MOLECULAR GENETICS OF MHC COMPLEMENT GENES

描述(改编自调查人员的摘要)：少校 组织相容性(MHC)III类区域包括 经典(补体C2和C4)和替代(补体因子B) 补体激活的途径。小鼠补体C3基因， 替代途径的另一个组成部分，也是两条途径的靶点， 与17号染色体上的MHC同线。结构和表达 已对MHC III类区域的基因和基因产物进行了表征。 补体基因表达的广泛组织和细胞分布 提示新的补体依赖功能。此外，洞察力是 关于井中补体的结构/功能相关性的揭示 公认的宿主防御和免疫病理功能。然而，所有的 这些研究评估活体意义的能力有限。 和/或取决于罕见补体缺乏症的发现或 补体耗竭的不完善模型。因此，我们使用了同源 重组以培育因子B和C3缺失的小鼠品系。 这些补体缺失菌株现在可以在体内研究这种重要性 补体激活的另一种途径在生理和 病理情况。这一中心目标对发展至关重要。 旨在调节补体依赖性炎症的策略(例如， 异种移植、缺血损伤、自身免疫性疾病)，同时保存或 增强宿主对病原微生物的反应。具体地说， 建议的研究集中在确定在体内的功能。 (A)天然(先天)宿主防御的替代途径，在(B)中 免疫功能，如对特定抗原(包括B组)的反应 淋巴细胞生物学)、免疫清除和免疫中介组织 (C)非免疫性组织损伤。 这些明确定义的功能将在小鼠身上进行研究，在这种物种中 有背景数据和实验操作免疫的能力 功能。这为阐明补体提供了一个理想的环境 将产生有趣和重要后果的依赖机制 用来控制人类疾病。

DESCRIPTION (Adapted from the investigator's abstract): The major histocompatibility (MHC) class III region includes genes for constituents of the classical (complement C2 and C4) and alternative (complement factor B) pathways of complement activation. The gene for mouse complement C3, another constituent of alternative pathway and the target for both pathways, is syntenic with the MHC on chromosome 17. The structure and expression of genes and gene products of the MHC class III region have been characterized. The wide tissue and cell distribution of complement gene expression suggested novel complement dependent functions. Moreover, insights were revealed regarding the structure/function correlates of complement in well recognized host defenses and immunopathological functions. However, all of these studies were limited in their capacity to assess in vivo significance and/or depended on the discovery of rare complement deficiencies or imperfect models of complement depletion. We have therefore used homologous recombination to develop mouse strains with deletions of factor B and C3. These complement null strains now permit in vivo studies of the importance of the alternative pathway of complement activation in physiological and pathological conditions. This central goal is critical for the development of strategies designed to modulate complement dependent inflammation (e.g., xenograft, ischemic injury, autoimmune disorders) while preserving or enhancing host response to pathogenic microorganisms. Specifically, the proposed studies focus on a determination of the in vivo function of alternative pathway in (a) natural (innate) host defenses, in (b) specific immune functions such as response to specific antigen (including B lymphocyte cell biology), immune clearance and immune mediated tissue injury, and (c) in nonimmune tissue injury. These well defined functions will be studied in mice, a species in which there are background data and capacity to experimentally manipulate immune functions. This provides an ideal setting for elucidating complement dependent mechanisms that will have interesting and important consequences for the control of human disease.