Behçet hastalığı'nın etiopatogenezi

Behçet hastalığı (BH), arter ve venlerde küçük ve büyük damarları etkileyen, etyolojisi ve patogenezi tam olarak bilinmeyen sistemik bir vaskülittir. Birçok viral ve bakteriyel nedenler detaylı olarak araştırılmış olup mikroorganizmaların tetikleyici rol oynadıkları ya da çapraz reaktif antijenler gibi (ısı şok proteinleri gibi) self antijenlerle etkileştikleri yaygın olarak kabul edilmektedir. BH ile en güçlü ilişkili gösteri- len genetik risk faktörü insan lökosit antijeni (HLA)-B51’dir. IL1, faktör V ve ICAM-1, KIR ve e NOS gibi MHC bölgesi dışındaki diğer genlerin patogenezde rol oynayabileceği düşünülmektedir. Sadece HLA-B51’in hastalık patogenezi ile direk ilişkili olduğu, diğerlerinin ise HLA-B51 ile güçlü linkage disequilibrium (bağlantı dengesizliği)’a sahip olduğu kabul edilmektedir. BH’lı hastalarda doğal ve edinsel immunitede birçok anormallikler tespit edilmiştir. Aktive nötrofiller hem kendilerini hem de Th1 hücrelerini uyaran bazı sitokinleri salgılar- lar. Bu derlemede BH’nın patogenezine dikkat çekip olası nedenler tartışılmıştır.

Etiopathogenesis of Behçet’s disease

Behçet's disease (BD) is a vasculitis with an unknown etiology and pathogesesis affecting the small and large vessels of the venous and arterial systems. Although several viral and bacterial causes have been investigated in detail for several years, of late it is widely accepted that microorganisms may play a role as a trigger, or as a cross-reactive antigens that interfere with self-antigens, such as heat-shock proteins. The genetic risk factor most strongly associated with BD is the human leukocyte antigen (HLA)-B51 allele. Some other genes such as IL-1, Factor V and ICAM-1, KIR and eNOS assumed to take a part in the pathogenezis are settled out of the MHC region. However, it has been accepted that, only HLA-B51 is directly related with pathogenezis of the disease, and others have strong linkage disequilibrium with HLA- B51. In patients with BD, several abnormalities in innate and acquired immunity were detected. Activated neutrophils secrete some cytokines, which prime themselves and also stimulate Th1 cells. In this review, we focus on the pathogenezis of BD and discuss the potential contribu- tors.

PDF

___

1. Behçet H. Über rezidivierende aphthöse, durch ein Virus verur- sachte Geschwure am Mund, am Auge und an den Genitalien. Dermatol Wochenschr 1937;105:1152-7.
2. Yurdakul S, Hamuryudan V, Yazıcı H. Behçet’s syndrome. Curr Opin Rheumatol 2004;16(1):38-42.
3. Yurdakul S. Behçet’s syndrome. Best Prac Res Clin Rheumatol 2008;22(5):793-809.
4. Sfikakis PP, Markomichelakis E, Alpsoy E, Assaad-Khalil S, Bodaghi B, Gul A, et al. Anti-TNF therapy in the management of Behçet’s disease – review and basis for recommendations. Rheumatology (Oxford) 2007;46(5):736-41.
5. Yazici H, Fresko I, Yurdakul S. Behçet’s syndrome: disease manifestations, management, and advances in treatment. Nat Clin Prac Rheumatol 2007;3(3):148-55.
6. Marshall SE. Behçe’s disease. Best Prac Res Clin Rheumatol 2004;18(3):291-311.
7. Seyahi E, Fresko I, Melikoglu M, Yazici H. The management of Behçet’s syndrome. Acta Rheum Port 2006;31(2):125-31.
8. Azizlerli G, Akdağ-Köse A, Sarıca R, Gül A, Tutkun-Tuğal I, Kulaç M, et al. Prevalence of Behçet’s disease in Istanbul, Tur- key. Int J Dermatol 2003;42(10):803-6.
9. Saylan T, Mat C, Fresko I, Melikoğlu M. Behçet’s disease in the Middle East. Clin Dermatol 1999;17(2):209-23.
10. Gül A, Inanç M, Öcal L, Aral O, Koniçe M. Familial aggrega- tion of Behçet’s disease in Turkey. Ann Rheum Dis 2000;59(8):622-5.
11. Davatchi F, Shahram F, Chams C, Chams H, Nadji A. Behçet’s disease. Acta Medica Ianica 2005;43(4):233-42.
12. Ziade N, Awada H. Late onset Behçet’s disease. Joint Bone Spine 2006;73(5):567-9.
13. Treudler R, Orfanos CE, Zoubolis ChC. Twenty-eight cases of juvenile-onset Adamantiades-Behçet’s disease in Germany. Dermatology 1999;199(1):15-9.
14. Kone-Paut I, Yurdakul S, Bahabri SA, Shafae N, Ozen S, Ozdogan H, et al. Clinical features of Behçet’s disease in children: an international collabarative study of 86 cases. J Pediatr 1998;132(4):721-5.
15. Kone-Paut I, Gorchakoff-Molinas A, Weschler B, Touitou I. Paediatric Behçet’s disease in France. Ann Rheum Dis 2002;61(7):655-6.
16. Tursen U, Gurler A, Boyvat A. Evaluation of clinical findings according to sex in 2313 Turkish patients with Behçet’s disease. Int J Dermatol 2003;42(5):346-51.
17. Al-Otaibi LM, Porter SR, Poate TWJ. Behçet’ disease: A review. J Dent Res 2005;84(3):209-22.
18. Kural-Seyahi E, Fresko I, Seyahi N, et al. The long-term mortality and morbidity of Behçet’s disease: a 2-decade outcome survey of 387 patients follewed at dedicated center. Medicine (Baltimore) 2003;82(1):60-76.
19. Srivastava N, Chand S, Bansal M, Srivastava K, Singh S. Familial Behçet’s disease. Indian J Dermatol Venereol Leprol 2007;73(4):260-1.
20. Karasneh J, Gül A, Ollier WE, Silman AJ, Worthingon J. Whole-genome screening for susceptibility genes in multicase families with Behçet’s disease. Arthritis Rheum 2005;52(6):1836-42.
21. Mizuki N, Meguro A, Tohnai I, Gul A, Ohno S, Mizuki N. Association of histocompatibility complex class I chain-related gene A and HLA-B alleles with Behçet’s disease in Turkey. Jpn J Ophthalmol 2007;51(6):431-6.
22. Arayssi T, Hamdan A. New insights into the pathogenesis and therapy of Behçet’s disease. Curr Opin Pharmacol 2004;4(2):183-8.
23. Günesacar R, Erken E, Bozkurt B, Ozer HT, Dinkci S, Erken EG, et al. Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behçet’s disease. Int J Immunogenet 2007;34(1):45-9.
24. Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Ai- zawa M. Close association of HLA-Bw51 with Behçet’s disea- se. Arch Ophthalmol 1982;100(9):1455-8.
25. Sano K, Yabuki K, Imagawa Y, Shiina T, Mizuki N, Ohno S, et al. The absence of disease-specific polymorphisms within HLA-B51 gene that is the susceptible locus for Behçet’s disea- se. Tissue Antigens 2001;58(2):77-82.
26. Hughes T, Coit P, Adler A, Yilmaz V, Aksu K, Düzgün N, et al. Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease. Nat Genet 2013;45(3):319-24.
27. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease. Nat Genet. 2010 Aug;42(8):698-702.
28. Sawalha AH, Hughes T, Nadig A, Yılmaz V, Aksu K, Keser G,et al. A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet's disease. Arthritis Rheum. 2011 Nov;63(11):3607-12.
29. Verity DH, Wallace GF, Vaughan RW, Kondeatis E, Madanat W, Zureikat H, et al. HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet’s disease. Tissue Antigens 1999;54(3):264-72.
30. Direskeneli H. Behçet’s disease: infectious aetiology, new autoantigens, and HLA-B51. Ann Rheum Dis 2001;60(11):996- 1002.
31. Calgüneri M, Kiraz S, Ertenli I, Benekli M, Karaaslan Y, Çelik I. The effect of prophylactic penicilin treatment on the course of arthritis episodes in patients with Behçet’s disease. A ran-
32. Zouboulis CC, May T. Pathogenesis of Adamantiades-Behçet’s disease. Med Microbiol Immunol 2003;192(3):149-55.
33. Ergun T, İnce U, Eksioglu-Demiralp E, et al. HSP 60 expres- sion in mucocutaneous lesions of Behçet’s disease. J Am Acad Dermatol 2001;45(6):904-9.
34. Direskeneli H, Saruhan-Direskeneli G. The role of heat shock proteins in Behçet’s disease. Clin Exp Rheumatol 2003;21(suppl.30):S44-8.
35. Birtas-Atesoglu E, Inanc N, Yavuz S, Ergun T, Direskeneli H. Serum levels of free heat shoch protein 70 and anti-HPS70 are elevated in Behçet’s disease. Clin Exp Rheumatol 2008;26(suppl.50):S96-8.
36. Kurokawa MS, Suzuki N. Behçet’s disease. Clin Exp Med 2004;3:10-20.
37. Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M,Hamza M, Ayed K. Cytokine profile in Behçet’s disease patients. Scand J Rheumatol 2002;31(4):205-10.
38. Musabak U, Pay S, Erdem H, Simsek I,Pekel A, Dinc A, et al. Serum IL-18 levels in patients with Behçet’s disease. Is its expression associated with disease activity or clinical presentation? Rheumatol Int 2006;26:545-50.
39. Hamzaoui A, Ghrairi H, Ammar J, Zekri S, Guemira F, Ham- zaoui K. IL-18 mRNA expression and IFN-gamma induction in bronchoalveolar lavage from Behçet’s disease. Clin Exp Rheumatol 2003;21(suppl.30):S8-14.
40. Yasuoka H, Yamaguchi Y, Mizuki N, Nishida T, Kawakami Y, Kuwana M. Preferential activation of circulating CD8+ and γδ T cells in patients with active Behçet’s disease and HLA-B51. Clin Exp Rheumatol 2008;26(suppl.50):S59-63.
41. Zierhut M, Mizuki N, Ohno S, Inoko H, Gül A, Onoe K, et al. Immunology and functional genomics of Behçet’s disease. Cell Mol Life Sci 2003;60(9):1903-22.
42. Raziuddin S, Al-Dalaan A, Bababri S, Siraj AK, Al-Sedairy S. Divergent Cytokine production profile in Behçet’s disease. Al- tered Th 1 / Th 2cell cytokine pattern. J Rheumatol 1998;25:329-33.
43. Hamzaoui K, Hamzaoui A, Kahan A, Hamza M, Chabbou A, Ayed K. Interleukin-6 in peripheral blood and inflammatory si- tes in Behçet’s disease. Mediators Inflamm 1992;1(4):281-5.
44. Yamakawa Y, Sugita Y, Nagatani T, Takahashi S, Yamakawa T, Tanaka S, et al. Interleukin-6 (IL-6) in patients with Behçet’s disease. J Dermatol Sci 1996;11(3):189-95.
45. Hirohata S, Isshi K, Oguchi H, Ohse T, Haraoka H, Takeuchi A, et al. Cerebrospinal fluid interleukin-6 in progressive Neuro- Behçet’s syndrome. Clin Immunol Immunopathol 1997;82(1):12-7. domized clinical trial. Arthritis Rheum 1996;39(12):2062-5.
46. Wang CR, Chuang CY, Chen CY. Anticardiolipin antibodies and interleukin-6 in cerebrospinal fluid and blood of Chinese patients with neuro-Behçet’s syndrome. Clin Exp Rheumatol 1992;10(6):599-602.
47. Karasneh J, Hajeer AH, Barrett J, Ollier WE, Thornhill M, Gul A. Association of specific interleukin 1 gene cluster polymorp- hisms with increased susceptibility for Behçet’s disease. Rheu- matology (Oxford) 2003;42(7):860-4.
48. Pay S, Simsek I, Erdem H, Dinc A. Immunopathogenesis of Behc ̧et’s disease with special emphasize on the possible role of antigen presenting cells. Rheumatol Int 2007;27(5):417-24.
49. Direskeneli H, Keser G, D’Cruz D, Khamashta MA, Akoğlu T, Yazici H, et al. Anti-endothelial cell antibodies, endothelial proliferation and von Willebrand factor antigen in Behçet’s di- sease. Clin Rheumatol 1995;14(1):55-61.
50. Lee KH, Chung HS, Kim HS, Oh SH, Ha MK, Baik JH, et al. Human α-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behçet’s disease. Arthritis Rheum 2003;48(7):2025-35.
51. Cervera R, Navarro M, Lopez-Soto A, Cid MC, Font J, Esparza J, et al. Antibodies to endothelial cells in Behçet’s disease: cell- binding heterogeneity and association with clinical activity. Ann Rheum Dis 1994;53(4):265-7.
52. Aydintug AO, Tokgöz G, D’Cruz DP, Gürler A, Cervera R, Düzgün N, et al. Antibodies to endothelial cells in patients with Behçet’s disease. Clin Immunol Immunopathol 1993;67(2):157- 62.
53. International Study Group for Behçet’s disease. Criteria for diagnosis of Behçet’s disease. Lancet 1990; 335:1708-1080.
54. Shimizu S, Chen KR, Ikemoto K, Han-Yaku H. Abrupt onset of severe Behçet’s disease: preceding oral ulceration is not essential for diagnosis. Br J Dermatol 1998;139(1):160-1.
55. Oztürk MA. Behçet hastalığında laboratuvar bulguları. Türkiye klinikleri J Int Med Sci 2005;1(25):55-8.
56. Yazici H, Esen F. Mortality in Behçet’s syndrome. Clin Exp Rheumatol 2008;26(suppl.51):S138-40.
57. Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gül A, et al. EULAR recommendations for thr management of Behçet’s disease: report of a task force of the European tanding Committee for International Clinical Studies Including Thera- peutics (ESCISIT). Ann Rheum Dis 2008;67(12):1656-62.