Background: A genomewide scan in a DA×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.
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.
- ASI, arthritis severity index
- CIA, collagen-induced arthritis
- CII, type II collagen
- EAU, experimental autoimmune uveitis
- IFA, incomplete Freund’s adjuvant
- MHC, major histocompatibility complex
- PIA, pristane-induced arthritis
- QTL, quantitative trait locus
- RA, rheumatoid arthritis
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Published Online First 28 February 2007
Funding: This work was funded by NIH grants number R01-AR46213, R01-AR052439 (NIAMS) and R01-AI54348 (NIAID) to PSG.
Competing interests: None.