Genetics of Autoimmune Hemolytic Anemia

描述(由申请人提供)：众所周知，遗传易感性在个人对系统性红斑狼疮(SLE)的易感性中起着主要作用。因此，定义导致这种疾病的原因机制将需要了解基因改变及其对自身免疫的贡献的性质。我们之前已经在(NZBxNZW)F2小鼠中发现了分别位于17、4、5、6、7、18、1和11号染色体上的8个Lbw1-8基因座，它们与一个或多个SLE疾病性状有关。Lbw2的区间特异性同源菌株已经产生，并鉴定了特定的成分表型。值得注意的是，NZB.NZW-Lbw2间隔同基因小鼠的自身免疫性溶血性贫血(AIHA)和随之而来的脾肿大显著减少，与免疫球蛋白水平缺陷、抗核抗体或B细胞激活无关。利用亚基因小鼠，进一步揭示了Lbw2至少包含三个影响AIHA的基因座。这项提议将使用一种新的全基因组测序方法，首先识别通过改变蛋白质结构或改变基因表达来影响基因功能的预测遗传变异，然后识别Lbw2亚区中最有可能的候选功能变异。这项提议有两个具体目标。第一个将根据NZB和NZW小鼠的全基因组序列识别Lbw2和其他影响狼疮的基因座的编码区候选变体。第二个目标将使用来自目标1的信息来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基因座相关变体促进RBC抗体的机制。识别易感基因并阐明它们在狼疮发病中的作用将为狼疮的发病机制提供重要的见解。 基因决定的自身免疫性疾病。

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.