Are anti-BP180 IgG1 or IgG4 autoantibodies pathogenic?
Are anti-BP180 IgG1 or IgG4 autoantibodies pathogenic?
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抗 BP180 IgG1 或 IgG4 自身抗体是否致病？
DOI：
10.1046/j.1523-1747.2002.19534.x
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Liu,Zhi
中科院分区：
文献类型：
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作者：
Liu,Zhi
大疱性类天疱疮（BP）是一种获得性自身免疫性皮肤病，其特征在于针对两种半桥粒抗原BP 230（BPAG 1）和BP 180（BPAG 2）的自身抗体以及表皮下水疱（Stanley et al，1981;迪亚兹et al，1990; Stanley，1999）。在这些患者的皮肤病变中，基底角质形成细胞在透明层水平从下层真皮脱离。BP抗半桥粒自身抗体可结合真皮-表皮连接处并激活补体系统。大多数BP血清与BP 180的NC 16 A结构域内的表位反应（Giudice等，1993）。针对BP 180 NC 16 A的自身抗体的血清水平与BP的严重程度相关（Haase等人，1998）。Gammon等人首先表明，在补体和白细胞的帮助下，BP自身抗体在皮肤器官培养系统中诱导真皮-表皮连接（DEJ）分离（Gammon等人，1982）。使用类似方法的进一步研究显示，抗人BP 180 NC 16 A抗体和嗜中性粒细胞是该组织损伤的原因（Sitaru等，2002）。Liu等人使用IgG被动转移方法，首先提供了针对鼠BP 180 NC 16 A同源物的兔抗体在小鼠中具有致病性的体内证据（Liu等人，1993）。随后，这一发现扩展到BP仓鼠模型，其中注射兔抗仓鼠BP 180的新生仓鼠出现BP皮肤病变（Yamamoto et al，2002）。这些体外和体内数据表明，特异性针对BP 180 NC 16 A结构域的抗体是致病性的。很明显，抗BP 180抗体与其靶标的结合是BP表皮下水疱形成的关键第一步。目前尚不清楚的是哪些IgG亚类是致病性的，并与疾病的严重程度直接相关。由于不同的IgG亚类具有不同的功能特性，因此了解答案具有极大的兴趣和临床意义。其中之一是激活补体的能力。IgG 3是最有效的补体激活剂，其次是IgG 1和IgG 2，而IgG 4不能固定补体。然而，关于这一问题的研究描绘了一幅有争议的画面。例如，Bernard et al和Laffitte et al证明抗BP 180自身抗体IgG 1是主要的IgG亚类，而Dopp et al得出结论，抗BP 180自身抗体IgG 4是BP中主要的IgG亚类（Bernard et al，1990; Dopp et al，2000; Laffitte et al，2001）。引起这一争议的因素很可能是其检测系统（即免疫印迹、免疫荧光或ELISA）、检测中的底物（含有BP 230和BP 180的表皮提取物、在原核或真核细胞中表达的重组BP 180抗原）的差异，更重要的是，所选BP患者人群（活动期、缓解期、未治疗或治疗状态的患者）。
Bullous pemphigoid (BP) is an acquired autoimmune skin disease characterized by autoantibodies against two hemidesmosomal antigens, BP230 (BPAG1) and BP180 (BPAG2) and subepidermal blisters (Stanley et al, 1981; Diaz et al, 1990; Stanley, 1999). In the skin lesions of these patients basal keratinocytes detach from the underlying dermis at the level of the lamina lucida. BP antihemidesmosomal autoantibodies can bind to the dermal-epidermal junction and activate the complement system. The majority of BP sera react with epitopes within the NC16A domain of BP180 (Giudice et al, 1993). The serum levels of autoantibodies to BP180 NC16A are correlated with the severity of BP (Haase et al, 1998). Gammon et al first showed that BP autoantibodies, with the help of complement and leukocytes, induce derma-epidermal junction (DEJ) separation in a skin organ culture system (Gammon et al, 1982). Further studies using a similar approach revealed that antihuman BP180NC16A antibodies and neutrophils are responsible for this tissue injury (Sitaru et al, 2002). Liu et al, using an IgG passive transfer approach, first provided in vivo evidence that rabbit antibodies directed against the murine BP180NC16A homolog are pathogenic in mice (Liu et al, 1993). Subsequently, this finding was extended to the BP hamster model, in which neonatal hamsters injected with rabbit antihamster BP180 develop BP skin lesions (Yamamoto et al, 2002). These in vitro and in vivo data demonstrate that antibodies specific for the BP180NC16A domain are pathogenic.It is clear that the binding of anti-BP180 antibody to its target is the critical first step in subepidermal blister formation in BP. What still remains unclear is which IgG subclass (es) are pathogenic and directly related to the severity of the disease. It is of great interest and clinical significance to know the answer since the different IgG subclasses have distinct functional properties. One of them is the ability to activate complement. IgG3 is the most effective complement activator, followed by IgG1 and IgG2, while IgG4 is not capable of fixing complement. Studies on this issue, however, have painted a controversial picture. For example, Bernard et al and Laffitte et al demonstrated that anti-BP180 autoantibody IgG1 is the predominant IgG subclass, whereas Dopp et al concluded that anti-BP180 autoantibody IgG4 is the predominant IgG subclass in BP (Bernard et al, 1990; Dopp et al, 2000; Laffitte et al, 2001). The factors causing this controversy are most likely the differences in their assay systems (ie, immunoblotting, immunofluorescence, or ELISA), substrates in their assays (epidermal extracts that contain both BP230 and BP180, recombinant BP180 antigen expressed in prokaryotic or eukaryotic cells), and more importantly, the selected BP patient populations (patients in active, remission, untreated or treated states).