Role of complement C4 in immune tolerance

描述（由申请人提供）：系统性红斑狼疮是一种不治之症。补体C4缺乏易患SLE和肱骨反应受损。我们建议在C4缺陷小鼠中恢复C4蛋白，并持续进行抗染色质反应，以测试C4重建可以改善主动自身免疫的假设。具体而言，将测试几种方法以研究C4重建诱导患有狼疮的成年小鼠对核抗原耐受的潜力： 1)骨髓移植重建髓源性C4; 2)用C4表达质粒DNA体内转染小鼠肝细胞; 3)C4位点的条件性Cre/IoxP基因修复。 所提出的实验将直接解决补体C4在正在进行的自身免疫应答的背景下对染色质特异性的自身反应性B细胞的功能沉默中的作用。拟议的研究可以提供一个概念的证据，即针对染色质和可能的其他核抗原的全身性自身免疫反应可以通过通常维持对这些抗原的免疫耐受性的分子和机制的特异性修复来调节。

DESCRIPTION (provided by applicant): Systemic Lupus Erythematosus is an incurable disease. Complement C4 deficiency predisposes both to SLE and to impaired humeral responses. We propose to restore C4 protein in C4-deficient mice with an ongoing anti-chromatin response to test the hypothesis that C4 reconstitution can ameliorate active autoimmunity. Specifically, several approaches will be tested to study the potential of C4 reconstitution to induce tolerance to nuclear antigens in adult mice with developed lupus: 1) bone marrow transfer to reconstitute myeloid-derived C4; 2) in vivo transfection of murine hepatocytes with C4 expression plasmid DNA; 3) conditional Cre/IoxP gene repair of C4 locus. The proposed experiments will directly address the role of complement C4 in functional silencing of autoreactive B cells specific to chromatin in the context of an ongoing autoimmune response. The proposed studies could provide a proof of the concept that systemic autoimmune responses directed against chromatin and possibly other nuclear antigens can be tuned down by specific repair of molecules and mechanisms that normally maintain immune tolerance to those antigens.