Kaneko Fumio, Oyama Noritaka, Yanagihori Hirokatsu, Isogai Emiko, Yokota Kenji, Oguma Keiji
Institute of Dermato-Immunology and -Allergy, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Fukushima, Japan.
Eur J Dermatol. 2008 Sep-Oct;18(5):489-98. doi: 10.1684/ejd.2008.0484. Epub 2008 Aug 8.
Behçet's disease (BD) is still considered as a mysterious multisystemic disorder characterized by recurrent involvement of muco-cutaneous, ocular, intestinal, vascular and/or nervous system organs. In this review, we would like to highlight and discuss several important advances in our understanding of the pathogenesis of BD based on the intrinsic genetic factors including HLA-B51 and MICA expression and extrinsic triggering factors. As one of the extrinsic triggering factors, we focused on the hypersensitivity against oral streptococci which might be acquired through the innate immune mechanism. It was found that HLA-B51 restricted CD8 T cell response was clearly correlated with the target tissues expressing MICA*009 by stress in active BD patients with HLA-B51 as the intrinsic factors. Bes-1 gene and HSP-65 derived from oral S. sanguinis, which is the uncommon serotype (KTH-1, strain BD113-20), are supposed to play important roles as an extrinsic factor in BD pathogenesis. The peptides of the Bes-1 gene are highly homologous with the retinal protein Brn3b and moreover, the Bes-1 peptides were homologous with HSP-65 derived from microorganisms in association with the counterpart human HSP-60, which appeared reactively in the patients. HSP-65/60 also has high homologies with the respective T cell epitope of BD patients. Although HSP-65/60 and the peptides of Bes-1 gene were found to stimulate PBMCs from BD patients in the production of pro-inflammatory Th1 type cytokines, some homologous peptides of HSP-65 with T cell epitopes were found to reduce IL-8, IL-12 and TNF-alpha produced from PBMCs of active BD patients. The findings might be correlated with the clinically therapeutic effects for BD patients with severe uveitis, who were led to immunotolerance by the peptide of human HSP-60 (336-351), as previously reported. Then, the pathogenesis of BD was discussed referring to intrinsic genetic factors and extrinsic triggering factors in aspects of streptococcal hypersensitivity, which might be acquired through the innate immune mechanisms. The BD symptoms were thought to be due to vascular reactions as immune responses in correlation with monocyte expressed streptococcal agents.
白塞病（BD）仍被视为一种神秘的多系统疾病，其特征为黏膜皮肤、眼部、肠道、血管和/或神经系统器官反复受累。在本综述中，我们想强调并讨论基于包括HLA - B51和MICA表达在内的内在遗传因素以及外在触发因素，我们对BD发病机制理解的几个重要进展。作为外在触发因素之一，我们聚焦于对口腔链球菌的超敏反应，这种超敏反应可能通过先天免疫机制获得。研究发现，在以HLA - B51作为内在因素的活动性BD患者中，HLA - B51限制的CD8 T细胞反应与因应激而表达MICA*009的靶组织明显相关。源自口腔血链球菌（罕见血清型KTH - 1，菌株BD113 - 20）的Bes - 1基因和HSP - 65，被认为作为外在因素在BD发病机制中起重要作用。Bes - 1基因的肽段与视网膜蛋白Brn3b高度同源，此外，Bes - 1肽段与源自微生物的HSP - 65以及相应的人类HSP - 60同源，后者在患者体内呈反应性出现。HSP - 65/60与BD患者各自的T细胞表位也有高度同源性。虽然发现HSP - 65/60和Bes - 1基因的肽段能刺激BD患者的外周血单核细胞（PBMCs）产生促炎性Th1型细胞因子，但发现一些与T细胞表位同源的HSP - 65肽段能减少活动性BD患者PBMCs产生的IL - 8、IL - 12和TNF -α。这些发现可能与先前报道的、对患有严重葡萄膜炎的BD患者的临床治疗效果相关，这些患者通过人HSP - 60（336 - 351）的肽段诱导产生免疫耐受。然后，从链球菌超敏反应方面，参考内在遗传因素和外在触发因素讨论了BD的发病机制，这种超敏反应可能通过先天免疫机制获得。BD症状被认为是由于与单核细胞表达的链球菌因子相关的免疫反应所导致的血管反应。
