate and adaptive immunity; these could, in principle, be subjected to specific modulation to overcome the immunosuppressive effects of the most commonly abused substance in the Western world.

Substance abuse (the problematic use of alco- hol, tobacco and other drugs) affects every aspect of our society and is a major health problem in the world today. It is estimated that alcohol exacts a worldwide health cost that parallels those of unsafe sex, measles and malaria. More than three-quarters of a million deaths were attributable to alcohol in 1990, of which 80% occurred in developing countries1. Although moderate use of alcohol has been shown in many studies to have a protective effect (FIG. 1), consuming more than two drinks of alcohol per day is associated with an increase in mortality2. In a cohort of patients from the United States, alcohol consumption showed a significant linear relationship to all- cause mortality for men and women under 60 years of age3. In France, where alcohol con- sumption is the highest in the world, men who consumed more than 60 ml of alcohol (approximately equal to five drinks) per day had an adjusted relative risk of total mortality 1.9 times that of those who consumed 0–25 ml per day (REF. 4). In the United States alone, it is estimated that alcohol abuse costs US $166

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Alcohol, host defence and society

Steve Nelson and Jay K. Kolls

S C I E N C E A N D S O C I E T Y

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Figure 1 | Biphasic effect of alcohol consumption on mortality. In many Western populations, occasional to moderate alcohol consumption has been associated with decreased relative risk of mortality. However, consuming three or more drinks of alcohol per day is associated with an increased all-cause mortality2.

P E R S P E C T I V E S

infection. Capps and Coleman, at Cook County Hospital, retrospectively examined the influence of alcohol abuse on the death rate in 3,422 cases of lobar pneumonia that occurred over an eight-year period16. The mortality rate of patients with pneumonia who had no or light use of alcohol was 23%, whereas 35 and 50% of moderate and exces- sive drinkers, respectively, died of pneumonia.

Even with the advent of antibiotics, infec- tion has continued to be a problem among alcohol abusers. Nolan’s study of admissions to a university community hospital showed that 124 of the 900 patients admitted (13.8%) were alcoholics and that the most common presenting problems in these individuals (16.9%) was bacterial pneumonia, whereas only 6.5% of non-alcoholics presented with pneumonia17. In a study of 158 patients that were hospitalized for pneumonia at the Johns Hopkins Hospital, 40% had a history of acute or chronic alcoholism, which was the most common predisposing risk factor for the occurrence of pneumonia in this study18. Interestingly, most of the patients reported a frequent or heavy schedule of alcohol use in the weeks immediately before their infection.

More recently, in 1995, a case-controlled study in Spain of 50 control subjects and 50 patients with community-acquired pneumo- nia identified high alcohol intake as a risk fac- tor for pneumonia19. Furthermore, in a sec- ond portion of the study that was designed to assess prognostic factors in patients with pneumonia, alcohol abuse was shown to worsen disease outcome. Compared with patients who consumed low amounts of alcohol, high-alcohol-intake patients (con- sumption of at least 100 grams of ethanol per day for at least the past two years) had a higher incidence of pneumonia with Gram- negative bacilli, more severe clinical symp- toms, longer intravenous antibiotic therapy, slower resolution of pulmonary infiltrates, multilobar involvement and pleural effusions, all of which contributed to a longer hospital stay (10.3 days as opposed to 6.9 days). On the basis of these data and other reports in the literature, it can be concluded that alco- hol abuse increases patient susceptibility to pneumonia, and increases the morbidity and mortality resulting from these infections.

Alcohol and infectious diseases Owing in part to the specific cellular defects in immunity, alcohol abuse continues to be rec- ognized as a worldwide exacerbating morbid- ity in a variety of infections including pneumo- nia20 and hepatitis C (REFS 21–23). Alcohol abuse has also been found to be an independent risk factor for the development of ADULT RESPIRATORY

(severe inflammation in the pancreas that results from pancreatic duct obstruction or alcohol abuse), various types of cancer and in infectious diseases. Alcohol use can also clearly have harmful effects on non-users, such as victims of alcohol-related motor crashes or violence, or families of drinkers whose health might suffer owing to eco- nomic harm to the household caused by the behaviour of the drinker.

Although large-scale epidemiological studies have reported that low levels of alco- hol consumption have a protective effect on heart disease compared with abstainers, this effect is relevant only for populations in which such low levels of drinking are the norm and in which heart disease is prevalent, namely among males over 45 years of age and post-menopausal women in developed countries10,11. Epidemiological and biological evidence leads to the conclusions that modest alcohol intake decreases mortality by protect- ing people from coronary heart disease and that heavy drinking increases mortality by increasing the risk of suicide, homicide, acci- dental injury and several diseases, including stroke, liver cirrhosis, upper respiratory and digestive cancers, and infections12. The Global Burden of Disease study13 concluded that alcohol tends to kill and disable in the young and to protect from cardiovascular diseases at greater ages, a pattern that results in many years of potential life lost to death and disability despite the reputed protective effect of alcohol.

Historical perspective Alcohol is a potent immunosuppressive drug and has been widely recognized for many centuries as an important risk factor for the development of infections. As early as 1785, Benjamin Rush, the first Surgeon General of the United States, reported in ‘An inquiry into the effects of ardent spirits upon the human body and mind’ 14 that alcohol abusers are predisposed to more, and more severe, infec- tions, particularly of the respiratory tract. In 1905, Sir William Osler wrote in his Principles and Practice of Medicine15 that alcoholism is “perhaps the most potent predisposing fac- tor” to lobar pneumonia and recommended “a little more exercise, a little less food, and a little less tobacco and alcohol” as a lifestyle. Osler examined the relationship between alcohol abuse and mortality, and reported that ~18% of all deaths examined occurred in total abstainers, 30% in moderate drinkers and 52% in those who used spirits to excess.

It was not until 1923 that the first clinical study was carried out to assess the quantita- tive relationship between alcohol abuse and

countries than in the developed world. This creates a situation in which men suffer most of the direct consequences of drinking, whereas women are the primary sufferers of such indi- rect effects as domestic violence, abandon- ment and household poverty1. However, maternal drinking during pregnancy can result in fetal alcohol syndrome, a group of physical and mental birth defects that is char- acterized by abnormal facial features (long, flattened philtrum, thin upper lip), growth retardation and central nervous system prob- lems, and is an important cause of mental disability in Western countries7,8.

Alcohol abuse and disease Many studies have established the causal role of alchohol in a wide range of physical, men- tal and social harms, with practically no organ in the body spared its ill effects9. The level of alcohol problems is related to both the per-capita alcohol consumption and the particular pattern of drinking. The Global Alcohol Database of the World Health Organization tracks mortality and morbid- ity from 20 alcohol-related causes1. As alluded to above, age-adjusted death rates for alcohol dependence syndrome, chronic ALCOHOLIC LIVER DISEASE (ALD) and CIRRHOSIS are highest in the high-alcohol-consumption countries of Eastern and Central Europe. Other conditions that are, by definition, caused by alcohol use include alcohol psy- chosis, alcoholic polyneuropathy, alcoholic cardiomyopathy and alcoholic gastritis. Alcohol might have a crucial causal role in oesophageal varices (dilated veins in the wall of the oesophagus that result from hyperten- sion in the portal circulation, caused by cir- rhosis of the liver), chronic pancreatitis

Glossary

ADULT RESPIRATORY DISTRESS SYNDROME

(ARDS). This disease is characterized by the acute onset of hypoxaemia, bilateral infiltrates on chest X-rays and no evidence of left ventricular heart failure. It can be precipitated by sepsis, pneumonia, surgery and/or trauma.

ALCOHOLIC LIVER DISEASE

A spectrum of entities including steatohepatitis, or lipid accumulation in the liver associated with ethanol abuse, alcoholic hepatitis, which is an acute inflammatory response in the liver associated with ethanol abuse, and cirrhosis.

BACTERIAL TRANSLOCATION

Transfer of bacteria or bacterial products from the lumen of the gastrointestinal tract to mesenteric lymph nodes and into the portal circulation.

CIRRHOSIS

Micro- or macronodular fibrosis in the liver, which can result from chronic alcohol abuse.

P E R S P E C T I V E S

mortality than controls25. Although most studies with acute alcohol show a suppressed cytokine/chemokine response, chronic ethanol consumption results in an enhanced cytokine/chemokine response (FIG. 2), particu- larly in the liver26. Evidence indicates that this pro-inflammatory effect of ethanol is due to an alteration in cellular redox state caused by enhanced release of reactive oxygen species (ROS) in the liver26 and enhanced BACTERIAL TRANSLOCATION of enteric bacteria, resulting in chronic endotoxin signalling in Kupffer cells and hepatocytes. Enhanced oxidative stress induced by chronic ethanol intake has been shown to increase the transcription of the tumour-necrosis-factor-α (TNF-α) gene, to stabilize TNF-α mRNA27 and to activate TNF-α-converting enzyme (TACE), resulting in enhanced production of TNF-α28.

Alcohol and the immune system Data from the past two decades have revealed that both acute and chronic ethanol abuse result in specific defects in cellular compo- nents of both the innate and the adaptive immune response (BOX 1). One of the crucial cells that initiate host defence against invad- ing pathogens in the lung is the alveolar macrophage29. Acutely, alcohol has been shown to suppress significantly the produc- tion of pro-inflammatory cytokines, such as TNF-α and interleukin-1β (IL-1β) (FIG. 2, in alveolar macrophages30–32 and human blood monocytes33). This is associated with a decrease in phosphorylation of Iκ Bα (inhibitor α of nuclear factor-κB), which is required for the efficient nuclear transloca- tion of nuclear factor-κB (NF-κB), a crucial transcription factor for the expression of pro- inflammatory cytokines such as TNF-α and IL-1β (REF. 34).

The coordinated release of these cytokines is crucial for the upregulation of adhesion molecules on vascular endothelial cells and the subsequent recruitment of polymor- phonuclear leukocytes (PMNs)29. Acute doses of alcohol in the intoxicating range (0.1–0.3 milligrams per decilitre) reproducibly sup- press PMN recruitment to the lung, partly by inhibiting the release of chemokines in the lung35. Moreover, acute ethanol also sup- presses PMN phagocytosis and the oxidative burst36. Recently, it has also been shown that ethanol can suppress IL-17 expression (REF. 38), a cytokine that is mainly produced by T cells and that seems to coordinate chemokine gene expression and subsequent lung PMN recruitment in response to K. pneumoniae infection38, which is commonly seen in people who abuse alcohol. Decreased PMN migra- tion caused by acute ethanol has also been

DISTRESS SYNDROME (ARDS), a complication of pneumonia24. Alcohol abuse can cause pneu- monia because of its sedative properties, which lead to diminished oropharyngeal tone, an increased risk of aspiration and diminished cough reflex and mucociliary clearance (FIG. 2). Moreover, alcohol abuse has been associated with a higher incidence

of pneumonia caused by Gram-negative bacteria, specifically Pseudomonas aeruginosa and, historically, Klebsiella pneumoniae20.

The enhanced mortality of K. pneumoniae infection in alcoholics has been modelled in experimental animals that consume oral alcohol25. In this model, alcohol-consuming mice had higher levels of bacteraemia and

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Figure 2 | Overview of alcohol abuse and the immune system. Ingested ethanol (EtOH) rapidly enters the bloodstream and freely enters various tissue compartments. Chronic ethanol ingestion and metabolism can lead to an altered cellular redox state due to increased production of reactive oxygen species (ROS) by Kupffer cells (KC) and translocation of bacteria and endotoxin (lipopolysaccharide, LPS). LPS signalling through Toll-like receptor 4 (TLR4) leads to the release of pro-inflammatory cytokines (tumour-necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)) and chemokines (IL-8 and monocyte chemoattractant protein-1). These events are thought to be crucial in the development of chronic liver disease. Local production of TNF-α can also induce the local production of the suppressor of cytokine signalling 3 (SOCS3), which can inhibit STAT (signal transducers and activators of transcription) signalling and so lead to the resistance of alcoholic liver disease patients to type-I interferons. Ethanol also results in the loss of splenic and circulating T and B cells, partly through apoptosis. In the lung compartment, ethanol suppresses the production of pro-inflammatory cytokines by the alveolar macrophages (AM) and of IL-17 by T cells in lung tissue or bronchiole-associated lymphoid tissue (BALT), which results in a diminished cytokine/chemokine cascade and hence defective polymorphonuclear leukocyte (PMN) recruitment and host defence. NF-κB, nuclear factor-κB.

P E R S P E C T I V E S

signalling in Kupffer cells through a Toll-like- receptor-4-mediated pathway. This signalling results in local production of TNF-α, which then signals through the p55 TNF receptor to cause local chemokine production and recruitment of inflammatory cells, which are thought to mediate liver injury53. Local pro- duction of TNF-α can also induce the local production of the suppressor of cytokine sig- nalling 3 (SOCS3), which antagonizes STAT (signal transducers and activators of tran- scription) signalling. This might explain why patients with ALD have lower responses to interferon-α treatment for hepatitis-C infec- tion54. Local production of IL-10, a suppres- sor of pro-inflammatory cytokines, such as TNF-α, and CXC chemokine production have been shown to be induced by ethanol55. This might suppress these crucial factors in the pulmonary compartment56 and so have a cru- cial role in the susceptibility of chronic alcohol abusers to pulmonary infections (FIG. 2).

Conclusion To optimally prevent alcoholism, we need sensitive screening tools and biological or genetic factors to identify high-risk groups on which to focus prevention efforts. Towards this end, there are continuing studies to define the genetic and sociological risk factors for alcoholism57,58, because the prevention of this disease will have a significant effect on preventing its sociological and immune alterations. For example, the association of a very low risk of alcoholism in Asian popula- tions with the liver mitochondrial aldehyde dehydrogenase 2 (ALDH2-2) genotype has recently been used therapeutically in a rat model in which basal levels of hepatic alde- hyde dehydrogenase were inhibited using antisense oligonucleotides targeting the ALDH2 gene, and this was associated with reduced ALDH activity, higher acetaldehyde levels after voluntary alcohol consumption and an aversion to alcohol59.

However, despite progress in these areas, clinicians are challenged with treating the end- organ injury as well as the immune conse- quences of alcoholism on a daily basis. There is, therefore, also a crucial need to under- stand the pathogenesis of both the organ response and the immune consequences of alcohol abuse to prevent end-organ injury. Recent data indicate that compartmentalized immunotherapy with the gene encoding interferon-γ (which can reverse the suppres- sive effect of alcohol on TNF-α production by alveolar macrophages) might also reverse the immunosuppressive effect of alcohol; this might have a role in augmenting traditional antibiotic therapy in alcoholic patients with

animals45,46. The decrease in lymphocyte num- bers has been associated with an increased sus- ceptibility to infections that require normal adaptive immune responses, such as L. mono- cytogenes 47. Moreover, components of the innate lymphocyte system, specifically natural killer cells, are also adversely affected by ethanol through suppression of the cytolytic effector molecules perforin and granzymes A and B (REF. 49), which is associated with decreased tumour surveillance (BOX 1).

Several lines of evidence indicate that ALD results from the action of specific immune cells, in addition to the potential direct toxic effects of alcohol and its meta- bolic by-products, principally acetaldehyde and oxidative species from lipid peroxida- tion49. Liver disease often progresses after con- tinued alcohol consumption ends49. Patients with ALD often have detectable autoantibod- ies and anti-hepatocyte cytotoxic T cells49. Recently, aldehydes from ethanol metabolism have been shown to form adducts on proteins that can then be recognized as neo-antigens, and these adducted proteins might be targets of autoimmunity in the liver50. Studies have also shown that, in experimental animals, bacterial translocation from the gastrointesti- nal tract51 is required for alcohol-induced liver injury52, which results in endotoxin-mediated

seen in human subjects using saline-solution- containing chambers placed over abraded skin to stimulate PMN migration, or ‘skin windows’39,40.

Although ethanol has broad effects on host cytokine and chemokine release, the molecular mechanisms underlying some of these effects have come into sharper focus. For example, administered acutely, ethanol has been shown to suppress NF-κB activity, which is required for efficient transcription of the genes that encode for TNF-α and many chemokines34. Consistent with these data, acute ethanol suppresses the induction of inducible nitric oxide synthase, the gene of which is regulated by NF-κB and which is required for adequate host defence against intracellular pathogens, such as Listeria mono- cytogenes and Mycobacterium tuberculosis41. In addition to these well-described effects on gene transcription, ethanol has also been shown to suppress cytokine production by inhibiting post-transcriptional events such as TACE-mediated cleavage of TNF-α (REF. 42).

Chronic administration of ethanol has been shown to result in fewer lymphocytes in the spleen, thymus and gut-associated lym- phoid tissue43, perhaps through an apoptotic mechanism44, and in decreased delayed-type hypersensitivity responses in experimental

Box 1 | Alcohol and cells of the immune system

Alveolar macrophages Acute ethanol. All the following are reduced: phagocytosis, superoxide generation, adherence, nuclear factor-κB (NF-κB) translocation, tumour-necrosis-factor-α (TNF-α)-converting enzyme (TACE) activity and release of TNF-α, interleukin-1β (IL-1β), granulocyte colony-stimulating factor (G-CSF) and CXC chemokines.

Chronic ethanol. Increased superoxide generation, NF-κB translocation, and TNF-α and TACE activity.

Polymorphonuclear leukocyte Acute ethanol. All the following are reduced: chemotaxis, adherence due to reduced CD18 expression, superoxide generation and phagocytosis.

Chronic ethanol. Leukopaenia and increased superoxide generation.

T cells Acute ethanol. Increased T-cell apoptosis and reduced IL-17 production.

Chronic ethanol. Lymphopaenia in blood and tissues, perhaps through apoptosis, and reduced IL-17 production and antibody production by T cells.

Natural killer cells Chronic ethanol. Reduced cytolytic mechanisms and expression of perforin and granzyme, which results in decreased anti-tumour activity.

Kupffer cells Chronic ethanol. Perhaps due to chronic ethanol abuse and translocation of bacterial endotoxin, and to cellular depletion of glutathione, there is increased reactive-oxygen-species generation, CXC chemokine production and TNF-α production.

Antigen-presenting cells Chronic ethanol. Reduced presentation of antigens. Owing to ethanol metabolism and the generation of aldehyde moieties, which can form protein adducts, neo-antigens can be formed, which contribute to autoantibody production and autoimmune hepatic inflammation and damage.

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44. Shao, H., Zhou, J. & Ewald, S. J. Regulation of signal transduction and DNA fragmentation in thymocytes by ethanol. Cell. Immunol. 164, 11–19 (1995).

45. Waltenbaugh, C. & Peterson, J. D. Ethanol impairs the induction of delayed hypersensitivity in C57BL/6 mice. Alcohol 14, 149–153 (1997).

46. Messingham, K. A., Fontanilla, C. V., Colantoni, A., Duffner, L. A. & Kovacs, E. J. Cellular immunity after ethanol exposure and burn injury: dose and time dependence. Alcohol 22, 35–44 (2000).

47. Saad, A. J., Domiati-Saad, R. & Jerrells, T. R. Ethanol ingestion increases susceptibility of mice to Listeria monocytogenes. Alcohol Clin. Exp. Res. 17, 75–85 (1993).

48. Spitzer, J. H. & Meadows, G. G. Modulation of perforin, granzyme A, and granzyme B in murine natural killer (NK), IL2 stimulated NK, and lymphokine-activated killer cells by alcohol consumption. Cell Immunol. 194, 205–212 (1999).

49. Lieber, C. S. Ethanol metabolism, cirrhosis and alcoholism. Clin. Chim. Acta 257, 59–84 (1997).

50. Rolla, R. et al. Detection of circulating antibodies against malondialdehyde–acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology 31, 878–884 (2000).

51. Thurman, R. G. et al. The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury. J. Gastroenterol. Hepatol. 13 (Suppl.), S39–S50 (1998).

52. Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U. & Thurman, R. G. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34, 101–108 (2001).

53. Yin, M. et al. Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice. Gastroenterology 117, 942–952 (1999).

54. Hong, F., Nguyen, V. A. & Gao, B. Tumor necrosis factor α attenuates interferon α signaling in the liver: involvement of SOCS3 and SHP2 and implication in resistance to interferon therapy. FASEB J. 15, 1595–1597 (2001).

55. Szabo, G., Mandrekar, P., Dolganiuc, A., Catalano, D. & Kodys, K. Reduced alloreactive T-cell activation after alcohol intake is due to impaired monocyte accessory cell function and correlates with elevated IL-10, IL-13, and decreased IFNγ levels. Alcohol Clin. Exp. Res. 25, 1766–1772 (2001).

56. Reddy, R. C. et al. Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10. Infect. Immun. 69, 1394–1401 (2001).

57. Turecki, G., Rouleau, G. A. & Alda, M. Family density of alcoholism and linkage information in the analysis of the COGA data. Genet. Epidemiol. 17 (Suppl. 1), S361–S366 (1999).

58. Peterson, L. E. et al. A genome-wide search for susceptibility genes linked to alcohol dependence. Genet. Epidemiol. 17 (Suppl. 1), S295–S300 (1999).

59. Garver, E. et al. Eliciting the low-activity aldehyde dehydrogenase Asian phenotype by an antisense mechanism results in an aversion to ethanol. J. Exp. Med. 194, 571–580 (2001).

60. Kolls, J. K. et al. Adenoviral-mediated interferon-γ gene therapy augments pulmonary host defense of ethanol- treated rats. Alcohol Clin. Exp. Res. 22, 157–162 (1998).

Online links

FURTHER INFORMATION Alcohol Education and Research Council: http://www.aerc.org.uk/ Educational Resources and Social Policy: http://www2. potsdam.edu/alcohol-info/ Eurocare: http://www.eurocare.org/ Institute of Alcohol Studies: http://www.ias.org.uk/ Louisiana State University Health Sciences Alcohol Research Center: http://alcoholresearch.lsuhsc.edu/ National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/ Thomas Jefferson University Alcohol Research Center: http://jeffline.tju.edu/CWIS/DEPT/Pathology/ARC/ Access to this interactive links box is free online.

pneumonia60. Moreover, appropriate early antibiotic therapy is crucial to prevent compli- cations of infection such as ARDS and multi- system organ dysfunction syndrome. The next decade will see advances in our understanding of the immune consequences of alcohol abuse at both the molecular and the cell-biological levels, which will hopefully result in therapies targeted at alterations in the cellular redox state and at the level of modulating specific gene expression to thwart the immunological consequences of alcohol abuse.

Steve Nelson and Jay K. Kolls are at the LSU Health Sciences Center Alcohol Research Center,

and Section of Pulmonary Critical Care, LSU Health Sciences Center, 533 Bolivar Street,

New Orleans, Louisiana 70112, USA. Correspondence to J.K.K. e-mail: [email protected]

DOI: 10.1038/nri744

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