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Alcohol intake, immune response, and the skin
Alcohol Intake, Immune Response, and the Skin ARNON D. COHEN, MD SIMA HALEVY, MD
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ncreased alcohol consumption has been associated with dermatological diseases including psoriasis, rosacea, nummular eczema, acne, porphyria cutanea tarda, and facial flushing.1,2 As alcohol consumption is associated with liver cirrhosis and malnutrition, the skin manifestations of these diseases may also indicate alcohol misuse. Alcohol seems to affect dermatological diseases by influencing metabolism (eg, porphyria cutanea tarda3), cutaneous vasculature (eg, rosacea4), and the immune response.5,6 Patients who consume alcohol excessively are at increased risk for infectious diseases, including HIV infection.7,8 When alcoholics develop an infectious disease, it is associated with increased morbidity and mortality.6 Immune suppression secondary to both malnutrition and liver disease may occur following alcohol consumption6; however, as the frequency and severity of infections are so pronounced among alcoholics, it seems that alcohol by itself may suppress the immune system.
Laboratory Findings In the last decades, numerous reports described the influence of alcohol on the immune system in vivo and in vitro. Alcohol has a variety of effects on cell-mediated and humoral immune responses. Alcohol also suppresses the function of polymorphonuclear function and the reticuloendothelial system.6 –22 Chronic alcoholism is associated with a depressed cell-mediated immune response,6 which may manifest in vivo by decreased delayed hypersensitivity reactions in skin tests19 and in vitro by a decreased blast transformation to mitogens.22 Alcohol affects the production, action sites, and metabolism of cytokines.14 Alcoholic patients with liver disease have increased serum levels of immunoglobulins,18 probably due to increased production of immunoglobulins by B lymphocytes; however, humoral response to antigenic challenges is diminished in alcoholics.6 From the Department of Dermatology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, BeerSheva, Israel. Address correspondence to Sima Halevy, MD, Head, Department of Dermatology, Soroka University Medical Center, Beer-Sheva, 84101 Israel. © 1999 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
Some patients with chronic alcoholism have mild neutropenia, which is aggravated by stress or infections and is reversible upon abstinence.6 The neutropenia in alcoholics is caused by bone marrow suppression, shown by a decrease in the number of mature granulocytes.17 Bone marrow suppression may be caused by suppression of colony-stimulating factor activity by alcohol.16 In acute alcohol intoxication, polymorphonuclear leukocytes activity is suppressed,6 as shown in vitro as decreased granulocyte adherence.13,18 In chronic alcoholism neutrophil chemotaxis is decreased, in particular in patients with liver cirrhosis20; alcohol, however, does not seem to affect phagocytic function of polymorphonuclears.13 Alcohol depresses macrophage functions (eg, mobilization, activation, and phagocytosis), manifested as decreased particle evacuation from the lungs, clinically observed as an increased rate of pneumonia in alcoholics.6,12 Although numerous studies on the effect of alcohol on the immune system exist, a “medline” literature search revealed only a few studies on the effect of alcohol on the immune system in dermatology, all of which were in patients with psoriasis.23–25 For further information on the influence of alcohol on the immune system in general medicine, the reader is referred to an extensive review on this topic by MacGregor.6
Psoriasis Psoriasis is an inflammatory dermatosis, considered by most authorities to be an immune-mediated disorder.5 The immune pathogenesis of psoriasis is associated with a Th-1 immune response, with overproduction of the cytokines IL-2, IL-6, IL-8, interferon-␥, transforming growth factor-␣ (TGF-␣), and tumor necrosis factor-␣ Precipitation or exacerbation of psoriasis has been associated with genetic background, emotional stress, streptococcal infections, and drugs. It is a well-described clinical phenomenon that alcohol consumption by some patients with psoriasis may induce exacerbation of the disease.2,26 –28 Ockenfels et al23,25 performed in vitro lymphocyte proliferation assays in psoriatic patients and controls. 0738-081X/99/$–see front matter PII S0738-081X(99)00025-5
Clinics in Dermatology
412 COHEN AND HALEVY
Both spontaneous and PHA-driven lymphocyte proliferation were lower in patients with psoriasis. However, the addition of ethanol increased the proliferation of lymphocytes from psoriatic patients by 200 –300%, as compared to controls. A co-culture model with keratinocytes obtained from psoriatic patients and T-lymphoma cell line (HUT-78) was generated by Ockenfels et al.24 In this model HUT-78 cells were co-incubated with keratinocytes from psoriatic patients, and were cultured for 24 hours with or without the addition of ethanol. Levels of IL-2, IL-6, IL-8, interferon-␥, and TGF-␣ were measured in the culture supernatants. It was found that TGF-␣ and interferon-␥ levels were elevated in the ethanol-treated psoriatic co-cultures by 150 –175%, as compared to controls, whereas IL-2, IL-6, and IL-8 levels were not significantly influenced. The co-culture model demonstrates an enhanced Th-1-type response in keratinocytes from psoriatic patients in the presence of ethanol. These in vitro findings may explain clinical observations of aggravation of psoriasis by alcohol consumption. Although the studies by Ockenfels et al23–25 might suggest that alcohol influences the cytokine network in psoriasis, it remains unclear whether this is the main influence of alcohol in psoriatic patients in vivo.
Conclusions It is apparent that alcohol is associated with dermatological diseases, some of which have an immune pathogenetic mechanism (eg, psoriasis); however, as laboratory evidence for the influence of alcohol on such dermatoses is scarce, further in vitro studies are necessary to clarify the influence of alcohol and its metabolites on the skin.
References 1. Higgins EM, du Vivier AWP. Cutaneous disease and alcohol misuse. BMJ 1994;50:85–98. 2. Rothenbor HW, Andersen HB. Alcohol and skin disorders. J Eur Acad Dermatol Venereol 1993;2:113–20. 3. Elder GH. The cutaneous porphyrias. Semin Dermatol 1990;9:63–9. 4. Wilkin JK. Oral thermal induced flushing in erythematoelangiectatic rosacea. J Invest Dermatol 1981;76:15– 8. 5. Gottlieb AB. Immunologic mechanisms in psoriasis. J Am Acad Dermatol 1988;18:1376 – 80. 6. MacGregor RR. Alcohol and immune defense. JAMA 1986;256:1474 –79. 7. Balla AK, Lischner HW, Pomerantz RJ, et al. Human studies on alcohol and susceptibility to HIV infection. Alcohol 1994;11:99 –103. 8. McManus TJ, Weatherburn P. Alcohol, AIDS and immunity. Br Med Bull 1994;50:115–23. 9. Mendenhall CL, Theus SA, Roselle GA, et al. Biphasic in
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vivo immune function after low- versus high-dose alcohol consumption. Alcohol 1997;14:255– 60. Singer DS, Parent L, Kolber MA. Ethanol: An enhancer of transplantation antigen expression. Alcohol Clin Exp Res 1989;13:480 – 4. Dunne FJ. Alcohol and the immune system. BMJ 1989;298: 543– 44. Bonalski JS, Phair JP. Alcohol, immunosuppression, and the lung. Arch Intern Med 1982;142:2073– 4. Brayton RG, Stokes PE, Schwartz MS, et al. Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. N Engl J Med 1970;282:123– 8. Deaciuc IV. Alcohol and cytokine networks. Alcohol 1997; 14:421–30. Hook-Nikanne J, Kariniemi AL, Renkonen OV, et al. Could bacterial acetaldehyde production explain the deterious effect of alcohol on skin diseases? Acta Derm Venereol (Stockh) 1995;75:330. Imperia PPS, Chikkappa G, Phillips PG. Mechanism of inhibition of granulopoiesis by ethanol. Proc Soc Exp Biol Med 1984;175:219 –25. Liu YK. Effects of alcohol on granulocytes and lymphocytes. Semin Hematol 1980;17:130 – 6. MacGregor RR, Gluckman SJ, Senior JR. Granulocyte function and levels of immunoglobulins and complement in patients admitted for withdrawal from alcohol. J Infect Dis 1978;138:747–55. Snyder N, Bessoff J, Dwyer JM, et al. Depressed delayed cutaneous hypersensitivity in alcoholic hepatitis. Am J Dig Dis 1978;23:353– 8. Van Epps DE, Strickland RG, Williams RC Jr. Inhibitors of leukocyte chemotaxis in alcoholic liver disease. Am J Med 1975;59:200 –7. Zhang P, Nelson S, Smmer WR, et al. Acute ethanol intoxication suppresses the pulmonary inflammatory response in rats challenged with intrapulmonary endotoxin. Alcohol Clin Exp Res 1997;21:773–78. Glassman AB, Bennett CE, Randall CL. Effects of ethyl alcohol on human peripheral lymphocytes. Arch Pathol Lab Med 1985;109:540 –2. Schopf RE, Ockenfels HM, Morsches B, et al. Ethanol enhances the mitogen-driven lymphocyte proliferation in patients with psoriasis. Acta Derm Venereol (Stockh) 1996;76:260 –3. Ockenfels HM, Kein-Maas C, Funk R, et al. Ethanol enhances the IFN-gamma, TGF-␣ and IL-6 secretion in psoriatic co-cultures. Br J Dermatol 1996;135:746 –51. Ockenfels HM, Morsches B, Schopf RE. Chloroquine, ethanol and indomethacin affect lymphocyte proliferation in patients with psoriasis (abstr). J Invest Dermatol 1993;100:216. Monk BE, Neil SM. Alcohol consumption and psoriasis. Dermatologica 1986;173:57– 60. Farber EM, Nall L. Psoriasis and alcoholism. Cutis 1994; 53:21–7. Baker BS, Fry L. The immunology of psoriasis. Br J Dermatol 1992;126:1–9.
I
ncreased alcohol consumption has been associated with dermatological diseases including psoriasis, rosacea, nummular eczema, acne, porphyria cutanea tarda, and facial flushing.1,2 As alcohol consumption is associated with liver cirrhosis and malnutrition, the skin manifestations of these diseases may also indicate alcohol misuse. Alcohol seems to affect dermatological diseases by influencing metabolism (eg, porphyria cutanea tarda3), cutaneous vasculature (eg, rosacea4), and the immune response.5,6 Patients who consume alcohol excessively are at increased risk for infectious diseases, including HIV infection.7,8 When alcoholics develop an infectious disease, it is associated with increased morbidity and mortality.6 Immune suppression secondary to both malnutrition and liver disease may occur following alcohol consumption6; however, as the frequency and severity of infections are so pronounced among alcoholics, it seems that alcohol by itself may suppress the immune system.
Laboratory Findings In the last decades, numerous reports described the influence of alcohol on the immune system in vivo and in vitro. Alcohol has a variety of effects on cell-mediated and humoral immune responses. Alcohol also suppresses the function of polymorphonuclear function and the reticuloendothelial system.6 –22 Chronic alcoholism is associated with a depressed cell-mediated immune response,6 which may manifest in vivo by decreased delayed hypersensitivity reactions in skin tests19 and in vitro by a decreased blast transformation to mitogens.22 Alcohol affects the production, action sites, and metabolism of cytokines.14 Alcoholic patients with liver disease have increased serum levels of immunoglobulins,18 probably due to increased production of immunoglobulins by B lymphocytes; however, humoral response to antigenic challenges is diminished in alcoholics.6 From the Department of Dermatology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, BeerSheva, Israel. Address correspondence to Sima Halevy, MD, Head, Department of Dermatology, Soroka University Medical Center, Beer-Sheva, 84101 Israel. © 1999 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
Some patients with chronic alcoholism have mild neutropenia, which is aggravated by stress or infections and is reversible upon abstinence.6 The neutropenia in alcoholics is caused by bone marrow suppression, shown by a decrease in the number of mature granulocytes.17 Bone marrow suppression may be caused by suppression of colony-stimulating factor activity by alcohol.16 In acute alcohol intoxication, polymorphonuclear leukocytes activity is suppressed,6 as shown in vitro as decreased granulocyte adherence.13,18 In chronic alcoholism neutrophil chemotaxis is decreased, in particular in patients with liver cirrhosis20; alcohol, however, does not seem to affect phagocytic function of polymorphonuclears.13 Alcohol depresses macrophage functions (eg, mobilization, activation, and phagocytosis), manifested as decreased particle evacuation from the lungs, clinically observed as an increased rate of pneumonia in alcoholics.6,12 Although numerous studies on the effect of alcohol on the immune system exist, a “medline” literature search revealed only a few studies on the effect of alcohol on the immune system in dermatology, all of which were in patients with psoriasis.23–25 For further information on the influence of alcohol on the immune system in general medicine, the reader is referred to an extensive review on this topic by MacGregor.6
Psoriasis Psoriasis is an inflammatory dermatosis, considered by most authorities to be an immune-mediated disorder.5 The immune pathogenesis of psoriasis is associated with a Th-1 immune response, with overproduction of the cytokines IL-2, IL-6, IL-8, interferon-␥, transforming growth factor-␣ (TGF-␣), and tumor necrosis factor-␣ Precipitation or exacerbation of psoriasis has been associated with genetic background, emotional stress, streptococcal infections, and drugs. It is a well-described clinical phenomenon that alcohol consumption by some patients with psoriasis may induce exacerbation of the disease.2,26 –28 Ockenfels et al23,25 performed in vitro lymphocyte proliferation assays in psoriatic patients and controls. 0738-081X/99/$–see front matter PII S0738-081X(99)00025-5
Clinics in Dermatology
412 COHEN AND HALEVY
Both spontaneous and PHA-driven lymphocyte proliferation were lower in patients with psoriasis. However, the addition of ethanol increased the proliferation of lymphocytes from psoriatic patients by 200 –300%, as compared to controls. A co-culture model with keratinocytes obtained from psoriatic patients and T-lymphoma cell line (HUT-78) was generated by Ockenfels et al.24 In this model HUT-78 cells were co-incubated with keratinocytes from psoriatic patients, and were cultured for 24 hours with or without the addition of ethanol. Levels of IL-2, IL-6, IL-8, interferon-␥, and TGF-␣ were measured in the culture supernatants. It was found that TGF-␣ and interferon-␥ levels were elevated in the ethanol-treated psoriatic co-cultures by 150 –175%, as compared to controls, whereas IL-2, IL-6, and IL-8 levels were not significantly influenced. The co-culture model demonstrates an enhanced Th-1-type response in keratinocytes from psoriatic patients in the presence of ethanol. These in vitro findings may explain clinical observations of aggravation of psoriasis by alcohol consumption. Although the studies by Ockenfels et al23–25 might suggest that alcohol influences the cytokine network in psoriasis, it remains unclear whether this is the main influence of alcohol in psoriatic patients in vivo.
Conclusions It is apparent that alcohol is associated with dermatological diseases, some of which have an immune pathogenetic mechanism (eg, psoriasis); however, as laboratory evidence for the influence of alcohol on such dermatoses is scarce, further in vitro studies are necessary to clarify the influence of alcohol and its metabolites on the skin.
References 1. Higgins EM, du Vivier AWP. Cutaneous disease and alcohol misuse. BMJ 1994;50:85–98. 2. Rothenbor HW, Andersen HB. Alcohol and skin disorders. J Eur Acad Dermatol Venereol 1993;2:113–20. 3. Elder GH. The cutaneous porphyrias. Semin Dermatol 1990;9:63–9. 4. Wilkin JK. Oral thermal induced flushing in erythematoelangiectatic rosacea. J Invest Dermatol 1981;76:15– 8. 5. Gottlieb AB. Immunologic mechanisms in psoriasis. J Am Acad Dermatol 1988;18:1376 – 80. 6. MacGregor RR. Alcohol and immune defense. JAMA 1986;256:1474 –79. 7. Balla AK, Lischner HW, Pomerantz RJ, et al. Human studies on alcohol and susceptibility to HIV infection. Alcohol 1994;11:99 –103. 8. McManus TJ, Weatherburn P. Alcohol, AIDS and immunity. Br Med Bull 1994;50:115–23. 9. Mendenhall CL, Theus SA, Roselle GA, et al. Biphasic in
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14. 15.
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17. 18.
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26. 27. 28.
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vivo immune function after low- versus high-dose alcohol consumption. Alcohol 1997;14:255– 60. Singer DS, Parent L, Kolber MA. Ethanol: An enhancer of transplantation antigen expression. Alcohol Clin Exp Res 1989;13:480 – 4. Dunne FJ. Alcohol and the immune system. BMJ 1989;298: 543– 44. Bonalski JS, Phair JP. Alcohol, immunosuppression, and the lung. Arch Intern Med 1982;142:2073– 4. Brayton RG, Stokes PE, Schwartz MS, et al. Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. N Engl J Med 1970;282:123– 8. Deaciuc IV. Alcohol and cytokine networks. Alcohol 1997; 14:421–30. Hook-Nikanne J, Kariniemi AL, Renkonen OV, et al. Could bacterial acetaldehyde production explain the deterious effect of alcohol on skin diseases? Acta Derm Venereol (Stockh) 1995;75:330. Imperia PPS, Chikkappa G, Phillips PG. Mechanism of inhibition of granulopoiesis by ethanol. Proc Soc Exp Biol Med 1984;175:219 –25. Liu YK. Effects of alcohol on granulocytes and lymphocytes. Semin Hematol 1980;17:130 – 6. MacGregor RR, Gluckman SJ, Senior JR. Granulocyte function and levels of immunoglobulins and complement in patients admitted for withdrawal from alcohol. J Infect Dis 1978;138:747–55. Snyder N, Bessoff J, Dwyer JM, et al. Depressed delayed cutaneous hypersensitivity in alcoholic hepatitis. Am J Dig Dis 1978;23:353– 8. Van Epps DE, Strickland RG, Williams RC Jr. Inhibitors of leukocyte chemotaxis in alcoholic liver disease. Am J Med 1975;59:200 –7. Zhang P, Nelson S, Smmer WR, et al. Acute ethanol intoxication suppresses the pulmonary inflammatory response in rats challenged with intrapulmonary endotoxin. Alcohol Clin Exp Res 1997;21:773–78. Glassman AB, Bennett CE, Randall CL. Effects of ethyl alcohol on human peripheral lymphocytes. Arch Pathol Lab Med 1985;109:540 –2. Schopf RE, Ockenfels HM, Morsches B, et al. Ethanol enhances the mitogen-driven lymphocyte proliferation in patients with psoriasis. Acta Derm Venereol (Stockh) 1996;76:260 –3. Ockenfels HM, Kein-Maas C, Funk R, et al. Ethanol enhances the IFN-gamma, TGF-␣ and IL-6 secretion in psoriatic co-cultures. Br J Dermatol 1996;135:746 –51. Ockenfels HM, Morsches B, Schopf RE. Chloroquine, ethanol and indomethacin affect lymphocyte proliferation in patients with psoriasis (abstr). J Invest Dermatol 1993;100:216. Monk BE, Neil SM. Alcohol consumption and psoriasis. Dermatologica 1986;173:57– 60. Farber EM, Nall L. Psoriasis and alcoholism. Cutis 1994; 53:21–7. Baker BS, Fry L. The immunology of psoriasis. Br J Dermatol 1992;126:1–9.