Impact of lupus susceptibility loci on peripheral tolerance and onset of disease

描述（由申请人提供）： 系统性红斑狼疮（SLE）和类风湿性关节炎（RA）等自身免疫性疾病的标志是产生与正常组织结合的抗体（自身抗体），并因此沉积在体内的多个器官系统中，导致炎症和组织破坏。虽然健康的个体有可能产生自身抗体，但他们没有，这表明产生自身抗体的细胞被称为耐受性的机制沉默。迄今为止，我们对自身免疫性疾病（如SLE）发病机制的认识大多来自动物模型的研究。一种这样的模型是新西兰黑（NZB）x白色（NZW）的杂交小鼠，其发展类似于人SLE的疾病。多种基因参与了人类自身免疫性疾病（如SLE）的发病机制。 同样，在该SLE小鼠模型中鉴定了基因组的三个主要区域（命名为Sle 1，Sle 2和Sle 3/Sle 5），这些区域含有促成疾病过程的基因。含有这些基因组间隔中的每一个的小鼠产生不同的组分表型（表现），例如自身抗体产生、肾脏病理学等，而他们的互动最终导致了全身性红斑狼疮这些狼疮易感基因是如何改变B细胞耐受性，从而产生自身抗体的，目前尚不清楚。使用小鼠模型产生高频率的定义，自身反应性B细胞，在目前的拨款申请中，我们建议研究这些狼疮易感位点如何影响B细胞耐受性和自身抗体产生，导致自身免疫性疾病SLE的发展。这将使我们能够确定导致疾病的有缺陷的耐受过程。随后，一旦这些基因组间隔中的基因被鉴定，我们就可以研究这些基因的产物如何特异性地改变所鉴定的B细胞耐受过程的功能。这样的机制的理解将允许新的诊断和治疗方法的系统性自身免疫性疾病的发展。

DESCRIPTION (provided by applicant): The hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is the production of antibodies that bind to normal tissues (autoantibodies) and, as a result are deposited in multiple organ systems in the body, resulting in inflammation and tissue destruction. Although healthy individuals have the potential to produce autoantibodies, they do not, suggesting that autoantibody producing cells are silenced by a mechanism called tolerance. Most of our understanding of the pathogenesis of autoimmune diseases such as SLE to date has come from the studies of animal models. One such model is the hybrid mouse of New Zealand Black (NZB) x White (NZW) which develop a disease that resembles human SLE. Multiple genes contribute to the pathogenesis of autoimmune diseases such as SLE in humans. Likewise, three major regions of the genome (named Sle1, Sle2 and Sle3/Sle5) containing the genes that contribute to the disease process were identified in this SLE mouse model. Mice containing each of these genomic intervals give rise to different component phenotypes (manifestations) such as autoantibody production, kidney pathology etc., while their interaction culminates in full-blown SLE. It is not well understood how these lupus susceptibility genes are altering B cell tolerance, allowing autoantibody production. Using mouse models producing a high frequency of defined, autoreactive B cells, in the current grant application we propose to study how each of these lupus susceptibility loci influence B cell tolerance and autoantibody production leading to the development of autoimmune disease SLE. This will allow us to identify the defective tolerance processes causing the disease. Subsequently, once the genes in these genomic intervals are identified, we can study how the products of these genes specifically alter the functioning of the identified B cell tolerance processes. Such a mechanistic understanding will allow novel diagnostic and therapeutic approaches for systemic autoimmune diseases to be developed.