Skin Dendritic Cells and Humoral Immunity

皮肤树突状细胞和体液免疫

• 批准号: 9151875
• 负责人: Daniel H Kaplan
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151875
• 关键词: Ablation; Antibodies; Antibody Formation; Antibody Response; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Atopic Dermatitis; Autoimmune Process; B-Lymphocytes; Bacteria; Bulla; CD4 Positive T Lymphocytes; Candida albicans; Cell physiology; Complex; Cutaneous; Defect; Dendrites; Dendritic Cells; Dermal; Dermis; Development; Disease; Ectromelia; Epidermis; Etiology; Generations; Gnotobiotic; Health; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; ITGAM gene; Immunity; Immunization; Immunoglobulin M; Infection; Infectious Ectromelia; Infectious Skin Diseases; Inflammatory; Job' s Syndrome; Langerhans cell; Lymphoid Tissue; Mediating; Mus; Mutation; Organism; Pathway interactions; Patients; Phenotype; Proteins; Recurrence; Role; Skin; Stratum corneum; Structure of germinal center of lymph node; Syndrome; T-Lymphocyte; Testing; Vaccines; Viral; Virus; Virus Diseases; Work; X-Linked Agammaglobulinemia; base; cell type; fungus; immune function; in vivo; interest; langerin; lymph nodes; microorganism; new therapeutic target; nonhuman primate; pathogen; prevent; receptor; resistance mechanism; response; skin disorder; uptake

 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.

 描述（由申请人提供）：基于 T 细胞的免疫在预防皮肤感染方面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 途径（例如高 IgE 综合征）存在抗体反应缺陷（例如 X 连锁无丙种球蛋白血症、高 IgM 综合征）的患者也患有复发性皮肤细菌化脓性和病毒感染。此外，还发现了对抗原的抗体反应。尽管体液反应对皮肤健康具有明显的重要性，但皮肤中的细菌是许多自身免疫性水疱疾病的致病因素，并参与特应性皮炎和特应性皮炎。皮肤抗原产生抗体反应的机制研究很少，皮肤驻留树突状细胞 (DC) 是在皮肤中获取抗原的专业抗原呈递细胞，朗格汉斯细胞 (LC) 形成致密的细胞。表皮中的 DC 网络将树突延伸至上表皮并进入角质层，我们发现 LC 1) 驱动 CD4+ T 滤泡辅助细胞的生成。 (Tfh) 为 B 细胞提供 T 细胞帮助，2) 足以在稳态条件下诱导体液反应，因此，LC 在稳态条件下的一个主要未被认识到的功能是 Tfh 的产生和相关的体液反应假设。该提议认为，LC 在针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 2 个主要的 DC 亚群。感染所有 3 个 DC 亚群都会促进不同的 Th 亚群分化，并且只有 LC 具有分化 Tfh 的能力。我们发现，除了扩展 Tfh 之外，LC 还转运完整的皮肤抗原。最后，我们勇敢地承认，在病原体感染过程中，LC 是促进抗体反应以及产生针对皮肤共生微生物的抗体所必需的，了解哪些 DC 亚群、条件和途径驱动皮肤抗原特异性抗体的形成至关重要。理解皮肤病原体的抵抗机制和抗体介导的皮肤病的病因学这项工作有可能为皮肤免疫功能的调节提供新的治疗靶点。