Effects of Sex-Specific Loci in Murine Arthritis

描述（由申请人提供）：蛋白聚糖诱导的关节炎（PGIA）是类风湿性关节炎（RA）的多基因到免疫尿液模型。在这个模型中，遗传易感的BALB/c女性比BALB/c男性更早患上关节炎。对易患关节炎的BALB/c菌株和几种抗关节炎的小鼠菌株之间F2杂交的全基因组扫描表明，性别是该疾病临床特征的主要调节因素，并影响B细胞和t细胞反应。我们发现控制PGIA严重程度、易感性和发病的qtl存在显著的性别偏倚。连锁分析发现15号染色体上有2个位点：Pgia8位点控制女性PGIA的严重程度，Pgia9位点仅与男性关节炎的严重程度有关。采用标记辅助育种方法，将DBA/2的整个15号染色体和Y号染色体转移到BALB/c遗传背景中，获得了双经济菌株BALB/c- 15DBA/2yDBA/2 （b ^DYD）。雌性B-15D小鼠对PGIA的易感程度明显低于BALB/c雌性小鼠，而双经济型B-15 DYD雄性小鼠比最易感的野生型BALB/c雌性小鼠更早发生PGIA。本研究假设，在PGIA动物模型中，染色体15和Y对易感性和严重程度都有强烈但相反且显著的性别偏倚效应。我们建议通过产生几个携带关节炎易感BALB/c背景中15号染色体或Y号染色体位点的同源菌株，来研究15号染色体和Y号染色体对PGIA临床和免疫表型的单独和相互影响。这一策略将有助于发现位于这2条染色体上的关节炎基因，并为性别限制性基因功能的机制提供见解。

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.