MAPPING OF ARTHRITIS SUSCEPTIBLE GENES

主要组织相容性复合体（MHC） 是已知的最重要的强直性脊柱炎的遗传易感因素 脊椎炎（AS）和类风湿性关节炎（RA）。MHC协会 然而，仅仅是这些似乎是不够的归纳， 自身免疫性疾病目前对兄弟姐妹的遗传学研究表明， 存在MHC非依赖性基因，这些基因参与了 RA的病理机制，并可能在AS以及。的 然而，自身免疫性疾病的复杂性和多基因性， 人类的遗传学研究非常困难，特别是由于 “远交”特征的人群，那里的发病率很低。 蛋白聚糖（聚集蛋白聚糖）诱导的进行性多关节炎（PGIA）是一种 一种与人类有许多相似之处的新型自身免疫动物模型 临床评估、实验室检查和 关节的组织病理学研究。的发展 关节炎是基于交叉反应的免疫反应之间的 在遗传易感的BALB/c中免疫人和小鼠自身PG 小鼠，发病率接近100%。其他鼠品系， 与BALB/c小鼠相同的H2 d单倍型，或BALB/c和 DBA/2父母，对关节炎有抗性。PGIA的易感性 在F2杂种中的“回归”，即，易感性的遗传是 隐性的尽管杂交实验遵循预期的结果， 孟德尔比率，并提出了一个单基因的特点，疾病， 初步染色体定位显示染色体上有三个非MHC基因座 9，11和15，位于第9号染色体30-34 cM之间的最西部区域）， 可能与疾病过程有关。至少有一个基因座， 然而，在小鼠基因组中还没有发现更多。现在我们 建议确定额外的位点，缩小局部的间隔， 疾病相关的基因座，并确定候选基因， 在关节炎易感BALB/c小鼠中的自身免疫过程。我们提出 进行扩展的高分辨率遗传连锁分析， 小鼠基因组中关节炎相关的基因座，并构建一个物理 9号染色体上疾病相关基因座的图谱，以确定 候选基因的定位克隆。

The strong association with the MHC (major histocompatibility complex) is the most important known, genetic predisposition factor of ankylosing spondylitis (AS) and rheumatoid arthritis (RA). The MHC association alone, however, seems to be insufficient for the induction of these autoimmune diseases. Current genetic studies of siblings indicate the existence of MHC-independent genes which are involved in the pathological mechanisms of RA, and probably in AS as well. The complexity and polygenic nature of autoimmune diseases, however, maker genetic studies extremely difficult in humans, especially due to the "outbred" character of the population, where the incidence is very low. Proteoglycan (aggrecan)-induced progressive polyarthritis (PGIA) is a novel autoimmune animal model which shares many similarities with human RA as indicated by clinical assessments, laboratory tests and histopathologic studies of diarthrodial joints. The development of arthritis is based upon cross-reactive immune responses between the immunizing human the mouse self PGs in genetically susceptible BALB/c mice, where the incidence is close to 100%. Other murine strains, with the same H2d haplotype as BALB/c mice, or F1 hybrids of BALB/c and DBA/2 parents, are resistant to arthritis. The susceptibility for PGIA "returns" in F2 hybrids, i.e., the inheritance of susceptibility is recessive. Although the intercross experiments followed the expected Mendelian ratio and suggested a monogenic character of the disease, the initial chromosome mapping revealed three non-MHC loci on chromosomes 9, 11 and 15, narrowest region between 30-34 cM of chromosome 9), which may be involved in disease processes. At least one locus, potentially more, however has not been identified yet in the mouse genome. Now we propose to identify additional locus, narrow the intervals of localized disease-associated loci and identify candidate genes that may control autoimmune processes in arthritis susceptible BALB/c mice. We propose to perform extended high resolution genetic linkage analysis to identify arthritis-associated loci in the mouse genome, and construct a physical map of the disease-associated locus on chromosome 9 to identify candidate genes by positional cloning.