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）的易感性中起主要作用。因此，对这种疾病的因果机制的定义将需要了解遗传改变及其对自身免疫的贡献的性质。我们先前已经在（NZBxNZW）F2小鼠中鉴定了分别位于染色体17、4、5、6、7、18、1和11上的8个被命名为Lbw 1 -8的基因座，其与一种或多种SLE疾病性状相关联。产生了Lbw 2的间隔特异性同源菌株，并鉴定了特定组分的表型。值得注意的是，NZB. NZW-Lbw 2间隔同源小鼠表现出自身免疫性溶血性贫血（AIHA）和随后的脾肿大显著减少，这与免疫球蛋白水平、抗核抗体或B细胞活化的缺陷无关。使用亚同源小鼠，进一步揭示Lbw 2含有至少三个影响AIHA的位点。该提案将使用一种新的全基因组测序方法，首先通过改变蛋白质结构或修饰基因表达来鉴定影响基因功能的预测遗传变异，然后鉴定Lbw 2亚基因座内最可能的候选“功能”变异。这项建议有两个具体目标。第一个将根据NZB和NZW小鼠的全基因组序列鉴定Lbw 2和其他狼疮影响基因座的编码区候选变体。第二个目的将使用来自目的1的信息来进一步评估编码区候选变体，以鉴定非编码候选变体，并定义Lbw 2基因座相关变体促进针对RBC的抗体的机制。鉴定易感基因并阐明其在狼疮诱导中的作用将为了解狼疮的发病机制提供重要的线索 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.