Evolution of the pathogenic autoimmun response in bullous pemphigoid

与癌症类似，自身免疫性疾病通常在年龄越大发生的频率越高。虽然自身侵袭性组织损伤的机制已被越来越多地研究，但从自身免疫到致病性自身抗体反应导致临床显性疾病的进展在很大程度上尚未被探索。类天疱疮包括一组影响老年人的免疫大疱性皮肤病，通常在前驱非大疱期之前。因此，类天疱疮为研究衰老个体致病性自身免疫反应的启动和调节提供了一个精致的模型。通过将基础研究与临床研究联系起来，本项目将能够表征类天疱疮自身免疫启动的致病机制及其与组织损伤的耦合。具体来说，自身反应性T细胞识别的自身抗原表位以及自身抗体致病性的不同可能决定因素，包括它们的分子特异性、同型和糖基化，将在“类天疱疮前期”和完全型类天疱疮患者以及最近建立的类天疱疮小鼠模型中进行表征。此外，对于新的机制见解，本研究的结果将极大地促进识别类天疱疮风险受试者，开发新的诊断和预后工具，以及更有效的治疗策略。重要的是，对类天疱疮发病机制的新见解和新开发的诊断工具可能会转化为更全面的研究，并最终用于其他与年龄相关的炎症和自身免疫性疾病的治疗。

Autoimmune diseases, similarly to cancer, generally show an increased frequency at higher age. While mechanisms of autoaggressive tissue damage have been increasingly investigated, the progression from autoimmunity to a pathogenic autoantibody response resulting in clinically overt disease is largely unexplored. The pemphigoids comprise a group of immunobullous skin disorders which affect the elderly and are typically preceded by a prodromal non-bullous stage. Therefore, the pemphigoids represent an exquisite model to study the initiation and regulation of a pathogenic autoimmune response in ageing individuals. By connecting basic to clinical research, the present project will allow to characterize the pathogenic mechanisms of the initiation of autoimmunity and its coupling to tissue damage in pemphigoids. Specifically, the autoantigenic epitopes that are recognized by autoreactive T cells as well as different possible determinants of the autoantibody pathogenicity, including their molecular specificity, isotype and glycosylation will be characterized in patients with “pre-pemphigoid” and full-blown pemphigoid as well as in a recently established mouse model of pemphigoid. In addition, to new mechanistic insights, the results of the present study will greatly facilitate the identification of subjects at risk to develop pemphigoid, the development of new diagnostic and prognostic tools, and of more effective therapeutic strategies. Importantly, new insights into the pathogenesis of the pemphigoids and newly developed diagnostic tools may be translated to more comprehensive research and, eventually, the management of other age-related inflammatory and autoimmune disorders.