Cia25 on rat chromosome 12 regulates severity of autoimmune arthritis induced with pristane and with collagen

Abstract

Background: A genomewide scan in a DAxACI 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. Objective: To characterise the effects of Cia25 on severity of arthritis in congenic rats. Methods: 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. Results: 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. Conclusions: 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.