Sakane T, Miura K
Division of Allergy and Rheumatic Diseases, Institute of Medical Science, St. Marianna University School of Medicine, Japan.
Nihon Rinsho. 1996 Mar;54(3):870-84.
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.
为阐明HLA - B51在白塞病中性粒细胞功能亢进中所起的作用，我们测定了白塞病患者、HLA - B51阳性健康个体以及HLA - B51转基因小鼠纯化的外周血中性粒细胞产生超氧化物的情况。结果显示，在人类中，无论疾病是否存在，中性粒细胞功能亢进与HLA - B51表型的拥有之间均存在显著相关性。来自HLA - B51转基因小鼠的FMLP刺激的中性粒细胞（无体外预刺激）可产生大量超氧化物，而来自HLA - B35转基因小鼠或非转基因小鼠的中性粒细胞则不能。因此，HLA - B51分子本身可能至少部分地导致了白塞病中性粒细胞功能亢进。该疾病中的CD4⁺αβ T细胞对源自人热休克蛋白（HSP）- 60的特定肽有强烈增殖反应；然而，正常受试者或类风湿性关节炎患者的CD4⁺αβ T细胞则无此反应。该肽具有人HSP60的氨基酸序列336 - 351，与分枝杆菌HSP - 65的特定肽相似但不完全相同。为阐明该肽是作为多克隆激活剂、特异性抗原还是超抗原样物质刺激患者的T细胞，我们还通过TCR Vβ亚家族特异性单克隆抗体和基于PCR单链构象多态性的技术分析了反应性T细胞的TCR使用情况。我们发现具有特定TCR Vβ亚家族的T细胞以抗原特异性方式对该肽产生增殖并数量增加。反复接触HSP的结果可能会打破对自身HSP的耐受性，并引发T细胞对自身和微生物HSP的反应。此类T细胞可能产生Th1样促炎细胞因子，并可能通过迟发型超敏反应、巨噬细胞激活以及中性粒细胞的激活和/或募集导致组织损伤。我们的数据为白塞病的自身免疫性质提供了新的线索；一种新的多步骤分子模拟机制可能通过激活先前由HSP自身肽致敏的T细胞的细菌抗原来诱导和/或加重白塞病。这将导致该疾病中自身反应性T细胞的阳性选择。
