首页> 外文期刊>Arthritis and Rheumatism >Detection of arthritis-susceptibility loci, including Ncf1, and variable effects of the major histocompatibility complex region depending on genetic background in rats.
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Detection of arthritis-susceptibility loci, including Ncf1, and variable effects of the major histocompatibility complex region depending on genetic background in rats.

机译:根据大鼠的遗传背景,检测关节炎易感基因座(包括Ncf1)和主要组织相容性复合体区域的可变作用。

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OBJECTIVE: To characterize the arthritis-modulating effects of 3 non-major histocompatibility complex (MHC) quantitative trait loci (QTLs) in rat experimental arthritis in the disease-resistant E3 strain, and to investigate the disease-modulating effects of the MHC region (RT1) in various genetic backgrounds. METHODS: A congenic fragment containing Ncf1 along with congenic fragments containing the strongest remaining loci, Pia5/Cia3 and Pia7/Cia13 on chromosome 4, were transferred from the arthritis-susceptible DA strain into the background of the completely resistant E3 strain. The arthritis-regulatory potential of the transferred alleles was evaluated by comparing the susceptibility to experimental arthritis in congenic rats with that in E3 rats. The RT1(u) haplotype from the E3 strain was transferred into the susceptible DA strain (RT1(av1)), and various F(1) and F(2) hybrids were generated to assess the effects of RT1 on arthritis susceptibility. RESULTS: The DA allele of Ncf1 did not break the arthritis resistance of the E3 rats, although it led to enhanced autoimmune B cell responses, as indicated by significantly elevated levels of anticollagen antibodies in congenic rats. Introgressing Pia5 and Pia7 loci on chromosome 4 broke the resistance to arthritis, and the MHC locus on chromosome 20 in DA rats enhanced arthritis when RT1 interacted with E3 genes. CONCLUSION: The findings in these congenic lines confirm the existence of 3 major QTLs that regulate the severity of arthritis and are sufficient to induce the transformation of a completely arthritis-resistant rat strain into an arthritis-susceptible strain. This study also reveals a dramatic difference in the arthritis-regulatory potential of the rat MHC depending on genetic background, suggesting that strong epistatic interactions occur between MHC and non-MHC genes.
机译:目的:表征3种非主要组织相容性复合体(MHC)定量性状基因位点(QTL)在抗病性E3株大鼠实验性关节炎中的关节炎调节作用,并研究MHC区域的疾病调节作用( RT1)在各种遗传背景中。方法:将含有Ncf1的同基因片段以及含有最强剩余基因座的同源片段(第4号染色体上的Pia5 / Cia3和Pia7 / Cia13)从对关节炎敏感的DA菌株转移到完全耐药的E3菌株的背景中。通过比较同基因大鼠和E3大鼠对实验性关节炎的敏感性,评估了转移的等位基因的关节炎调节潜力。从E3株RT1(u)单倍型转移到易感DA株(RT1(av1)),并生成各种F(1)和F(2)杂种,以评估RT1对关节炎敏感性的影响。结果:Ncf1的DA等位基因虽然能增强自身免疫B细胞的反应,但并未破坏E3大鼠的关节炎抵抗力,这在同基因大鼠中抗胶原蛋白抗体的水平显着提高了。当RT1与E3基因相互作用时,DA鼠中第4染色体上的Pia5和Pia7基因座渗入破坏了对关节炎的抵抗力,而第20染色体上的MHC基因座增强了关节炎。结论:在这些同系系中的发现证实存在3个主要的QTL,它们调节关节炎的严重程度,足以诱导完全对关节炎具有抵抗力的大鼠品系转化为对关节炎敏感的品系。这项研究还揭示了取决于基因背景的大鼠MHC的关节炎调节潜力的巨大差异,表明MHC和非MHC基因之间发生了强烈的上位相互作用。

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