Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen-induced arthritis

Objective. Collagen-induced arthritis (CIA) is a polygenic model of experim entally induced autoimmunity and chronic joint inflammation. This study map s genetic loci that regulate CW susceptibility in DA/Bkl (Dt) and BN/SsNHsd (BN) rats. Methods. Genome scans covering chromosomes 1-20 and internal mapping techni ques using 159 simple sequence-length polymorphism markers were used to ide ntify quantitative trait loci (QTLs) that regulate CIA in (DA x BN)F-2 hybr ids. Serum antibody titers to type II collagen were determined by enzyme-li nked immunosorbent assay. Results. DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resist ant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of ( DA x BN)F-I rats (7 of 60) and 31% of (DA x BN)F-2 rats (307 of 1,004) deve loped CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logari thm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively plus a suggesti ve QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on c hromosomes,7, 12, 1, and 19, A new QTL, Ciaa3, associating with anticollage n antibody titer (antibody to PII LOD 6.5; antibody to rat type Il collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in ( DA x F344) and (DA x ACI) rats, only Cia1 in the major histocompatibility c omplex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenc ed CIA severity in (DA x BN)F-2 rats. Conclusion. Since CIA. exhibits many of the pathologic features of rheumato id arthritis, the data indicate that the variety of genetic elements regula ting human autoimmune and rheumatic diseases may be much larger and more va ried than originally envisioned.