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首页> 外文期刊>The Journal of investigative dermatology. >Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies.
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Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies.

机译：大疱性类天疱疮自身抗体识别的细胞外BP180表位紧密聚集。

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摘要

Bullous pemphigoid is a blistering skin disease associated with autoantibodies against the BP180 antigen, a transmembrane component of the hemidesmosome. Anti-BP180 antibodies have been demonstrated to be pathogenic in a passive transfer mouse model. One extracellular site on human BP180 (MCW-1) was previously shown to be recognized by 50-60% of bullous pemphigoid sera. To facilitate the identification of additional autoantibody-reactive epitopes, recombinant forms of the BP180 ectodomain were generated using both bacterial and mammalian expression systems. One recombinant protein, sec180e, that was expressed in COS-1 cells and that contained the entire BP180 ectodomain, provided us with a tool to detect conformational epitopes. Bullous pemphigoid sera immunoadsorbed against the major noncollagenous NC16A domain no longer reacted with sec180e, indicating that autoantibody reactivity to the BP180 ectodomain is restricted to the NC16A region. Immunoblot analysis of bullous pemphigoid sera immunoadsorbed with a series of recombinant NC16A peptides revealed the presence of three novel autoantigenic sites that, along with the MCW-1 epitope, are clustered within the N-terminal 45 amino acid stretch of NC16A. All 15 bullous pemphigoid sera tested reacted with a recombinant protein containing this BP180 segment. No disease-associated epitopes were detectable within the remaining 28 amino acids of NC16A. Thus, bullous pemphigoid patient autoantibodies react with a set of epitopes on the BP180 ectodomain that are highly clustered. This autoantibody-reactive region on human BP180 shows overlap with the corresponding murine BP180 site that is targeted by antibodies that are pathogenic in the mouse model of bullous pemphigoid. These findings suggest new directions for the development of diagnostic and therapeutic tools for this disease.
机译：大疱性类天疱疮是与针对BP180抗原的自身抗体相关的水疱性皮肤病，BP180抗原是半脂质体的跨膜成分。已证明抗BP180抗体在被动转移小鼠模型中具有致病性。先前显示人类BP180（MCW-1）上的一个胞外位点可被50-60％的大疱性类天疱疮血清识别。为了促进鉴定其他自身抗体反应性表位，使用细菌和哺乳动物表达系统产生了BP180胞外域的重组形式。一种在COS-1细胞中表达并包含整个BP180胞外域的重组蛋白sec180e，为我们提供了检测构象表位的工具。免疫吸附在主要非胶原NC16A结构域上的大疱性类天疱疮血清不再与sec180e反应，表明对BP180胞外域的自身抗体反应性仅限于NC16A区。用一系列重组NC16A肽免疫吸附的大疱天疱疮血清的免疫印迹分析显示，存在三个新颖的自身抗原性位点，连同MCW-1表位，聚集在NC16A的N端45个氨基酸序列内。测试的所有15种大疱性类天疱疮血清均与含有该BP180片段的重组蛋白反应。在NC16A的其余28个氨基酸中未检测到与疾病相关的表位。因此，大疱性类天疱疮患者自身抗体与BP180胞外域上高度簇集的一组表位反应。人BP180上的此自身抗体反应区显示与相应的鼠BP180位点重叠，该位点被在大疱性类天疱疮小鼠模型中致病的抗体靶向。这些发现为该疾病的诊断和治疗工具的开发提出了新的方向。

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