Skin Dendritic Cells and Humoral Immunity

 描述(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得到了充分的研究，并以患有遗传缺陷的患者为最好的例证。 CD4+Th17途径(如高IgE综合征)。抗体反应产生缺陷的患者(如X连锁无丙种球蛋白血症、高IgM综合征)也会反复出现皮肤细菌性化脓性感染和病毒感染。此外，对皮肤中发现的抗原的抗体反应在许多自身免疫性水泡疾病中是致病的，并参与特应性皮炎和特应性进行曲。尽管体液反应对皮肤健康和疾病具有明显的重要性，但对皮肤抗原产生抗体反应的机制研究很少。皮肤树突状细胞(DC)是一种在皮肤中获得抗原的专业抗原提呈细胞。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和角质层，在那里它们能够获得抗原。我们发现，在稳态条件下，LC 1)驱动为B细胞提供T细胞帮助的CD4+T滤泡辅助细胞(TFH)的产生足以诱导体液反应。因此，LC在动态平衡条件下的一个主要未被认识的功能是TFH的产生和相关的体液反应。这一建议的中心假设是LC在产生对皮肤抗原的抗体反应中具有独特的作用。除了表皮中的LC外，真皮中还有两个主要的DC亚群。在皮肤感染的情况下，所有3个DC亚群都促进了不同的Th亚群分化。我们假设这种区别也发生在稳态条件下，并且只有LC有能力区分TFH。我们推测，除了扩增TFH外，LC还将完整的皮肤抗原运送到B细胞。最后，我们假设LC在病原体感染期间促进抗体反应和产生针对皮肤共生微生物的抗体是必需的。了解哪些DC亚群、条件和途径推动了皮肤抗原特异性抗体的形成，这对于了解皮肤对病原体的抵抗机制和抗体介导的皮肤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.