Genetics of Autoimmune Hemolytic Anemia

描述（由申请人提供）：众所周知，遗传易感性在个体对系统性红斑狼疮（SLE）的易感性中起着重要作用。因此，定义导致这种疾病的因果机制将需要了解遗传改变及其对自身免疫的贡献的性质。我们之前已经在（NZBxNZW）F2小鼠中分别鉴定出染色体17、4、5、6、7、18、1和11上的8个位点Lbw1-8，它们与一种或多种SLE疾病特征相关。产生了Lbw2的区间特异性同源菌株，并鉴定了其特异性组分表型。值得注意的是,NZB。NZW-Lbw2间隔基因小鼠表现出自身免疫性溶血性贫血（AIHA）和随之而来的脾肿大的显著减少，这与免疫球蛋白水平、抗核抗体或B细胞活化的缺陷无关。在亚基因小鼠中进一步发现Lbw2含有至少三个影响AIHA的位点。该方案将使用一种新颖的全基因组测序方法，首先确定通过改变蛋白质结构或修改基因表达来影响基因功能的预测遗传变异，然后确定Lbw2亚座中最可能的候选“功能性”变异。这项建议有两个具体目的。第一项研究将根据NZB和NZW小鼠的全基因组序列，确定Lbw2和其他狼疮影响位点的编码区候选变体。第二个目标将使用目标1的信息进一步评估编码区候选变体，识别非编码候选变体，并定义Lbw2位点相关变体促进红细胞抗体的机制。易感基因的鉴定和阐明其在狼疮诱导中的作用应该为狼疮的发病机制提供重要的见解

DESCRIPTION (provided by applicant): It is well established that genetic predisposition plays a major role in the susceptibility of individuals to systemic lupus erythematosus (SLE). Therefore, definition of the causal mechanisms responsible for this disease will require knowledge of both the genetic alterations and the nature of their contribution to autoimmunity. We have previously identified in (NZBxNZW)F2 mice eight loci designated Lbw1-8 on chromosomes 17, 4, 5, 6, 7, 18, 1 and 11, respectively, that were linked to one or more SLE disease traits. Interval-specific congenic strains for Lbw2 been generated and the specific component phenotypes have been identified. Notably, NZB.NZW-Lbw2 interval congenic mice demonstrated a marked reduction in autoimmune hemolytic anemia (AIHA) and consequent splenomegaly that was not associated with defects in immunoglobulin levels, anti-nuclear antibodies, or B cell activation. Using subcongenic mice it was further revealed that Lbw2 contained at least three loci affecting AIHA. This proposal will use a novel whole genome sequencing approach to first identify predicted genetic variants that affect gene function either by altering protein structure or modifying gene expression, and then identify the most likely candidate 'functional' variant within Lbw2 subloci. This proposal has two specific aims. The first will identify coding-region candidate variants for Lbw2 and other lupus-affecting loci based on the whole genome sequences of the NZB and NZW mice. The second aim will use the information from aim 1 to further evaluate the coding-region candidate variants, to identify non-coding candidate variants, and to define the mechanisms by which the Lbw2 locus- related variants promote antibodies to RBC. Identification of the susceptibility genes and elucidation of their roles in the induction of lupus should provide significant insights into the etiopathogenesis of genetically- determined autoimmune diseases.