Autoantibodies to desmocollin 3 in pemphigus exclusively recognize calcium-dependent epitope in extracellular domain 2
Autoantibodies to desmocollin 3 in pemphigus exclusively recognize calcium-dependent epitope in extracellular domain 2
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天疱疮中的桥粒胶蛋白 3 自身抗体专门识别细胞外结构域 2 中的钙依赖性表位
DOI：
10.1016/j.jid.2021.01.032
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发表时间：
2021
影响因子：
6.5
通讯作者：
Nakama Takekuni
中科院分区：
文献类型：
--
作者：
Koga Hiroshi;Teye Kwesi;Otsuji Yoshihiko;Ishii Norito;Hashimoto Takashi;Nakama Takekuni
天疱疮是一组自身免疫性大疱性疾病，其特征是存在抗黏附分子、桥粒和桥粒粘连蛋白(DSCs)的自身抗体。抗DSC3抗体在天疱疮中的致病性已被证实，但其特征尚未阐明。我们的目的是利用DSC3结构域交换的桥粒芯糖蛋白2分子来分析抗DSC3抗体的特性，将桥粒芯糖蛋白2的前序列和5个胞外(EC)结构域替换为人DSC3的相应结构域。利用这些蛋白，我们建立了一种ELISA方法，并对56例天疱疮患者的血清进行了分析。在34例DSC3全EC区阳性的天疱疮血清中，15例(44.1%)EC2区阳性，其他区极少阳性。我们用EDTA酶联免疫吸附试验检测了其与DSC3中一个钙依赖表位的反应性。在EDTA存在下，与EC2结构域的反应活性大部分受到影响。在体外实验中，副肿瘤性天疱疮患者的免疫球蛋白与EC2预吸附相比，与EDTA处理的EC2相比，既能防止DSC3的减少，又能防止角质形成细胞的分离。本研究揭示了抗DSC3抗体对EC2区钙依赖表位的优势识别作用及其通过DSC3缺失对角质形成细胞黏附的致病作用。
Pemphigus is a group of autoimmune bullous diseases characterized by the presence of autoantibodies against adhesion molecules, desmogleins, and desmocollins (DSCs). The pathogenicity of anti-DSC3 antibodies in pemphigus has been demonstrated; however, its characteristics have not yet been elucidated. We aimed to analyze the characteristics of anti-DSC3 antibodies using DSC3 domain‒swapped desmoglein 2 molecules in which the prosequence and five extracellular (EC) domains of desmoglein 2 were replaced with the corresponding domains of human DSC3. Using these proteins, we established an ELISA and analyzed sera from 56 patients with pemphigus. In 34 pemphigus sera positive for DSC3 full-EC domains, 15 sera (44.1%) were positive for EC2 domain, whereas other domains were rarely positive. We assessed the reactivity to a calcium-dependent epitope in DSC3 by ELISA with EDTA. The reactivity with the EC2 domain was mostly compromised in the presence of EDTA. In the in vitro assay, IgG from patients with paraneoplastic pemphigus preadsorbed with EC2 prevented both reduction of DSC3 and keratinocyte dissociation as compared with that with EDTA-treated EC2. This study revealed a predominant recognition of calcium-dependent epitopes in EC2 domain by anti-DSC3 antibodies and its pathogenicity on keratinocyte adhesion through DSC3 depletion.