Pemphigus and Pemphigoid

描述(由申请人提供)：这是RO1 AR32081-25的修订版，它测试了人类对桥粒芯糖蛋白1(DSG1)和Dsg3的自身抗体反应是多样化的假设，范围从在正常人中检测到的非致病性和持续性反应到在寻常型天疱疮(PV)和叶天疱疮/Fogo Selvan em(PF/FS)患者中发现的坦率的致病反应。正常和疾病个体的皮肤表型是由这些自身抗体的表位特异性驱动的。由于DSG1和DSG3之间的广泛同源性，预测表位交叉反应和表位扩散等现象在具有适当遗传背景的个体中是可行的。这一假说解释了非致病性和致病性抗DSGL和抗Dsg3自身抗体在患者和正常人中的流行，从PV到PF或PF到PV的罕见表型转变，以及在巴西FS流行地区存在一种新形式的“地方性PV”。我们感兴趣的是在PV和PF/FS的正常、临床前期和临床期的自身免疫反应的进展过程中，确定抗DSGL和抗Dsg3自身抗体的精细表位特异性和抗Dsg3自身抗体的Ig G亚类限制。我们的研究表明，从非致病性抗DSGL反应(在具有抗EC5结构域的正常人中发现)到致病性(在FS患者中发现)与出现针对该抗原的抗ED-2自身抗体群体有关。这些项目是由我们独特的来自PV、非地方性PF、FS和正常捐赠者的血清库推动的，其中包括疾病演变的不同阶段的患者。我们描述了令人兴奋的新的、未报道的研究，这些研究严重超出了这项赠款的目标，例如，在FS中出现高频率和独特的抗DSGL IgM自身抗体，在PV、PF/FS中存在抗E钙粘素自身抗体，仅举两例。我们还鉴定了几个来自PV、PF和FS的B细胞克隆，并对Ig G V区基因进行了测序，开始探索这些患者自身免疫反应的多样性。同样，我们还产生了人/鼠IgM单抗，将进一步分析V基因的多样性。最后，我们将通过噬菌体展示技术产生人源性抗独特型抗体，并试图阻断PV或PF/FS自身抗体与其目标表皮抗原的结合，从而预防疾病。

DESCRIPTION (provided by applicant): This is a revised version of the RO1 AR32081-25 which tests the hypothesis that the autoantibody response in humans against desmoglein 1 (Dsg1) and Dsg3 is diverse, ranging from a non-pathogenic and persistent response detected in normal individuals to a frankly pathogenic reaction found in pemphigus vulgaris (PV) and pemphigus foliaceus/fogo selvagem (PF/FS) patients. The skin phenotype in normal and diseased individuals is driven by the epitope specificity of these autoantibodies. It is predicted that phenomena such as epitope cross-reactivity and epitope spreading are feasible in individuals with the appropriate genetic background due to the extensive homology between Dsg1 and Dsg3. This hypothesis explains the prevalence of non-pathogenic and pathogenic anti-Dsgl and anti-Dsg3 autoantibodies in patients and normal individuals, the rare transition of phenotype from PV to PF or PF to PV and the existence of a novel form of "endemic PV" in endemic regions of FS in Brazil. We are interested on determining the fine epitope specificity and the IgG subclass restriction of anti-Dsgl and anti-Dsg3 autoantibodies during the progression of the autoimmune response from normal, pre-clinical and clinical stages of PV and PF/FS. Our studies show that conversion from non-pathogenic anti-Dsgl response (found in normal individuals with anti-EC5 domain) to pathogenic (found in FS patients) is linked to the emergence of population of anti-Ed-2 autoantibodies to this antigen. These projects are facilitated by our unique bank of sera from PV, non-endemic PF, FS and normal donors, which include patients in different stages of disease evolution. We describe exciting novel, unreported studies that stern out of the aims of this grant, e.g. the high frequency and distinctive presence of anti-Dsgl IgM autoantibodies in FS and the presence of anti-E cadherin autoantibodies in PV, PF/FS to name two. We have also characterized several B cell clones from PV, PF and FS and sequenced the IgG V region genes and began to explore the diversity of the autoimmune response in these patients. Similarly, we have also generated human/mouse IgM monoclonal antibodies, which will be further analyzed for V gene diversity. Finally, we will generate human anti-idiotypic antibodies by phage display technology and attempt to block binding of PV or PF/FS autoantibodies to their target epidermal antigens, thus preventing disease.