ETIOPATHOGENESIS OF BEHCET'S SYNDROME: RECENT DEVELOPMENTS AND CURRENT CONTROVERSIES

Year 1999, Volume: 12 Issue: 2, 101 - 106, 03.12.2016

Haner Direskeneli Emel Ekşioğlu-demiralp Tevfik Akoğlu

Abstract

Genetic, infectious and immune dysfunctions are implicated in the etiopathogenesis of Behget’s Syndrome (BS). Histopathological studies reveal mixed cellular infiltrations consisting of mostly T lymphocytes, monocyte-macrophages and neutrophils. Although a viral etiology is also suggested, atypical streptoccocci (Strep Sanguis, Salivarius etc) is the most investigated. Increased pro- inflammatory and Th1 type cytokines such as TNF-a, IFN-y, IL-2, IL-6 and IL-8 are found to be increased in the sera and in vitro culture supernatants. A controversial point is whether neutrophils are primarily defective (hyper-reactive) or activated due to the cytokine profile. Streptoccocal proteins such as KTH-1 or 65 kD mycobacterial heat shock protein (HSP) and its cross-reactive human homologue are shown to cause T and B cell responses in patients with BS. Both CD4+ and y8 T cells are activated with antigen-specific oligoclonal expansions and increased secretions of IFN-y, IL-8 and TNF-a. The link with HLA-B51 which is present as a susceptibility or a severity marker of BS, is suggested to be related to neutrophil hyperreactivity with increased neutrophil burst responses also in FILA- B51 transgenic animals. T cell responses to an HLA- B51 derived peptide and its retinal-S antigen homologue in posterior uveitis patients suggest that auto-immune responses might also be relevant. The same peptides are linked to uveitis also in rats and imply that different manifestations of BS may be
related to various and possibly organ-specific antigens.
Key Words: Behget’s Syndrome, Immune
response

References

• Yazıcı H, Yurdakul S, Hamuryudan V. Behçet's
• Syndrome. In: blippel JH, Dieppe DA, eds.
• Rheumatology, London: E1osby, 1998, 7:26:1-6.
• Ohno S, Ohguchi El, Hirose S, Elatsuda H, Wakisaka A, Aizawa H. Close association of HLA Bw51 in Behçet's Disease. Arch Ophthalmol 1982:100:1455-1458.
• Emmi T, Salvati G, Brugnolo F, Elarchione T. Immunopathological aspects of Behçet's Disease. Clin Exp Rheumatol 1995; / 3:687-691.
• Lehner T, Batchelor JR. Classification and immunogenetics of Behçet's syndrome. In: Lehner T, Barnes CG, eds. Behçet ’s Syndrome: Clinical and immunological features. Hew York, Academic Press, 1979:13-32.
• Yazıcı H, Akokan G, Yalçın B, et al. The high prevelance of HLA-B5 in Behçet's Disease. Clin Exp Immunol 1977;30:259-261.
• Yurdakul S, Günaydın I, Tiizün Y, et al. The prevelance of Behçet's Syndrome in a rural area in Turkey. J Rheumatol 1988:15:820-822.
• Sakamoto El, Akazawa K, Hishioka Y, Sanui II. Inomata H, Hose Y. Prognostic factors of vision in patients with Behçet's disease. Opthalmology 1995:102:317-321.
• Falk l, Rötzschke O, Takiguchi El, et al. Peptide motifs of HLA-B51-B52, and -B78 molecules and implications for Behçet's disease. Int Immunol 1995;7:223-228.
• Takeno El, Kariyone A, Yamashita H, et al. Excessive function of peripheral blood neutrophils from patients with Behçet’s disease and from HLA-B51 transgenic mice. Aithritis Rheum 1995:35:426-433.
• Kibaroğlu A, Direşkendi II, Ekşioğlu-Deıniralp E, et al. The relationship between the presence of HLA- B5I or HLA-B27 and neutrophil oxidative burst function. 8^ International Congress on Behçet's Disease. 7-9 October 1998, Reggio-Emilia, Italy. PI4 (109)
• Elizuki H, Ohno S. Immunogenetic studies of Behçet's disease. Rew Rheum 1996:63:520-527.
• Eleğe JL, Dilsen H, Sanguedolce V, et al. Overproduction of monocyte derived THF-a, IL-6, IL 8 and increased neutrophil superoxide generation in Behçet's Disease. A comparative study with familial Elediterranean fever and healthy subjects. J Rheumatol 1993:20:1544-1549.
• Pronai L, Ichikawa Y, Hakazawa H, et al. Enhanced superoxide generation and the decreased superoxide scavenging activity of peripheral blood
• Marmara Medical Journal Volume 12 No: 2 April 1999
• leucocytes in Behçet's Disease-effect of colchicine. Clin Exp Rheumatol 1991,-9:227-233.
• Carletto A, Pacor ML, Biasi D, et al. Changes of neLitrophil migration without modification of in vitro metabolism and adhesion in Behçet's Disease. J Rheumatol 1997;27:1332-1336.
• Özgün Ş, Akoğlu T, Direşkendi ti, Yurdakul S, Yazıcı H, Hekim n. neutrophil adhesion to endothelial cells and factors affecting adhesion in patients with Behçet 's Disease. Ann Rheum Dis 1996/55:128- 133.
• Ekşioğlu-Demiralp E, Kibaroğlu A, Yavuz Ş, et al. neutrophil activation in Behçet's Disease. 8™ International Congress on Behçet's disease. 7-9 October 1998, Reggio-Emi'ia, Italy. P37 (136)
• I 7. Budak-Alpdoğan T, Demirçay Z, Alpdoğan Ö, et al. Behçet's Disease in patients with Chronic myelogenous Leukemia: The role of Interferon- alpha treatment in the occurrence of Behçet’s symptoms? Ann Hematology 1997/74:45-48.
• Budak-Alpdoğan T, Demirçay Z, Alpdoğan Ö, et al. Skin hyperreactivity of Behçet's patients (Pathergy reaction) is also positive in interferon-alpha treated chronic myeloid leukemia patients, indicating similary altered neutrophil functions in both disorders. Br J Rheumatol 1998/37:1148-1151.
• Şahin Ş, Lawrence R, Direşkendi H, Hamuryudan H, Yazıcı It, Akoğlu T. Monocyte activity in Behçet's Disease. Br J Rheumatol 1996/35:424-429.
• Akoğlu TP, Direşkendi H, Yazıcı H, et al. TNF-a, soluble-IL-2 and soluble CD-8 in Behçet's Disease, J Rheumatol, 1990; 17:1 107-1 108.
• Hirohata S, Oka H, Mizushima Y. Streptococcal- related antigens stimulate production of IL-6 and IFN-g by T cells from patients with Behçet 's Disease. Cell Immunol ¡992/140:410-419.
• Suzuki N, Sakane T, Ueda Y, Tsunematsu T. Abnormal B cell function in patients with Behçet’s Disease. Arthritis Rheum 1986/29:212-219.
• Direşkendi H, Keser O, D'Cruz D, et al. Anti- endothelial cell antibodies, endothelial proliferation and von Willebrand factor antigen in Behçet's disease. Clin Rheumatol 1995/14:55-61.
• Lehner T, Lavery E, Smith, et al. Association between the 65 kD heat shock protein. Streptococcus sanguis, and the corresponding antibodies in Behçet’s syndrome. Infect Immun 1991/59:1434-1441.
• Direşkendi H, Hasan A, Shinnick T, et al. Recognition of B cell epitopes of the 65 KDa HSP in Behçet's Disease. Scan J Immunol 1996/43:464- 471.
• Taşçı B, Direşkendi ft, Serdaroğlu P, et al. Humoral immune response against m-hsp65 in the cerebrospinal fluid of neuro-Behçet's patients. Clin Exp Immunol 1998/113:100-104.
• Ekşioğlu-Demiralp E, Kibaroğlu A, Direskeneli H, et al. Phenotypic characteristics of B cells in Behçet 's Disease: Increased activity in B cell subsets. J Rheumatology 1999/26:826-832.
• Ergun T, Gürbüz O, Harvell J, et at. The histopathology of Pathergy: chronological study of skin hyperreactivity in Behçet’s disease. Int J Dermatology 1998/37:929-933.
• Gül A, Esin S, Düşen H, et al. Immunohistology of skin pathergy reaction in Behçet 's disease, British J Dermatology 1995/132:901-907.
• Sugi-lkai H, Hakazawa M, Nakamura S, Ohno S, Minami M. Increased frequencies of interleukin-2 and interferon-gamma producing T cells in patients with Behçet’s disease Invest Ophthalmol Vis Sci 1998/36:6:996-1004.
• Demiralp-EE, Direskeneli H, Karsh P, et al. Increased T lymphocytes CD4 + CD16+, CD4 + CD56+ and CD8+CD1 lb subsets in Behçet’s Disease. In: Hamza M, eds. Behçet's Disease: Proceedings of the 7th International Conference. Tunis: Pub Adhoua, 1997:44-47.
• Direskeneli H, Ekşioğlu Demiralp E, Kibaroğlu A, et al. Gligoclonal T cell expansions in patients with Behçet's disease. Clin Exp Immunol (1999, in press)
• Fortune F, Walker J, Lehner T. The expression of gd T cell receptor and the prevalance of primed, activated and IgA-bound T cells in Behçet's syndrome. Clin Exp Immunol 1990/82:326-332.
• Suzuki Y, Hoshi K, Matsuda T, et at. Increased peripheral blood gd + T cells and natural killer cells in Behçet's disease. J Rheumatol 1992/19:588- 592.
• Hirohata S, Oka H, Mizushima Y. Streptococcal related antigens stimulate production of IL-6 and interferon-g by T cells from patients with Behçet ’s Disease. Cell Immunology 1992/140:410-419. >
• Mochizuki N, Suzuki N- Takeno M, et al. Fine antigen specificity of human gd T cell lines established by repetitive stimulation with a serotype (KTH-1) of a gram-positive bacterium, Str Sanguis. Eur J Immunol 1994/27:1536-1543.
• Mantaş C, Direskeneli II, Ekşioğlu-Demiralp E, Akoğlu T, Serum levels of IL-4 and IL 10 in Behçet’s Disease. J Rheumatol 1999 (in press)
• Poccia F, Piselli P, Vendetti S, et al. Heat shock protein expression on the membrane of T cells undergoing apoptosis. Immunology 1996/88:6-12.
• Ergun T, Ümit I, Demiralp E, et al. Expression of 60 kD heat shock protein in mucocutaneous lesions in Behçet's Disease 8th International Congress on Behçet's Disease. 7-9 October 1998, Reggio-Emilia, İtalya. P52 (151).
• Pervin K, Childerstone A, Shinnick T, et al. T cell epitope expression of mycobacterial and homologous human 65-kilodalton Heat Shock protein peptides in short term cell lines from patients with Behçet's Disease. J Immunol 1993/151:2273-2282.
• Hasan A, Fortune F, Wilson A, et al. Role of yS T cell in pathogenesis and diagnosis of Behçet's disease Lancet 1996/347:789-794.
• 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 Behçet's disease in Japan. Clin Exp Immunol 1997/108:204-211.
• Direskeneli H, Ekşioğlu-Demiralp E, Ergun T, et al. T cell responses to 60/65 kD HSP derived peptides in Turkish Behçet's Disease patients. Immunology Letters 199 7/3 79:P. 1.07.08.
• Marmara Medical Journal Volume 12 No: 2 April 1999
• Saruhan-Direskeneli O, Celet B, Direskeneli H. The response of the HSP65 specific T cell lines to human HSP60 peptides in Behçet's Disease. 8tfl International Congress on Behçet’s Disease. 7-9 October 1998, Reggio-Emilia Italy. P49 (148)
• Stanford MR, Rasp E, Whiston R, et al. Heat shock protein peptides reactive in patients with Behçet’s disease are uveitogenic in Lewis rats. Clin Exp Immunol 1994;97:226-231.
• De Smet MD, Yamamato JH, Mochizuki M, et al. Cellular immune responses of patients with uveitis to retinal antigens and their fragments. Am J Ophthalmol 1990; ! 10:135-142.
• Wildner O, Thurau SR. Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex
• association with auto-immune disease. Eur J Immunol 1994;24:2579-2585.
• Yavuz $. Direskeneli H, Bozkurt H, et al. T cell responses to a retinal-S antigen and an HLA-B derived cross-reactive peptide in uveitis patients with Behcet's disease. Arthritis Rheum 1998;9:538.
• Thurau SR, Diedrichs-Mohring M, Fricke 11, Arbogast
• S, Wildner G. Molecular mimicry as a therapeutic approach for an autoimmune disease: oral
• treatment of uveitis patients with an MHC-peptide crossreactive with autoantigen -first results. Immunology Letters 1997,57:! 93-201.
• Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the muco-cutaneous lesions of the Behcet’s Syndrome. Ann Intern Med 1998; 128:443- 450.