Autoimmunity against desmocollins in pemphigus

IgG自身抗体对桥粒的主要非桥粒蛋白（Dsg）成分桥粒素（Dsc）的反应已经在疱疹样天疱疮、素食性天疱疮、IgA天疱疮以及非典型和副肿瘤天疱疮患者中被发现。虽然Dsg1和Dsg3特异性自身抗体的致病潜力已被广泛表征，但Dsg1特异性IgG自身抗体的致病性仅在体外得到证实。因此，本工作包旨在剖析调节致病性dsc特异性自身抗体和最终导致表皮粘附丧失的后续事件的机制。为此，将使用新开发的Dsc自身免疫小鼠模型。这些模型将抗Dsc抗体诱导棘层溶解的分子特征与起泡临床表型相结合，再现了主动自身免疫反应和由自身抗原免疫和/或Dsc自身免疫反应的最终效应期（即抗体被动转移诱导的组织损伤）诱导的起泡疾病。

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).