Lupus and the inhibitory dual receptor hypothesis

描述(由申请人提供)：我们将研究我们新开发的抑制性双受体假说，该假说涉及针对凋亡细胞膜(ACM)决定因素的自身抗体的特性，该决定因素选择性地区分死于凋亡性死亡的细胞和健康细胞。我们发现，抗ACM抗体与凋亡细胞形成免疫复合体，触发抗炎信号转导通路。因此，我们的研究将描述ACM抗体增强与双重抑制受体、早期补体因子和凋亡细胞相互作用的机制。特别是，我们的研究指出了与受体酪氨酸激酶家族的关键相互作用。为了了解与发病机制的更大相关性，我们还将调查抗ACM抗体是否以及如何阻断致病性核抗原自身抗体的促炎作用，推测这种抗体可能触发TLR7和TLR9。我们将对免疫球蛋白-核抗原复合体的体外抑制作用进行表征和可视化，并研究其对自身免疫性肾炎小鼠体内疾病活动性的免疫调节作用。此外，为了探讨与临床疾病的相关性，我们还将评估SLE患者的IgM和Ig G亚类特异性抗ACM自身抗体和狼疮相关自身抗体之间是否存在相关性，以及与狼疮临床疾病活动的某些特征的保护作用之间是否存在相关性。我们期待这些研究将揭示免疫调节和自身免疫发病机制的新见解，并提供从基础研究到开发新的治疗方法治疗SLE的重要桥梁。 公共卫生相关性：我们将研究某些自然产生的针对濒死细胞的抗体如何与细胞受体相互作用，并触发抗炎信号转导途径。我们还将在系统性红斑狼疮患者中寻找这种影响。

DESCRIPTION (provided by applicant): We will investigate our newly developed inhibitory dual receptor hypothesis regarding the properties of autoantibodies to apoptotic cell membrane (ACM) determinants, which selectively discriminate cells dying from apoptotic death from healthy cells. We have discovered that anti-ACM antibodies form immune complexes with apoptotic cells that trigger anti-inflammatory signal transduction pathways. Therefore, our studies will characterize the mechanistic features by which ACM antibodies are postulated to enhance interactions with dual sets of inhibitory receptor; for early complement factors and for apoptotic cells. In particular, our investigations point to a critical interaction with the TAM family of receptor tyrosine kinases. To understand the greater relevance to pathogenesis, we will also investigate whether and how anti-ACM antibodies block the pro-inflammatory effects of pathogenic IgG autoantibodies to nuclear antigens, postulated to trigger TLR7 and TLR9. We will be characterize and visualize the in vitro inhibitory effects for IgG-nuclear antigen complexes, and we will also study their immune modulatory properties on the in vivo disease activity in murine models of autoimmune glomerulonephritis. Moreover, to investigate the relevance to clinical disease, we will also assess whether there is a correlation between levels in SLE patients of IgM and IgG subclass-specific anti-ACM autoantibodies and with lupus- associated autoantibodies, and with protection from certain features of lupus clinical disease activity. We anticipate that these studies will reveal new insights into immune regulation and autoimmune pathogenesis, and provide the essential bridge from basic studies to the development of a new therapeutic approach to the treatment of SLE. PUBLIC HEALTH RELEVANCE: We will investigate how certain naturally occurring antibodies to dying cells can interact with cell receptors and trigger anti-inflammatory signal transduction pathways. We will also look for such effects in patients with systemic lupus erythematosus.