Immunopathology of Behçet's Disease
Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine
Behçet's disease (BD) is a chronic inflammatory disorder with recurrent oral aphthosis, skin lesions, uveitis, and genital ulcers as its main manifestations. More serious involvement of the central nervous system (CNS), gastrointestinal tract, and large vessels is observed in some patients. Because of the diverse clinical manifestations, diagnosis is made on the basis of symptoms. Therapeutic approach is determined according to the disease phenotype, and anti-TNFα mAb therapy is available for serious subtypes of BD in patients with ocular, CNS, gastrointestinal tract, and large vascular involvement. This therapy is ineffective in some patients, but it generally improves prognosis greatly and has proved effective in cases of organ involvement. Both genetic and environmental factors have been shown to contribute to the immunopathology of BD, and whether BD is an autoimmune disease or an autoinflammatory disorder is a subject of debate. In the 1990s, we and others showed that 60/65 kD heat shock protein (HSP) T cells play a pathological role in mediating cross-immune reactions between microbial pathogens and hosts, although no disease specific antibodies have been ever identified. On the other hand, its clinical features, responsiveness to colchicine, and increased levels of proinflammatory cytokines rather suggest that BD is an autoinflammatory disorder. A recent genome-wide association study (GWAS) and subsequent studies have shown that BD is associated with IL10, IL23R/IL12RB2, ERAP1, CCR1, STAT4, KLRC4, TLR4, NOD2, MEFV in addition to HLA-B*51, suggesting that both innate and acquired immune systems are involved in the development of BD. IL10, CCR1 and KLRC4 suggest the involvement of macrophages and NK cells, while IL23R/IL12RB2 and STAT4 indicate that Th1/Th17 cells play pathological roles. TLR4 and NOD2 indirectly suggest that microbial organisms are environmental factors. Moreover, epistasis between HLA-B*51 and risk allele of ERAP1 suggest the contribution of an antigen-specific CD8+T cell response to the disease. Elucidation of the immunopathology of BP would lead to new therapeutic targets.
ϊγεγο 2016; 12(1), 15-25
Behçet's disease, HLA-B51, autoimmune disease, autoinflammatory disease, anti-TNFα mAb
Mitsuhiro Takeno, Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan