Epitope-Dependent Pathogenicity of Antibodies Targeting a Major Bullous Pemphigoid Autoantigen Collagen XVII/BP180.
Epitope-Dependent Pathogenicity of Antibodies Targeting a Major Bullous Pemphigoid Autoantigen Collagen XVII/BP180.
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针对主要大疱性类天疱疮自身抗原胶原 XVII/BP180 的抗体的表位依赖性致病性。
DOI：
10.1016/j.jid.2015.11.030
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发表时间：
2016
影响因子：
6.5
通讯作者：
Shimizu H
中科院分区：
文献类型：
--
作者：
Wada M;Nishie W;Ujiie H;Izumi K;Iwata H;Natsuga K;Nakamura H;Kitagawa Y;Shimizu H
在大疱性类天疱疮这种常见的自身免疫性水泡性疾病中，免疫球蛋白G自身抗体针对XVII(COL17)/BP180半桥粒跨膜型胶原蛋白的不同表位。针对COL17细胞外非胶原性16A区的抗体可能是致病的；然而，针对非胶原性16A区的抗体的致病作用尚不清楚。在这项研究中，我们用致病和非致病的单抗(MAb)分别针对非胶原性16A结构域(mAbTS39-3)和C末端结构域(mAbC17-c1)，证明了免疫复合物与细胞表面COL17结合后的内吞作用是导致皮肤脆性的关键现象。被动转移IgG1mAbTS39-3而不是mAbC17-c1可诱导表达COL17的转基因小鼠真皮-表皮分离。有趣的是，单抗C17-C1与受体小鼠皮肤的真皮-表皮交界处有很强的结合，表明单抗与COL17的结合不足以诱导皮肤脆性。在培养的正常人表皮角质形成细胞中，单抗TS39-3通过巨噬细胞吞噬与细胞表面COL17结合后内化免疫复合体，而不是C17-C1，导致COL17表达降低。这项研究表明，针对COL17的抗体的致病性是表位依赖的，这与巨噬细胞吞噬介导的免疫复合物的内吞有关，最终导致基底层角质形成细胞COL17表达的耗竭。
In bullous pemphigoid, the common autoimmune blistering disorder, IgG autoantibodies target various epitopes on hemidesmosomal transmembrane collagen XVII (COL17)/BP180. Antibodies (Abs) targeting the extracellular noncollagenous 16th A domain of COL17 may be pathogenic; however, the pathogenic roles of Abs targeting non-noncollagenous 16th A regions are poorly understood. In this study using a pathogenic and a nonpathogenic monoclonal antibody (mAb) targeting the noncollagenous 16th A domain (mAb TS39-3) and the C-terminus domain (mAb C17-C1), respectively, we show that endocytosis of immune complexes after binding of Abs to cell surface COL17 is a key phenomenon that induces skin fragility. Passive transfer of IgG1 mouse mAb TS39-3 but not mAb C17-C1 induces dermal-epidermal separation in neonatal human COL17-expressing transgenic mice. Interestingly, mAb C17-C1 strongly binds with the dermal-epidermal junction of the recipient mice skin, suggesting that binding of Abs with COL17 is insufficient to induce skin fragility. In cultured normal human epidermal keratinocytes treated with these mAbs, mAb TS39-3 but not mAb C17-C1 internalizes immune complexes after binding with cell surface COL17 via macropinocytosis, resulting in reduced COL17 expression. This study shows that pathogenicity of Abs targeting COL17 is epitope dependent, which is associated with macropinocytosis-mediated endocytosis of immune complexes and finally results in the depletion of COL17 expression in basal keratinocytes.