Combined autoimmune models of arthritis reveal shared and independent qualitative (Binary) and quantitative trait loci
Combined autoimmune models of arthritis reveal shared and independent qualitative (Binary) and quantitative trait loci
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DOI：
10.4049/jimmunol.170.5.2283
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发表时间：
2003-03-01
影响因子：
4.4
通讯作者：
Glant, TT
中科院分区：
文献类型：
--
作者：
Adarichev, VA;Valdez, JC;Glant, TT
胶原诱导的关节炎（CIA）和蛋白多糖诱导的关节炎（PGIA）在病理学和遗传学方面都是类风湿关节炎的小鼠模型。使用cia易感但pgia耐药的DBA/1小鼠和cia耐药但pgia易感的BALB/c小鼠的F-2杂交，我们的目标是1)确定模型特异性和赋予疾病易感性的共享位点，2)确定是否有任何病理生理参数可以用作区分非关节炎和关节炎小鼠的标记，以及3)分析是否有任何免疫亚性状显示与关节炎相关位点共定位。为了鉴定染色体位点，我们对939f杂交小鼠进行了基因组扫描。为了进行病理生理分析，我们测量了促炎性和抗炎性细胞因子（IL-1、IL-6、tnf - α、ifn - γ、IL-4、IL-10、IL-12）、ag特异性T细胞增殖和IL-2产生、血清IgG1和IgG2水平（自身抗体和异源抗体）以及可溶性CD44。除了在之前的研究中发现的多个CIA和pgia相关基因座外，我们还发现了9个新的CIA和8个新的pgia相关基因座。综合统计分析表明，在CIA和PGIA人群中，IL-2的产生、T细胞增殖和ifn - γ水平在关节炎动物和非关节炎动物之间存在显著差异。高水平的tnf - α、ifn - γ、IL-2和Ab的产生在CIA的F2杂交种中被检测到，而T细胞增殖、IL-2和ifn - γ的产生以及向IgG2a同型的转变是PGIA的更多特征。数量性状位点分析表明，许多免疫亚性状与关节炎相关性状共定位。在两种模型中，均发现5、10、17、18和X染色体上的数量性状位点控制关节炎。
Collagen-induced arthritis (CIA) and proteoglycan-induced arthritis (PGIA) are murine models for rheumatoid arthritis both in terms of their pathology and genetics. Using the F-2 hybrids of the CIA-susceptible, but PGIA-resistant DBA/1 mice, and the CIA-resistant, but PGIA-suseeptible BALB/c mice, our goals were to 1) identify both model-specific and shared loci that confer disease susceptibility, 2) determine whether any pathophysiological parameters could be used as markers that distinguish between nonarthritic and arthritic mice, and 3) analyze whether any immune subtraits showed colocalization with arthritis-related loci. To identify chromosomal loci, we performed a genome scan on 939 F, hybrid mice. For pathophysiological analyses, we measured pro- and anti-inflammatory cytokines (IL-1, IL-6, TNF-alpha, IFN-gamma, IL-4, IL-10, IL-12), Ag-specific T cell proliferation and IL-2 production, serum IgG1 and IgG2 levels of both auto- and heteroantibodies, and soluble CD44. In addition to multiple CIA- and PGIA-related loci identified in previous, studies, we have identified nine new CIA- and eight new PGIA-linked loci. Comprehensive statistical analysis demonstrated that IL-2 production, T cell proliferation, and IFN-gamma levels differed significantly between arthritic and nonarthritic animals in both CIA and PGIA populations. High levels of TNF-alpha, IFN-gamma, IL-2, and Ab production were detected in F2 hybrids with CIA, whereas T cell proliferation, IL-2 and IFN-gamma production, and a shift to IgG2a isotype were more characteristic of PGIA. Quantitative trait loci analysis demonstrated colocalization of numerous immune subtraits with arthritis-related traits. Quantitative trait loci on chromosomes 5, 10, 17, 18, and X were found to control arthritis in both models.