Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity.
Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity.
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DOI：
10.1172/jci44425
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发表时间：
2010-11
期刊：
影响因子：
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通讯作者：
J. Yamagami;A. Payne;Stephen Kacir;K. Ishii;D. Siegel;J. Stanley
中科院分区：
文献类型：
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作者：
J. Yamagami;A. Payne;Stephen Kacir;K. Ishii;D. Siegel;J. Stanley
天疱疮是一种危及生命的自身免疫性疾病，其中桥粒芯糖蛋白（Dsgs）特异性抗体导致角质形成细胞粘附丧失和水疱。为了了解抗体如何引起致病性以及不同患者中的抗体之间是否存在最终可用于靶向针对这些抗体的特异性治疗的共性，我们表征了通过噬菌体展示从3名寻常型天疱疮患者和2名落叶型天疱疮患者克隆的Dsg特异性mAb。可变重链基因的使用受到限制，但相似的基因用于致病性和非致病性mAb。然而，大多数致病性但非致病性mAb的重链互补决定区3（H-CDR 3）共享一个氨基酸共有序列。H-CDR 3的随机化和定点突变表明，该序列的变化可以阻断致病性，但不一定结合。此外，对于具有较长H-CDR 3的2种抗体，色氨酸对于致病性是关键的，但不是结合，这一结果与阻断色氨酸受体位点一致，认为色氨酸受体位点是Dsg介导的粘附所必需的。这些研究表明H-CDR 3对于人自身抗体的致病性是关键的，小区域（甚至1个氨基酸）可以介导致病性，并且致病性可以与这些抗体中的结合解偶联。
Pemphigus is a life-threatening autoimmune disease in which antibodies specific for desmogleins (Dsgs) cause loss of keratinocyte cell adhesion and blisters. In order to understand how antibodies cause pathogenicity and whether there are commonalities among antibodies in different patients that could ultimately be used to target specific therapy against these antibodies, we characterized Dsg-specific mAbs cloned by phage display from 3 patients with pemphigus vulgaris and 2 with pemphigus foliaceus. Variable heavy chain gene usage was restricted, but similar genes were used for both pathogenic and nonpathogenic mAbs. However, the heavy chain complementarity-determining region 3 (H-CDR3) of most pathogenic, but not nonpathogenic, mAbs shared an amino acid consensus sequence. Randomization of the H-CDR3 and site-directed mutagenesis indicated that changes in this sequence could block pathogenicity but not necessarily binding. In addition, for 2 antibodies with longer H-CDR3s, a tryptophan was critical for pathogenicity but not binding, a result that is consistent with blocking the tryptophan acceptor site that is thought to be necessary for Dsg-mediated adhesion. These studies indicate that H-CDR3 is critical for pathogenicity of a human autoantibody, that a small region (even 1 amino acid) can mediate pathogenicity, and that pathogenicity can be uncoupled from binding in these antibodies.