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
Statistics from Altmetric.com
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.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.