Structure and mechanism of pemphigus autoantibodies

天疱疮是一组具有潜在生命危险的抗体介导的自身免疫性疾病。 棘层松解引起细胞黏附丧失的皮肤和其他复层上皮细胞 皮肤起水泡和腐蚀物。天疱疮的棘层松解是由自身抗体引起的 针对桥粒细胞-粘附性连接-特别是针对跨膜钙粘附素- 在细胞间结合以调节桥粒黏附的家族蛋白。几个亚型 已知的天疱疮包括两种主要形式的寻常型天疱疮(PV)和 叶天疱疮(Pf)。广泛地说，PV的特征是基底层的棘层松解。 粘膜型(粘膜型)或粘膜和皮肤(粘皮型)，而PF是 以皮肤角膜下上层的棘层松解为特征。 已从每种形式的天疱疮患者中鉴定出致病性天疱疮自身抗体 疾病，但缺乏关于天疱疮自身抗体的结构信息。因此，准确的 以天疱疮自身抗体为靶点的表位，以及 调解承认，仍然未知。这里提出的研究的总体目标是 将原子水平的定义引入天疱疮的研究 结构生物学的现代方法。原子分辨率共晶结构将 明确识别功能区并定义精确的分子相互作用 天疱疮自身抗体与钙粘附素细胞黏附的调节作用 他们瞄准的蛋白质。此外，为了确定不同的天疱疮自身抗体如何损害 桥粒的结构和起泡的原因，我们将分析它们对重组的影响 使用低温电子显微镜断层扫描获得高分辨率的桥粒连接。这项研究建议 这里将对天疱疮自身抗体的相互作用产生一个原子水平的理解 桥粒的发现，有望改变我们对天疱疮的理解。

Pemphigus is a group of potentially life-threatening antibody-mediated autoimmune diseases of the skin and other stratified epithelia in which acantholysis – the loss of cell adhesion – causes skin blistering and erosions. Acantholysis in pemphigus is caused by autoantibodies directed against desmosome cell-adhesive junctions – specifically against the transmembrane cadherin- family proteins that bind between cells to mediate adhesion in desmosomes. Several subtypes of pemphigus disease are known, including two major forms pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Broadly, PV is characterized by acantholysis in the basal layers of mucosae (mucosal form) or mucosae and skin (muco-cutaneous form), while PF is characterized by acantholysis specifically in the subcorneal upper layers of the skin. Pathogenic pemphigus autoantibodies have been identified from patients with each form of the disease, but structural information on pemphigus autoantibodies is lacking. Thus, the precise epitopes targeted by pemphigus autoantibodies, and the antibody regions (paratopes) that mediate recognition, remain unknown. The overall goal of the research proposed here is to bring atomic-level definition to the study of pemphigus disease through the application of modern methods of structural biology. Atomic resolution co-crystal structures will unambiguously identify functional regions and define the precise molecular interactions mediating recognition between pemphigus autoantibodies and the cadherin cell-adhesion proteins they target. In addition, to determine how different pemphigus autoantibodies impair desmosome structure and cause blistering, we will analyze their effects on reconstituted desmosome junctions at high resolution using cryo-EM tomography. The research proposed here will produce an atomic-level understanding of the interaction of pemphigus autoantibodies with desmosomes, and is expected to transform our understanding of pemphigus disease.