Pathophysiology of the Behçet's Disease

Umit Türsen, Umit Türsen

Abstract

Behçet's disease (BD) is a multisystemic disease of unknown etiology characterized by chronic relapsing oral-genital ulcers and uveitis. Multiple systemic associations including articular, gastrointestinal, cardiopulmonary, neurologic, and vascular involvement are also observed in BD. Although the etiopathogenesis of the disease remains unknown, increased neutrophil functions such as chemotaxis, phagocytosis, and excessive production of reactive oxygen species (ROS), including superoxide anion, which may be responsible for oxidative tissue damage seen in BD, and also immunological alterations, T lymphocyte abnormalities in both subpopulation and function have been considered to be correlated with the etiopathogenesis of BD. There is some clinical evidence suggesting that emotional stress and hormonal alterations can influence the course and disease activity of BD.

Figures

Figure 1
Figure 1
Proposed model of the pathogenesis in Behçet's disease. Ag: antigen; APC: antigen-presenting cells; HSP: heat shock protein; IFN: interferon; IL: interleukin; IPP: isoprenyl pyrophosphate; PPP: prenyl pyrophosphate; TCR: T-cell receptor; Th1: T-helper cells type 1; TNF-α: tumor necrosis factor α.

References

    1. Tursen U, Gurler A, Boyvat A. Evaluation of clinical findings according to sex in 2313 Turkish patients with Behçet’s disease. International Journal of Dermatology. 2003;42(5):346–351.
    1. Gürler A, Boyvat A, Tursen U. Clinical manifestations of Behçet’s disease: an analysis of 2147 Ppatients. Yonsei Medical Journal. 1997;38(6):423–427.
    1. Ateş NA, Tursen U, Tamer L, et al. Glutathione S-transferase polymorphisms in patients with drug eruption. Archives of Dermatological Research. 2004;295(10):429–433.
    1. Tamer L, Tursen U, Eskandari G, et al. N-acetyltransferase 2 polymorphisms in patients with Behcet’s disease. Clinical and Experimental Dermatology. 2005;30(1):56–60.
    1. Koptagel Ilal G, Tuncer O, Enbiyaoglu G, Bayramoglu Z. A psychosomatic investigation of Behcet’s disease. Psychotherapy and Psychosomatics. 1983;40(1–4):263–271.
    1. Sánchez Sobrino P, Fernández CP, Ferreiro JLL, Gil BM, Carballeira RP, García-Mayor RV. Behçet disease with isolated acth deficiency. Endocrinologia y Nutricion. 2009;56(9):463–466.
    1. Tursen U. Activation markers in Behcet’s disease. Turkderm. 2009;43:74–86.
    1. Hirohata S, Kikuchi H. Behçet’s disease. Arthritis Research and Therapy. 2003;5(3):139–146.
    1. Saglam K, Serce A, Yilmaz M, et al. Trace elements and antioxidant enzymes in Behçet’s disease. Rheumatology International. 2002;22(3):93–96.
    1. Erel A, Özsoy E, Biberoglu G, et al. Serum levels of vitamins A, C, and E, β-carotene, selenium, and zinc in patients with Behçet's disease: a controlled study. Biological Trace Element Research. 2003;95(2):97–105.
    1. Mege JL, Dilsen N, Sanguedolce V, et al. Overproduction of monocyte derived tumor necrosis factor α, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behcet’s disease. A comparative study with familial Mediterranean fever and healthy subjects. The Journal of Rheumatology. 1993;20(9):1544–1549.
    1. Şahin S, Lawrence R, Direskeneli H, Hamuryudan V, Yazici H, Akoğlu T. Monocyte activity in Behcet’s disease. Rheumatology. 1996;35(5):424–429.
    1. Şahin Ş, Akoglu T, Direskeneli H, Şen LS, Lawrence R. Neutrophil adhesion to endothelial cells and factors affecting adhesion in patients with Behçet's disease. Annals of the Rheumatic Diseases. 1996;55(2):128–133.
    1. Maytin EV. Heat shock proteins and molecular chaperones: implications for adaptive responses in the skin. Journal of Investigative Dermatology. 1995;104(4):448–455.
    1. Lehner T. The role of heat shock protein, microbial and autoimmune agents in the aetiology of Behcet’s disease. International Reviews of Immunology. 1997;14(1):21–32.
    1. Lehner T, Lavery E, Smith R, Van Der Zee R, Mizushima Y, Shinnick T. Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behcet’s syndrome. Infection and Immunity. 1991;59(4):1434–1441.
    1. Imamura Y, Kurokawa MS, Yoshikawa H, et al. Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behçet’s disease. Clinical and Experimental Immunology. 2005;139(2):371–378.
    1. Kaneko S, Suzuki N, Yamashita N, et al. Characterization of T cells specific for an epitope of human 60-kD heat shock protein (hsp) in patients with Behcet’s disease (BD) in Japan. Clinical and Experimental Immunology. 1997;108(2):204–212.
    1. Tanaka T, Yamakawa N, Yamaguchi H, et al. Common ntigenicity between Yersinia enterocolitica-derived heat-shock protein and the retina, and its role in uveitis. Ophthalmic Research. 1996;28(5):284–288.
    1. Stanford MR, Kasp E, Whiston R, et al. Heat shock protein peptides reactive in patients with Behcet’s disease are uveitogenic in Lewis rats. Clinical and Experimental Immunology. 1994;97(2):226–231.
    1. Taysi S, Kocer I, Memisogullari R, Kiziltunc A. Serum oxidant/antioxidant status in patients with Behçet’s disease. Annals of Clinical and Laboratory Science. 2002;32(4):377–382.
    1. Aynacioglu AS, Bozkurt A, Nacak M, et al. N-acetyltransferase polymorphism in patients with Behçet’s disease. European Journal of Clinical Pharmacology. 2001;57(9):659–662.
    1. Yoshida T, Tanaka M, Sotomatsu A, Okamoto K, Hirai S. Serum of Behcet’s disease enhances superoxide production of normal neutrophils. Free Radical Research. 1998;28(1):39–44.
    1. Kose K, Yazici C, Cambay N, Ascioglu O, Dogan P. Lipid peroxidation and erythrocyte antioxidant enzymes in patients with Behçet’s disease. Tohoku Journal of Experimental Medicine. 2002;197(1):9–16.
    1. Çimen MYB, Kaya TI, Eskandari G, Tursen U, Ikizoglu G, Atik U. Oxidant/antioxidant status in patients with recurrent aphthous stomatitis. Clinical and Experimental Dermatology. 2003;28(6):647–650.
    1. Calis M, Ates F, Yazici C, et al. Adenosine deaminase enzyme levels, their relation with disease activity, and the effect of colchicine on adenosine deaminase levels in patients with Behçet’s disease. Rheumatology International. 2005;25(6):452–456.
    1. Önder M, Gürer MA. The multiple faces of Behçet's disease and its aetiological factors. Journal of the European Academy of Dermatology and Venereology. 2001;15(2):126–136.
    1. Yazici C, Köse K, Çaliş M, Demir M, Kirnap M, Ateş F. Increased advanced oxidation protein products in Behçet’s disease: a new activity marker? British Journal of Dermatology. 2004;151(1):105–111.
    1. Moshage H. Nitric oxide determinations: much ado about NO·-thing? Clinical Chemistry. 1997;43(4):553–556.
    1. Parks DJ, Cheung MK, Chan CC, Roberge FG. The role of nitric oxide in uveitis. Archives of Ophthalmology. 1994;112(4):544–546.
    1. Örem A, Vanizor B, Çimşit G, Kiran E, Değer O, Malkoç M. Decreased nitric oxide production in patients with Behcet’s disease. Dermatology. 1999;198(1):33–36.
    1. Salvarani C, Boiardi L, Casali B, et al. Endothelial nitric oxide synthase gene polymorphisms in Behçet’s disease. The Journal of Rheumatology. 2002;29(3):535–540.
    1. Evereklioglu C, Çekmen M, Özkiriş A, Karabaş L, Çaliş M. The pathophysiological significance of red blood cell nitric oxide concentrations in inflammatory Behçet’s disease. Mediators of Inflammation. 2003;12(4):255–256.
    1. Kiraz S, Ertenli I, Çalgüneri M, et al. Interactions of nitric oxide and superoxide dismutase in Behçet’s disease. Clinical and Experimental Rheumatology. 2001;19(5):S25–S29.
    1. Yilmaz G, Sizmaz S, Yilmaz ED, Duman S, Aydin P. Aqueous humor nitric oxide levels in patients with Behçet disease. Retina. 2002;22(3):330–335.
    1. Er H, Evereklioglu C, Cumurcu T, et al. Serum homocysteine level is increased and correlated with endothelin-1 and nitric oxide in Behçet’s disease. British Journal of Ophthalmology. 2002;86(6):653–657.
    1. Ikeda U, Ikeda M, Minota S, Shimada K. Homocysteine increases nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells. Circulation. 1999;99(9):1230–1235.
    1. Hirano T. Interleukin-6 and its relation to inflammation and disease. Clinical Immunology and Immunopathology. 1991;62(1):S60–S65.
    1. Ghate JV, Jorizzo JL. Behcet’s disease and complex aphthosis. Journal of the American Academy of Dermatology. 1999;40(1):1–18.
    1. Xiong M, Elson G, Legarda D, Leibovich SJ. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. American Journal of Pathology. 1998;153(2):587–598.
    1. Takagi H, King GL, Ferrara N, Aiello LP. Hypoxia regulates vascular endothelial growth factor receptor KDR/Flk gene expression through adenosine A2 receptors in retinal capillary endothelial cells. Investigative Ophthalmology and Visual Science. 1996;37(7):1311–1321.
    1. Salvarani C, Boiardi L, Casali B, et al. Vascular endothelial growth factor gene polymorphisms in Behçet’s disease. The Journal of Rheumatology. 2004;31(9):1785–1789.
    1. Winters B, Mo Z, Brooks-Asplund E, et al. Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice. Journal of Applied Physiology. 2000;89(6):2382–2390.
    1. Zumbach MS, Boehme MWJ, Wahl P, Stremmel W, Ziegler R, Nawroth PP. Tumor necrosis factor increases serum leptin levels in humans. Journal of Clinical Endocrinology and Metabolism. 1997;82(12):4080–4082.
    1. Moses AGW, Dowidar N, Holloway B, Waddell I, Fearon KCH, Ross JA. Leptin and its relation to weight loss, ob gene expression and the acute-phase response in surgical patients. British Journal of Surgery. 2001;88(4):588–593.
    1. Dickstein G, Schechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. Journal of Clinical Endocrinology and Metabolism. 1991;72(4):773–778.
    1. Clayton RN. Short Synacthen test versus insulin stress test for assessment of the hypothalamo-pituitary-adrenal axis: controversy revisited. Clinical Endocrinology. 1996;44(2):147–149.
    1. Colak R, Ozkan Y, Cengiz SU, Saral Y, Kandi BC, Halifeoglu I. A comparison between the effects of low (1 μg) and standard dose (250 μg) ACTH stimulation tests on adrenal cortex functions with Behçet’s disease. JEADV. 2006;20(6):721–725.
    1. Chrousos GP, Elenkov IJ. Interactions of the endocrine and immune systems. In: De Groot LJ, Jameson JL, editors. Endocrinology. 4th edition. Philadelphia, Pa, USA: Saunders; 2001. pp. 571–586.
    1. Arlt W, Allolio B. Adrenal insufficiency. The Lancet. 2003;361(9372):1881–1893.
    1. Jorgensen C, Bressot N, Bologna C, Sany J. Dysregulation of the hypothalamo-pituitary axis in rheumatoid arthritis. The Journal of Rheumatology. 1995;22(10):1829–1833.
    1. Rovensky J, Bakošová J, Koška J, Kšinantová L, Ježová D, Vigaš M. Somatotropic, lactotropic and adrenocortical responses to insulin-induced hypoglycemia in patients with rheumatoid arthritis. Annals of the New York Academy of Sciences. 2002;966:263–270.
    1. Gutierrez MA, Garcia ME, Rodriguez JA, Rivero S, Jacobelli S. Hypothalamic-pituitary-adrenal axis function with active rheumatoid arthritis: a controlled study using insülin hypoglicemia stress test and prolactin stimulation. The Journal of Rheumatology. 1999;26:277–281.
    1. Gutiérrez MA, Garcia ME, Rodriguez JA, Rivero S, Jacobelli S. Hypothalamic-pituitary-adrenal axis function and prolactin secretion in systemic lupus erythematosus. Lupus. 1998;7(6):404–408.
    1. Johnson EO, Vlachoyiannopoulos PG, Skopouli FN, Tzioufas AG, Moutsopoulos HM. Hypofunctin of the stres axis in Sjogren’s syndrome. The Journal of Rheumatology. 1998;25:1508–1514.
    1. Lahita RG. The role of sex hormones in systemic lupus erythematosus. Current Opinion in Rheumatology. 1999;11(5):352–356.
    1. Ahmed SA, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. American Journal of Pathology. 1985;121(3):531–551.
    1. Bork K, Fischer B, Dewald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. American Journal of Medicine. 2003;114(4):294–298.
    1. Yavuz S, Ozilhan G, Elbir Y, Tolunay A, Eksioglu-Demiralp E, Direskeneli H. Activation of neutrophils by testosterone in Behçet’s disease. Clinical and Experimental Rheumatology. 2007;25(4):S-46–S-51.
    1. Paus R. Does prolactin play a role in skin biology and pathology? Medical Hypotheses. 1991;36(1):33–42.
    1. Poumay Y, Jolivet G, Pittelkow MR, et al. Human epidermal keratinocytes upregulate expression of the prolactin receptor after the onset of terminal differentiation, but do not respond to prolactin. Archives of Biochemistry and Biophysics. 1999;364(2):247–253.
    1. Foitzik K, Langan EA, Paus R. Prolactin and the skin: a dermatological perspective on an ancient pleiotropic peptide hormone. Journal of Investigative Dermatology. 2009;129(5):1071–1087.
    1. Atasoy M, Karatay S, Yildirim K, Kadi M, Erdem T, Senel K. The relationship between serum prolactin levels and disease activity in patients with Behcet’s disease. Cell Biochemistry and Function. 2006;24(4):353–356.
    1. Apaydin KC, Duranoglu Y, Özgürel Y, Saka O. Serum prolactin levels in Behcet’s disease. Japanese Journal of Ophthalmology. 2000;44(4):442–445.
    1. Houman H, Ben Ghorbel I, Lamloum M, et al. Prolactin levels in Behçet’s disease: no correlation with disease manifestations and activity. Annales de Medecine Interne. 2001;152(3):209–211.
    1. Keser G, Oksel F, Ozgen G, Aksu K, Doganavsargil E. Serum prolactin levels in Behçet's Syndrome. Clinical Rheumatology. 1999;18:351–352.
    1. Karakus S, Ozcebe O, Demiroğlu H, Ozatli D, Buyukasik Y, Haznedaroglu I. Evaluation of plasma hormone levels in Behcet’s disease. In: Bang D, Lee ES, Lee S, editors. In: Proceedings of the 9th International Conference on Behçet’s Disease; 2000; Seoul, Korea. p. 549.
    1. Gül N, Gül A, Alagöl F, et al. The role of 21-hydroxylase deficiency in the pathogenesis of Behçet’s disease. In: Bang D, Lee ES, Lee S, editors. In: Proceedings of the 9th International Conference on Behçet’s Disease; 2000; Seoul, Korea. p. 625.
    1. Mat C, Demirkesen C, Çökerler ÖA, et al. receptors density in scrotal skin of Behçet’s Disease. In: Bang D, Lee ES, Lee S, editors. In: Proceedings of the 9th International Conference on Behçet’s Disease; 2000; Seoul, Korea. pp. 646–648.
    1. Proença HSFM, Ferreira C, Miranda M, Castanheira-Dinis A, Monteiro-Grillo M. Serum prolactin levels and Behçet disease. European Journal of Ophthalmology. 2007;17(3):404–407.
    1. Arck PC, Slominski A, Theoharides TC, Peters EMJ, Paus R. Neuroimmunology of stress: skin takes center stage. Journal of Investigative Dermatology. 2006;126(8):1697–1704.
    1. Reich A, Orda A, Wiśnicka B, Szepietowski JC. Plasma concentration of selected neuropeptides in patients suffering from psoriasis. Experimental Dermatology. 2007;16(5):421–428.
    1. Salomon J, Baran E. The role of selected neuropeptides in pathogenesis of atopic dermatitis. Journal of the European Academy of Dermatology and Venereology. 2008;22(2):223–228.
    1. Jang YH, Lee S, Lee ES. Role of neuropeptides in Behçet’s disease in relation to clinical activity. Journal of Dermatological Science. 2006;41(1):77–79.
    1. Aki T, Karincaoglu Y, Seyhan M, Batcioglu K. Serum substance P and calcitonin gene-related peptide levels in Behçet’s disease and their association with disease activity. Clinical and Experimental Dermatology. 2006;31(4):583–587.
    1. Al-Dalaan A, Al-Sedairy S, Al-Balaa S, et al. Enhanced interleukin 8 secretion in circulation of patients with Behcet’s disease. The Journal of Rheumatology. 1995;22(5):904–907.
    1. Vollmar AM. The role of atrial natriuretic peptide in the immune system. Peptides. 2005;26(6):1086–1094.
    1. Ahluwalia A, MacAllister RJ, Hobbs AJ. Vascular actions of natriuretic peptides—cyclic GMP-dependent and -independent mechanisms. Basic Research in Cardiology. 2004;99(2):83–89.
    1. Tursen U, Ulubas B, Kaya TI, Pekdemirt H, Ikizoğlu G. Cardiac complications in Behçet's disease. Clinical and Experimental Dermatology. 2002;27:651–653.
    1. Yaği R, Totan Y, Özlük E, Özyurt H, Akbay G, Eksioğlu M. Serum levels of natriuretic peptides in patients with Behcet’s disease. Clinical Rheumatology. 2008;27(9):1153–1158.
    1. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. The New England Journal of Medicine. 2004;350(7):655–663.
    1. Aiura K, Ueda M, Endo M, Kitajima M. Circulating concentrations and physiologic role of atrial natriuretic peptide during endotoxic shock in the rat. Critical Care Medicine. 1995;23(11):1898–1906.
    1. Maack T, Suzuki M, Almeida FA, et al. Physiological role of silent receptors of atrial natriuretic facator. Science. 1987;238(4827):675–678.
    1. Gur A, Sarac AJ, Burkan YK, Nas K, Cevik R. Arthropathy, quality of life, depression, and anxiety in Behcet’s disease: relationship between arthritis and these factors. Clinical Rheumatology. 2006;25(4):524–531.
    1. Koçak M, Başar MM, Vahapoğlu G, Mert HC, Güngör S. The effect of behçet’s disease on sexual function and psychiatric status of premenopausal women. Journal of Sexual Medicine. 2009;6(5):1341–1348.
    1. Taner E, Coşar B, Burhanoğlu S, Calikoğlu E, Onder M, Arikan Z. Depression and anxiety in patients with Behçet’s disease compared with that in patients with psoriasis. International Journal of Dermatology. 2007;46(11):1118–1124.
    1. Uğuz F, Dursun R, Kaya N, Savas Cilli A. Quality of life in patients with Behçet’s disease: the impact of major depression. General Hospital Psychiatry. 2007;29(1):21–24.
    1. Capoore HS, Payne CMER. Does psychological intervention help chronic skin conditions? Postgraduate Medical Journal. 1998;74(877):662–664.
    1. Seo SB, Park SJ, Park ST, et al. Disodium cromoglycate inhibits production of immunoglobulin E. Immunopharmacology and Immunotoxicology. 2001;23(2):229–237.
    1. Martin MW, O’Sullivan AJ, Gomperts BD. Inhibition by cromoglycate and some flavonoids of nucleoside diphosphate kinase and of exocytosis from permeabilized mast cells. British Journal of Pharmacology. 1995;115(6):1080–1086.
    1. Theoharides TC, Bielory L. Mast cells and mast cell mediators as targets of dietary supplements. Annals of Allergy, Asthma and Immunology. 2004;93(2):S24–S34.
    1. Arck PC, Handjiski B, Hagen E, Joachim R, Klapp BF, Paus R. Indications for a ’brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P. The FASEB Journal. 2001;15(13):2536–2538.
    1. Arck PC, Handjiski B, Kuhlmei A, et al. Mast cell deficient and neurokinin-1 receptor knockout mice are protected from stress-induced hair growth inhibition. Journal of Molecular Medicine. 2005;83(5):386–396.
    1. Wang L, Million M, Rivier J, et al. CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice. PLoS One. 2011;6(2, article 16377)

Source: PubMed

Подписаться