Investigations on antigen-dependent and -independent functions of distinct myeloid subsets of phagocytes in host defence and maintenance of self-tolerance during infection and inflammation

不同骨髓吞噬细胞亚群在感染和炎症期间宿主防御和维持自我耐受中抗原依赖性和独立性功能的研究

• 批准号: 255918677
• 负责人: Professor Dr. Stefan Uderhardt
• 金额: --
• 依托单位: Medizinische Klinik 3 - Rheumatologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/255918677?language=en
• 关键词: Investigations; antigen; dependent; independent; functions

The immune system uses a variety of innate and adaptive (antigen-specific) effector modalities to protect the host against pathogen invasion. These immune defenses are potent and can cause substantial damage to host tissues, requiring a layered and interwoven array of control mechanisms to limit such collateral damage during and after infection. A key locus of such control is at the level of antigen presentation to cells of the adaptive immune system during periods of inflammatory tissue damage, when the immune system must meet two competing obligations - to promote an effect anti-pathogen response through immunogenic presentation of microbial antigens and limit anti-self responses by avoiding such immunogenic display of self-antigens. In recent work from the applicant, it was demonstrated that a major mechanism used to achieve this end involves the specialization of subsets of phagocytes (myeloid cells), such that inflammatory macrophages preferentially acquire and present pathogen-derived over self-derived material, while another population of non-immunogenic phagocytes takes up and disposes tissue debris. These cell-type specific activities are also coordinated between the cell subsets via lipid mediators that limit uptake of self-components by the immunogenic inflammatory phagocyte subset. In this proposal I detail plans for extending these initial observations at the cell and molecular levels, (1) defining more thoroughly the subset specific role of distinct myeloid cells in various sites and under different conditions of infection and inflammation that engage in these dichotomous activities of tissue clearance vs. initiation of anti-pathogen effector responses, (2) identifying the receptors and signaling mechanisms that underlie these different functionalities, and (3) defining the integrated function of these cells through cross-regulatory connections. When placed in the larger context of additional mechanisms that enforce immune homeostasis, such as regulatory T cells, feedback expression of inhibitory receptors, central and peripheral deletional mechanisms, and the like, the results of these investigations will help identify components of the regulatory apparatus whose malfunction can give rise to autoimmune disease and suggest targets for future therapeutic efforts.

免疫系统使用多种先天性和适应性（抗原特异性）效应器模式来保护宿主免受病原体入侵。这些免疫防御是有效的，并且可以对宿主组织造成实质性损害，需要分层和交织的控制机制阵列来限制感染期间和之后的这种附带损害。这种控制的关键位点是在炎性组织损伤期间抗原呈递至适应性免疫系统的细胞的水平，此时免疫系统必须满足两个竞争性义务-通过微生物抗原的免疫原性呈递促进有效的抗病原体应答和通过避免自身抗原的这种免疫原性呈递限制抗自身应答。在申请人最近的工作中，证明了用于实现该目的的主要机制涉及吞噬细胞（骨髓细胞）亚群的特化，使得炎性巨噬细胞优先获得和呈递病原体来源的物质而不是自身来源的物质，而另一群非免疫原性吞噬细胞吸收和处置组织碎片。这些细胞类型特异性活性也通过脂质介质在细胞亚群之间协调，脂质介质限制免疫原性炎症吞噬细胞亚群对自身组分的摄取。在这份提案中，我详细介绍了在细胞和分子水平上扩展这些初步观察的计划，（1）更彻底地定义不同骨髓细胞在不同部位和不同感染和炎症条件下的亚群特异性作用，这些亚群特异性作用参与组织清除与启动抗病原体效应反应的这些二分活动，（2）识别这些不同功能的受体和信号机制，（3）通过交叉调节连接定义这些细胞的整合功能。当放置在更大的背景下的额外的机制，如调节性T细胞，抑制性受体的反馈表达，中央和外周缺失机制等，这些调查的结果将有助于确定组件的监管机构的功能障碍可能会引起自身免疫性疾病，并建议未来的治疗工作的目标。