Effects of Sex-Specific Loci in Murine Arthritis

描述（由申请方提供）：蛋白聚糖诱导的关节炎（PGIA）是类风湿性关节炎（RA）的多基因至免疫尿液模型。在该模型中，遗传易感的BALB/c雌性动物比BALB/c雄性动物更早发生关节炎。关节炎敏感的BALB/c菌株和几种关节炎抗性小鼠菌株之间的F2杂交的全基因组扫描表明，性别是该疾病的临床特征的主要调节剂，并影响B-和T-细胞反应。我们发现控制PGIA严重性、易感性和发病的QTL具有明显的性别偏向性。连锁分析在15号染色体上发现2个位点：Pgia 8位点控制女性PGIA的严重程度，Pgia 9位点仅负责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同源突变株BALB/c-15 DBA/2 yDBA/2（B.^ DYD）。雌性B-15 D小鼠的PGIA敏感性显著低于BALB B/c雌性，而双染色体B-15 DYD雄性甚至比最敏感的野生型BALB B/c雌性更早发生PGIA。该提议假设15号染色体和Y染色体在PGIA动物模型中对易感性和严重性均具有强烈但相反且显著的性别偏倚效应。我们建议通过在关节炎易感的BALB/c背景下产生几个携带15号染色体或Y染色体位点的同源株，来研究15号染色体和Y染色体对PGIA临床和免疫表型的单独和相互作用。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，并为性别限制基因功能的机制提供深入了解。

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.