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* Medical Inflammation Research, Lund University, Lund, Sweden; and
Department of Laboratory Medicine, Section of Clinical Chemistry, Lund University, Malmö University Hospital, Malmö, Sweden
Genetic segregation analysis between NOD and C57BL strains have been used to identify loci associated with autoimmune disease. Only two loci (Cia2 and Cia9) had earlier been found to control development of arthritis, whereas none of the previously identified diabetes loci was of significance for arthritis. We have now made a high-powered analysis of a backcross of NOD genes on to the B10.Q strain for association with collagen-induced arthritis. We could confirm relevance of both Cia2 and Cia9 as well as the interaction between them, but we did not identify any other significant arthritis loci. Immune cellular subtyping revealed that Cia2 was also associated with the number of blood macrophages. Congenic strains of the Cia2 and Cia9 loci on the B10.Q background were made and used to establish a partial advanced intercross (PAI). Testing the PAI mice for development of collagen-induced arthritis confirmed the loci and the interactions and also indicated that at least two genes contribute to the Cia9 locus. Furthermore, it clearly showed that Cia2 is dominant protective but that the protection is not complete. Because these results may indicate that the Cia2 effect on arthritis is not only due to the deficiency of the complement C5, we analyzed complement functions in the Cia2 congenics as well as the PAI mice. These data show that not only arthritis but also C5-dependent complement activity is dominantly suppressed, confirming that C5 is one of the major genes explaining the Cia2 effect.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Swedish Research Council, Swedish Foundation for Strategic Research (INGVAR), Greta and Johan Kock’s Research Foundation, King Gustav V’s 80th Anniversary Foundation, Anna Greta Crafoord (Crafoord) Foundation, Kock Foundation, Österlund Foundation, Swedish Association against Rheumatism, Swedish Medical Research Council, Strategic Research Foundation, and the European Union projects MUGEN and AUTOCURE.
2 Current address: Cartela AB, Box 709, Lund 22007, Sweden.
3 Address correspondence and reprint requests to Dr. Rikard Holmdahl, Medical Inflammation Research, BMC, I11, Lund University, Lund 22184, Sweden. E-mail address: rikard.holmdahl{at}med.lu.se
4 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; PAI, partial advanced intercross; MAC, membrane attack complex; CII, collagen type II; LOD, logarithm of the odds; jnt, joint.
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