Increased susceptibility to collagen-induced arthritis in female mice carrying congenic Cia40/Pregq2fragments

Abstract

Introduction Collagen-induced arthritis (CIA) in mice is a commonly used experimental model for rheumatoid arthritis (RA). We have previously identified a significant quantitative trait locus denoted Cia40 on chromosome 11 that affects CIA in older female mice. This locus colocalizes with another locus, denoted Pregq2 , known to affect reproductive success. The present study was performed to evaluate the role of the Cia40 locus in congenic B10.Q mice and to identify possible polymorphic candidate genes, which may also be relevant in the context of RA. Methods Congenic B10.Q mice carrying an NFR/N fragment surrounding the Cia40 / Pregq2 loci were created by 10 generations of backcrossing (N10). The congenic mice were investigated in the CIA model, and the incidence and severity of arthritis as well as the serum levels of anti-collagen II (CII) antibodies were recorded. Results Significant effects on onset, incidence, severity, and anti-CII antibody titers were observed in female mice carrying a heterozygous congenic Cia40/Pregq2 fragment of NFR/N origin, containing one or more polymorphic genes. Congenic male mice did not show increased incidence of CIA, but males carrying a heterozygous fragment showed a significant increase in severity in comparison with wildtype B10.Q males (littermates). Conclusion The Cia40/Pregq2 locus at chromosome 11 contains one or more polymorphic genes of NFR/N origin that significantly influence both incidence and severity of CIA in heterozygous congenic mice of the B10.Q strain. The major polymorphic candidate genes for the effects on CIA are Cd79b , Abca8a , and Map2k6 . The congenic fragment also contains polymorphic genes that affect reproductive behavior and reproductive success. The Sox9 gene, known to influence sex reversal, is a candidate gene for the reproductive phenotype.

Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice

“…Antibodies to CII have been detected in serum and synovial fluid of patients with RA [ 28 , 29 ]. As in RA, anti-CII antibody production contributes to the development of CIA [ 30 , 31 ]. The beneficial effect of DCA on arthritis is likely due to the down-regulation of B cells producing anti-CII antibodies because DCA-treated mice displayed significantly lower levels of anti-CII antibodies (Figure 3a ).…”

B cells as effectors and regulators of sex-biased arthritis

“…Most of the models of experimental arthritis including DQ8 mice do not develop the sex-biased arthritis that is observed in humans. A quantitative trait loci on chromosome 11 has been shown to affect incidence and severity of arthritis and anti CII antibodies in female mice in a mouse model of arthritis [81]. Although, there are not many models where arthritis is observed with a sex-bias similar to that in humans, an antigen-induced arthritis model using methylated bovine serum albumin showed severe arthritis in old females compared to young female and male mice even though antibodies and T cell response were similar in all groups [82].…”

Definition of arthritis candidate risk genes by combining rat linkage-mapping results with human case-control association data

“…In the present study we describe results of an alternative method. We aimed to define candidate risk genes in regions on Rattus norvegicus chomosome 4 and 10 (RNO4 and 10) that influence experimental RA,10 11 12 13 14 15 16 and in the corresponding human chromosome regions which link to, and associate with, RA 17 18 19. As well as RA, the targeted regions also associate with other inflammatory diseases, and there is evidence for more than one risk gene in each region 20 21 22 23 24 25 26 27 28 29 30 31 32 33…”