Skin Dendritic Cells and Humoral Immunity

皮肤树突状细胞和体液免疫

• 批准号: 9047238
• 负责人: Daniel H Kaplan
• 金额: $ 33.48万
• 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/9047238
• 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; Hyperimmunoglobulin M Syndrome; ITGAM gene; Immunity; Immunization; 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; 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（通过应用提供）：基于T细胞的免疫在预防皮肤感染中的重要性是研究良好的，并且最能体现在遗传缺陷的患者中 CD4+ TH17途径（例如Hyper IgE综合征）。患有抗体反应缺陷的患者（例如X连锁的Agammaglobloblobolinemia，HyperIGM综合征）也患有复发性皮肤细菌性化脓性和病毒感染。此外，在许多自身免疫性疾病中，在皮肤中发现的抗体对抗原的反应是致病性的，并参与了特应性皮炎和特应性三月。尽管对皮肤健康和疾病的体液反应显而易见，但对皮肤抗原产生抗体反应的机制非常差。皮肤居住的树突状细胞（DC）是专业的抗原呈现细胞，可在皮肤中获得抗原。一个DC子集，Langerhans细胞（LC），在表皮中形成密集的DC网络。他们将树突延伸到上表皮，并将其延伸到角膜层，在那里他们能够获得抗原。我们发现LC 1）驱动为B细胞提供T细胞帮助的CD4+ T卵泡细胞（TFH）的产生足以在稳态条件下诱导体液反应。这是LC在体内稳态条件下的主要未经批准的功能是TFH的产生和相关的体液反应。该提议的中心假设是LC在对皮肤抗原的抗体反应的产生中具有独特的作用。除表皮中的LC外，真皮中还有2个主要子集。在皮肤感染的情况下，所有3个DC子集都会促进不同的TH子集分化。我们假设这种障碍也发生在稳态条件下，并且只有LC具有区分TFH的能力。我们假设，除了扩展TFH，LC外，还将完整的皮肤抗原转移到B细胞中。最后，我们假设需要LC来促进病原体感染期间抗体反应以及针对皮肤共生微生物的抗体。了解哪种DC子集，条件和途径驱动对皮肤抗原特异的抗体的形成对于理解对皮肤病原体抗性的机制和抗体介导的皮肤病的病因至关重要。这项工作有可能为调节皮肤免疫功能的新型治疗靶标提供。