Brenner Max, Laragione Teresina, Mello Adriana, Gulko Pércio S
Laboratory of Experimental Rheumatology, The Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, 350 Community Drive, Room 139, Manhasset, NY 11030, USA.
Ann Rheum Dis. 2007 Jul;66(7):952-7. doi: 10.1136/ard.2006.066225. Epub 2007 Feb 28.
A genomewide scan in a DA x ACI F2 intercross studied for collagen-induced arthritis (CIA) identified the severity quantitative trait locus Cia25 on rat chromosome 12. Cia25 co-localises with loci regulating several forms of autoimmune diseases in rats, mice and humans, suggesting a common gene.
To characterise the effects of Cia25 on severity of arthritis in congenic rats.
DA.ACI(Cia25) congenic rats were constructed according to a genotype-guided strategy, and tested for pristane-induced arthritis (PIA) and CIA, induced with rat type II collagen (CII). A well-established scoring system previously shown to correlate with histological damage, including cartilage and bone erosions, synovial hyperplasia and synovial inflammation, was used.
The introgression of ACI alleles at Cia25 into DA background, as in DA.ACI(Cia25) rats, was enough to significantly reduce arthritis severity by 60% in PIA and by 40% in CIA, both in males and females compared with DA rats of the same sex. Levels of IgG anti-CII in male DA.ACI(Cia25) rats were 83% lower than in male DA. Levels of anti-CII in females were not affected by the congenic interval.
Cia25 contains a gene that regulates disease severity in two distinct models of autoimmune arthritis. Although both genders were protected in arthritis studies, only male congenic rats had a dramatic reduction in levels of anti-CII, suggesting the possibility of a second arthritis gene in this interval that operates via the regulation of autoantibodies in a sex-specific manner. The identification of the gene(s) accounting for Cia25 is expected to generate novel prognostic biomarkers and targets for therapy.
在一项针对胶原诱导性关节炎（CIA）进行研究的DA×ACI F2杂交实验中，全基因组扫描在大鼠12号染色体上鉴定出严重程度数量性状位点Cia25。Cia25与调控大鼠、小鼠和人类多种自身免疫性疾病的位点共定位，提示存在一个共同基因。
研究Cia25对同源基因大鼠关节炎严重程度的影响。
根据基因型指导策略构建DA.ACI（Cia25）同源基因大鼠，并对其进行 pristane诱导性关节炎（PIA）和用大鼠II型胶原（CII）诱导的CIA测试。使用了一个先前已证明与组织学损伤相关的成熟评分系统，包括软骨和骨侵蚀、滑膜增生和滑膜炎症。
将Cia25处的ACI等位基因导入DA背景中，如在DA.ACI（Cia25）大鼠中，足以使PIA中关节炎严重程度显著降低60%，在CIA中降低40%，与同性别的DA大鼠相比，雄性和雌性均如此。雄性DA.ACI（Cia25）大鼠中抗CII IgG水平比雄性DA大鼠低83%。雌性抗CII水平不受同源基因区间的影响。
Cia25包含一个调节两种不同自身免疫性关节炎模型中疾病严重程度的基因。尽管在关节炎研究中两性均受到保护，但只有雄性同源基因大鼠的抗CII水平显著降低，提示该区间可能存在第二个通过性别特异性方式调节自身抗体来发挥作用的关节炎基因。确定导致Cia25的基因有望产生新的预后生物标志物和治疗靶点。
