Effects of Sex-Specific Loci in Murine Arthritis

描述(申请人提供)：蛋白多糖诱导的关节炎(PGIA)是一种类风湿性关节炎(RA)的多基因免疫尿液模型。在这个模型中，遗传易感的BALB/c雌性比BALB/c雄性更早患上关节炎。对关节炎敏感的BALB/c菌株和几个抗关节炎的小鼠菌株之间的F2杂交的全基因组扫描表明，性别是疾病临床特征的主要调节因素，并影响B细胞和T细胞的反应。我们发现控制PGIA严重程度、易感性和发病的QTL具有显著的性别偏向。连锁分析在15号染色体上发现了2个基因座：Pgia8基因座控制女性PGIA的严重程度，Pgia9基因座仅控制男性关节炎的严重程度。利用分子标记辅助育种技术，将DBA/2的15号染色体和Y染色体全部转入BALB/c遗传背景中，获得了一个双染色体株系：Balb/c-15DBA/2yDBA/2(B.^DYD)。雌性B-15D小鼠对PGIA的敏感性显著低于BALB/c雌性小鼠，而双染色体B-15DYD雄性小鼠发生PGIA的时间甚至早于最敏感的野生型BALB/c雌性小鼠。这一建议假设15号染色体和Y号染色体在PGIA动物模型中都具有强烈但相反的、显著的性别偏见的易感性和严重性影响。我们建议通过在关节炎易感的BALB/c背景中产生几个携带15号染色体或染色体Y基因座的同源菌株来研究15号染色体和Y染色体对PGIA临床和免疫学表型的单独和相互影响。这一策略将有助于发现位于这两条染色体上的关节炎基因，并为性别限制基因功能的机制提供洞察力。

DESCRIPTION (provided by applicant): Proteoglycan-induced arthritis (PGIA) is a polygenic to immune urine model for rheumatoid arthritis (RA). In this model, genetically susceptible BALB/c females develop arthritis earlier on than the BALB/c males. Genome-wide scans of F2 crosses between the arthritis-susceptible BALB/c strain and several arthritis-resistant murine strains indicated that sex is a major moderator of clinical traits of the disease, and influences B- and T-cell responses. We have found that QTLs which control severity, susceptibility and onset of PGIA, were significantly sex-biased. Linkage analysis identified 2 loci on chromosome 15: Pgia8 locus controls PGIA severity in females, and Pgia9 locus is responsible for the arthritis severity in males only. Using marker-assisted breeding, we transferred the entire chromosome 15 and chromosome Y of DBA/2 into BALB/c genetic background and generated a double consomic strain: BALB/c- 15DBA/2yDBA/2 (B.^DYD). Female B-15D mice were significantly less PGIA-susceptible than BALB/c females, while double consomic B-15 DYD males developed PGIA even earlier than the most susceptible wild type BALB/c females. This proposal hypothesizes that chromosomes 15 and Y both have strong but opposite and significantly sex-biased effects upon susceptibility and severity in the PGIA animal model. We propose to investigate separate and mutual effects of chromosomes 15 and Y on clinical and immunological phenotypes of PGIA through the generation of several congenic strains, which carry either chromosome 15 or hromosome Y loci in arthritis-susceptible BALB/c background. This strategy will facilitate the discovery of the arthritis genes located on these 2 chromosomes and provide insight into the mechanisms of sex-restricted gene function.