Skin Dendritic Cells and Humoral Immunity

 描述（由申请人提供）：基于T细胞的免疫在预防皮肤感染中的重要性已得到充分研究，并且最好的例证是具有遗传缺陷的患者， CD4+ Th17通路（如高IgE综合征）。抗体应答产生缺陷的患者（例如X连锁无丙种球蛋白血症、高IgM综合征）也会遭受复发性皮肤细菌化脓性和病毒感染。此外，对皮肤中发现的抗原的抗体应答在许多自身免疫性起泡疾病中是致病性的，并且参与特应性皮炎和特应性进展。尽管体液应答对皮肤健康和疾病的重要性显而易见，但对产生针对皮肤抗原的抗体应答的机制的研究非常少。皮肤树突状细胞（DC）是一种专职的抗原提呈细胞，在皮肤中获得抗原。一个DC亚群，朗格汉斯细胞（LC），在表皮中形成致密的DC网络。它们将树突延伸到上表皮并进入角质层，在那里它们能够获得抗原。我们已经发现LC 1）驱动为B细胞提供T细胞帮助的CD 4 + T滤泡辅助细胞（Tfh）的产生，以及2）足以在稳态条件下诱导体液应答。因此，在稳态条件下LC的一个主要未被认识到的功能是产生Tfh和相关的体液反应。该建议的中心假设是LC在产生对皮肤抗原的抗体应答中具有独特的作用。除了表皮中的LC之外，真皮中还有2个主要的DC亚群。在皮肤感染的情况下，所有3个DC亚群促进不同的Th亚群分化。我们假设这种区别也发生在稳态条件下，只有LC有能力区分Tfh。我们假设除了扩增Tfh外，LC还将完整的皮肤抗原转运至B细胞。最后，我们假设，LC需要在病原体感染和产生针对皮肤微生物的抗体，以促进抗体反应。了解哪种DC亚群、条件和途径驱动皮肤抗原特异性抗体的形成对于理解对皮肤病原体的抗性机制和抗体介导的皮肤疾病的病因学至关重要。这项工作有可能为调节皮肤免疫功能提供新的治疗靶点。

 DESCRIPTION (provided by applicant): The importance of T cell based immunity in preventing skin infections is well studied and best exemplified by patients with genetic defects in the CD4+ Th17 pathway (e.g. hyper IgE syndrome). Patients with defects in the generation of antibody responses (e.g. X-linked agammaglobulinemia, hyper IgM syndrome) also suffer from recurrent skin bacterial pyogenic and viral infections. In addition, antibody responses to antigen found in the skin are pathogenic in numerous autoimmune blistering diseases and participate in atopic dermatitis and the atopic march. Despite the clear importance of humoral responses to skin health and disease, the mechanisms that generate antibody responses to cutaneous antigen are very poorly studied. Skin-resident dendritic cells (DC) are professional antigen presenting cells that acquire antigen in the skin. One DC subset, Langerhans cells (LC), form a dense DC network in the epidermis. They extend their dendrites to the upper epidermis and into the stratum corneum where they are able to acquire antigen. We have discovered that LC 1) drive the generation of CD4+ T follicular helper cells (Tfh) that provide T cell help for B cells ad 2) are sufficient to induce humoral response under steady-state conditions. Thus, a major unappreciated function of LC during homeostatic conditions is the generation of Tfh and the associated humoral response. The central hypothesis of this proposal is that LC have a unique role in the generation of antibody responses to cutaneous antigen. In addition to LC in the epidermis, there are 2 major subsets of DC in the dermis. In the setting of a skin infection all 3 DC subsets promote distinct Th subset differentiation. We hypothesize that this distinction occurs during steady-state conditions as well and that only LC have the capacity to differentiate Tfh. We hypothesized that in addition to expanding Tfh, LC also transport intact cutaneous antigen to B cells. Finally, we hypothesize that LC are required to promote antibody responses during pathogen infection and for the generation of antibodies against skin commensal microorganisms. Understanding which DC subset, conditions and pathways drive the formation of antibodies specific for cutaneous antigen is critical to understanding the mechanisms of resistance to skin pathogens and the etiology of antibody-mediated skin diseases. This work has the potential to provide novel therapeutic targets for the modulation of skin immune function.