Pemphigus and Pemphigoid

描述（由申请人提供）：这是RO 1 AR 32081 -25的修订版，其检验了以下假设：人体中抗桥粒芯糖蛋白1（Dsg 1）和Dsg 3的自身抗体反应是多样的，范围从正常个体中检测到的非致病性和持续性反应到寻常型天疱疮（PV）和落叶型天疱疮/森林性天疱疮（PF/FS）患者中发现的明显致病性反应。正常和患病个体中的皮肤表型由这些自身抗体的表位特异性驱动。据预测，由于Dsg 1和Dsg 3之间的广泛同源性，表位交叉反应性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。这一假设解释了患者和正常人中非致病性和致病性抗Dsg 1和抗Dsg 3自身抗体的普遍存在、表型从PV到PF或PF到PV的罕见转变以及巴西FS流行地区存在一种新型“地方性PV”。我们感兴趣的是在PV和PF/FS的正常、临床前和临床阶段的自身免疫应答的进展期间确定抗Dsgl和抗Dsg 3自身抗体的精细表位特异性和IgG亚类限制。我们的研究表明，从非致病性抗Dsgl应答（在具有抗EC 5结构域的正常个体中发现）到致病性（在FS患者中发现）的转化与针对该抗原的抗Ed-2自身抗体群体的出现有关。这些项目得益于我们独特的PV、非地方性PF、FS和正常供体血清库，其中包括处于疾病演变不同阶段的患者。我们描述了令人兴奋的新的，未报道的研究，严厉的目的，这一补助金，例如，高频率和独特的存在抗Dsgl IgM自身抗体在FS和存在抗E钙粘蛋白自身抗体在PV，PF/FS，仅举两例。我们还对PV、PF和FS的几个B细胞克隆进行了表征，并对IgG V区基因进行了测序，并开始探索这些患者自身免疫反应的多样性。类似地，我们还产生了人/小鼠IgM单克隆抗体，将进一步分析V基因多样性。最后，我们将通过噬菌体展示技术产生人抗独特型抗体，并尝试阻断PV或PF/FS自身抗体与其靶表皮抗原的结合，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.