[Research for basic and clinical aspects of Behcet's disease--recent advance and future--].
To elucidate the role played by HLA-B51 in the neutrophil hyperfunction of Behcet's disease, we determined the superoxide production by purified peripheral blood neutrophils from Behcet's disease patients, from HLA-B51 positive healthy individuals, and from HLA-B51 transgenic mice. As a result, a significant correlation between the neutrophil hyperfunction and the possession of HLA-B51 phenotype, regardless of the presence of the disease, was observed in humans. FMLP-stimulated neutrophils (without in vitro priming) from HLA-B51 transgenic mice, but not those from HLA-B35 transgenic mice or from nontransgenic mice, produced substantial amounts of superoxide. The HLA-B51 molecule itself may thus be responsible, at least in part, for neutrophil hyperfunction in Behcet's disease. CD4+ alphabeta T cells in this disease proliferated vigorously in response to specific peptide derived from human heat shock protein (HSP)-60; however, CD4+ alphabeta T cells from normal subjects or patients with rheumatoid arthritis did not. This peptide has the amino acid sequence 336-351 of human HSP60, which is similar, but not identical to specific peptide of mycobacterial HSP-65. To clarify whether the peptide stimulates patients' T cells as a polyclonal activator, a specific antigen or superantigen-like substance, we have also analyzed TCR usage of responsive T cells by means of TCR Vbeta subfamily-specific mAbs and PCR single strand conformation polymorphism-based technique. We found that T cells with specific TCR Vbeta subfamilies proliferated and increased in number in response to the peptide by an antigen-specific fashion. The result of recurrent exposure to the HSP may break the tolerance to self HSP, and provoke T cell responses to self and microbial HSP. Such T cells may produce Th1-like proinflammatory cytokines and lead to tissue injury possibly via delayed-type hypersensitivity reaction, macrophage activation, and activation and/or recruitment of neutrophils. Our data shed a new light on the autoimmune nature of Behcet's disease; a novel multistep molecular mimicry mechanism may induce and/or exacerbate Behcet's disease by bacterial antigens that activate T cells previously educated by self-peptide(s) of HSP. This would lead to positive selection of autoreactive T cells in this disease.
Division of Allergy and Rheumatic Diseases, Institute of Medical Science, St. Marianna University School of Medicine, Japan.
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D000818:Animals; D001528:Behcet Syndrome / Q000175:diagnosis / Q000209:etiology; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D015235:HLA-B Antigens; D006360:Heat-Shock Proteins; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D009504:Neutrophils / Q000276:immunology; D012015:Reference Standards; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use
D015235:HLA-B Antigens; C035270:HLA-B5 antigen; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus