Behçet Syndrome
Transkript
Behçet Syndrome
Behçet’s Disease: Autoinflammatory features Ahmet Gül Istanbul University, Istanbul Faculty of Medicine, Turkey Outline Clinical picture Characteristics of inflammatory response Autoinflammatory features Genetics Controversial issues HLA Class I association Antigen‐specific / adaptive immune responses ? Efficacy of “T‐cell specific” treatments Nothing to declare relevant to this presentation Dr. Hulusi Behçet 3 patients with recurrent Oral aphthous ulcers Genital ulcers Uveitis A distinct disease Possible viral etiology ? Role of focal infection ? Dermatologische Wochenschrift 1937; 105:1152‐7 Behçet’s Disease 34‐year‐old female Recurrent attacks of oral and genital aphthous ulcers for 7 years Loss of appetite and fever during attacks Eye inflammation during severe attacks 41‐year old male Recurrent attacks of oral aphthous ulcers, genital ulcers and eye inflammation with loss of vision Acne‐like lesions Fever with myalgias Behçet’s Disease Multi‐system disorder Vasculitis affecting all sizes and types of vessels with a thrombotic tendency More severe disease course in males and in those aged <25 at disease onset Behçet’s Disease Unknown etiology Enhanced and dysregulated inflammatory response Complex genetic (multifactorial) disease Env Gene-3 iron men t-1 Gene-1 Gene-2 Envir onme nt-2 Behçet’s Disease Recurrent inflammatory attacks Usually self limited and heal without scarring Behçet’s Disease Recurrent inflammatory attacks Can cause permanent tissue damage Behçet’s Disease Recurrent inflammatory attacks Innate immune response Increased proinflammatory cytokine expression Increased superoxide generation Non‐specific hyperreactivity Pathergy phenomenon Behçet’s Disease Increased non‐specific inflammatory response Pathergy phenomenon Skin hyperreactivity to trauma Can also be induced in vessels oral mucosa genital mucosa joints etc. Behçet’s Disease Recurrent inflammatory attacks Innate immune response Increased proinflammatory cytokine expression Increased superoxide generation Non‐specific hyperreactivity Pathergy phenomenon Adaptive immune response ? Th1 type polarization Oligoclonal T cell expansions Behçet’s Disease Immune reactivity against Self antigens HSP60 Other hsp proteins (aB‐crystalline) Alpha enolase Tropomyosin Kinectin Retinal S, IRBP, UACA, SBP PINK1, SWAP70 (by SEREX, Vural et al. unpublished data) Microbial antigens Streptococcal antigens Herpes simplex virus Gram negative bacteria, Staphylococcus aureus, etc. Behçet’s Disease Immune reactivity against microbial antigens Adaptive immune response and cross‐reactivity to self antigens Between microbial and self hsp60 proteins? Immune reactivity against HSP60‐derived peptides (T cell, γδ T cell, B cell) Uveitis induced by HSP60‐derived peptides in Lewis rats HSP60 336‐351 + CFA + B. Pertussis Danger signal ‐ activation of innate immune response by pathogen‐associated molecular patterns LPS, lipoteichoic acid, hsp, etc. Behçet’s Disease Overlapping clinical features with hereditary autoinflammatory disorders Oral aphthous ulcers HIDS, TRAPS, MWS Genital ulcers HIDS Arthritis FMF, TRAPS, PAPA, Blau, MWS, HIDS Amyloidosis All Meningoencephalitis FMF, NOMID, MWS Uveitis NOMID, TRAPS, Blau Orchyepididymitis FMF Acne‐like lesions PAPA Pathergy reaction PAPA Behçet’s Disease Autoinflammatory disorders Seemingly unprovoked episodes of inflammation Relative lack of an obvious autoimmune pathology No pathogenic high‐titre autoantibodies No antigen‐specific T cells Genetic defects in innate immune system Behçet’s disease Complex genetic disorder – HLA Class I association Efficacy of “T cell specific” treatments (i.e. Cyclosporin A) McGonagle & McDermott. PLoS Medicine 2006 Geographic Distribution Higher frequency of HLA‐B51 in healthy populations Verity et al. Br J Ophthalmol 2003; 87: 1175‐83. Behçet’s Disease and HLA‐B51 Greek Italian Japanese Mizuki et al. Invest Ophthalmol Vis Sci 2000; 41: 3702‐8 Behçet’s Disease and HLA-B51 Direct pathogenic role for HLA-B51 ? Increased neutrophil activity Transgenic mouse model (Takeno et al. A&R 1995) Susceptibility to infection by certain microbes Molecular mimicry Cross reactivity Presentation by HLA Class II molecules (Wildner et al. Eur J Immunol 1997; Kurhan-Yavuz et al. Clin Exp Immunol 2000) Interaction with NK cell KIR receptors (KIR3DL1) Behçet’s Disease and HLA‐B51 Presentation of BD‐specific peptide(s) No B51‐restricted CD8 response Interaction with KIR3DL1 on NK, CD8 and γδ T cells ? Maenaka et al. J Immunol 2000; 165: 3260-7. Behçet’s Disease and KIR3DL1 Bw4 positive (n = 352) Healthy controls = 153 Behçet’s disease = 199 Bw4 negative (n = 124) Healthy controls = 82 Behçet’s disease = 42 χ2 for trend P = 0.019 for DL1/DL1 OR = 1.7 (1.1‐2.6) P = 0.013 Duymaz‐Tozkır J, et al. (unpublished) Behçet’s Disease and KIR3DL1 B51 negative (n = 271) Healthy controls = 180 Behçet’s disease = 91 for DL1/DL1 and Bw4 positives OR = 2.1 (1.2-3.6) P = 0.007 Duymaz‐Tozkır J, et al. (unpublished) Distribution of KIR3DL1/DS1 Alleles HLA‐Bw4 positive patients and controls * * HC BD HC (n=127) BD (n=175) OR (95% CI) P KIR3DL1*001 %39,4 %51,4 1,6 (1‐2,5) 0,038 KIR3DS1*013 %52 %33,7 0,47 (0,29‐0,75) 0,001 Duymaz‐Tozkır J, et al. (unpublished) Distribution of KIR3DL1/DS1 Alleles HLA‐B*51 negative patients and controls * * HC BD HC (n=81) BD (n=48) OR (95% CI) P KIR3DL1*001 %32,1 %64,6 3,8 (1,8-8,1) 0,0001 KIR3DS1*013 %60,5 %25 0,2 (0,09-0,5) 0,0001 Duymaz‐Tozkır J, et al. (unpublished) Behçet’s Disease and HLA‐B51 HLA‐Bw4 (B51) + peptide and KIR3DL1 interaction Strong inhibitory signal Defective clearence /persistence of certain antigens ? Viral etiology ? Defective inhibitory signal due to peptides Changed affinity of KIR3DL1 with aminoacids at P7 and P8 Disrupted inhibitory signal Activation of NK, CD8 or γδ T cells Behçet’s Disease and HLA‐B51 Unfolded protein response ? Slow folding HLA Class I molecule similar to HLA‐B27 HLA‐B27 transgenic animal models suggest ER stress and unfolded protein response as a possible mechanism Spliced XBP‐1 transcripts in peripheral blood monocytes Unspliced Spliced Karasneh et al. Arthritis Rheum 2005; 52: 1836-42 Karasneh et al. Arthritis Rheum 2005; 52: 1836-42 BD and Autoinflammatory Disorders Association with “autoinflammatory genes” ? MEFV Increased frequency of MEFV mutations Association with vascular involvement ? Atagündüz et al. Clin Exp Rheumatol 2003; 21: S35‐7 Rabinovich et al. Scand J Rheumatol 2007; 36: 48‐52 Co‐incidental BD and FMF Touitou et al. Human Mutation 2000; 16: 271‐2 Japanese, Matsuda et al. Intern Med 2006; 45: 799‐800 TNFRSF1A Association with venous thrombosis (extracranial) ? Amoura et al. Arthritis Rheum 2005; 52: 608‐11 Behçet’s Disease Not a single gene disorder Genetic polymorphisms in innate immune system? Candidate suscetibility genes in the linkage area ? Whole genome association studies ? Gene expression microarray studies Uric Acid and Inflammasome Proteins Increased skin response to urate in Behçet’s disease Cakir et al. Urate crystal test in Behcet's syndrome. Br J Rheumatol 1993; 32: 1112‐4. Increased inflammatory response to uric acid in Behçet’s disease Gogus et al. Oxidative burst response to monosodium urate crystals in patients with Behcet's syndrome. Clin Exp Rheumatol 2005; 23 (4 Suppl 38): S81‐5. Behçet’s Disease Targeting the correct inflammatory pathways ? Colchicine Thalidomide Corticosteroids Azathioprine Cyclosporin A Interferon alpha Anti‐TNF ? Istanbul University Istanbul Faculty of Medicine Department of Internal Medicine Division of Rheumatology Ahmet Gül Sevil Kamali Murat İnanç Lale Öcal ARC Epidemiology Unit University of Manchester Ali Hajeer Jumana Karasneh Jane Worthington Bill Ollier Alan J Silman Meral Koniçe Orhan Aral Fulya Cosan Department of Physiology Güher Saruhan Direskeneli Aytül Uyar Jülide Duymaz Department of Ophthalmology Ilknur Tugal Tutkun DETAE, Department of Genetics Duran Üstek Neslihan Abaci Aris Çakiris Basar Oku Ugur Özbek Burçak Vural