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关于凋亡细胞膜（ACM）决定因子的自身抗体特性的抑制性双受体假说，这些决定因子选择性地区分凋亡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物，触发抗炎信号转导途径。因此，我们的研究将描述ACM抗体被假设增强与双组抑制受体相互作用的机制特征；早期补体因子和凋亡细胞。特别是，我们的研究指出了与受体酪氨酸激酶的TAM家族的关键相互作用。为了了解与发病机制的更大相关性，我们还将研究抗acm抗体是否以及如何阻断致病性IgG自身抗体对核抗原的促炎作用，这些核抗原被认为会触发TLR7和TLR9。我们将对igg -核抗原复合物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小球肾炎小鼠模型体内疾病活性的免疫调节特性。此外，为了研究与临床疾病的相关性，我们还将评估SLE患者中IgM和IgG亚类特异性抗acm自身抗体水平与狼疮相关自身抗体水平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之间是否存在相关性。我们预计这些研究将揭示免疫调节和自身免疫发病机制的新见解，并为SLE治疗的基础研究和新治疗方法的开发提供必要的桥梁。

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.