Autoimmunity against desmocollins in pemphigus

已在疱疹样天疱疮、增殖性天疱疮、伊加天疱疮以及非典型和副肿瘤性天疱疮患者中鉴定出针对桥粒的主要非桥粒芯糖蛋白（Dsg）组分桥粒柯林斯（Dsc）的IgG自身抗体应答。虽然Dsg 1和Dsg 3特异性自身抗体的致病潜力已被广泛表征，但Dsc特异性IgG自身抗体的致病性仅在体外得到证实。因此，本工作包的工作旨在剖析调节致病性Dsc特异性自身抗体的机制以及最终导致表皮粘附丧失的后续事件。为此，将使用新开发的针对Dsc的自身免疫小鼠模型。这些模型联合收割机将抗Dsc ab诱导的棘层松解的特征性分子特征与起泡临床表型结合，并再现了主动自身免疫应答和由用自身抗原免疫诱导的起泡疾病和/或对Dsc的自身免疫应答的最终效应阶段（即，由抗体的被动转移诱导的组织损伤）。

IgG autoantibody responses against major non-desmoglein (Dsg) components of desmosomes, the desmocollins(Dsc), have been identified in patients with pemphigus herpetiformis, pemphigus vegetans, IgA pemphigus, as well as atypical and paraneoplastic pemphigus. While the pathogenic potential of autoantibodies specific for Dsg1 and Dsg3 has been extensively characterized, the pathogenicity of Dsc-specific IgG autoantibodies has only been demonstrated in vitro. Therefore, the work of the present workpackage is aimed at dissecting the mechanisms that regulate pathogenic Dsc-specific autoantibodies and the subsequent events that eventually lead to epidermal loss of adhesion. For this purpose, newly developed mouse models of autoimmunity against Dsc will be used. These models combine the characteristic molecular features of anti-Dsc ab-induced acantholysis with a blistering clinical phenotype and reproduce the active autoimmune response and the blistering disease induced by the immunization with the autoantigen and/or the final effector phase of the autoimmune response to Dsc (i.e., the tissue damage induced by the passive transfer of antibodies).