Identification of a new non-major histocompatibility complex genetic locuson chromosome 2 that controls disease severity in collagen-induced arthritis in rats

Objective. To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type II collagen-i nduced arthritis (CIA), Methods. We conducted a genome-wide scan to identify CIA regulatory quantit ative trait loci (QTL) in an F-2 cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II c ollagen (RII). These strains share the MHC/RT1(av1) haplotype required for susceptibility to RII-induced CIA. Results. F-2 females had higher median arthritis scores than did males. Rel ative resistance in the males was determined by inheriting either a DA or a n ACI Y chromosome and was independent of the source of the X chromosome. T n addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of o dds score 4.6). Cia7 is in a region that shows linkage conservation with ch romosomal regions that regulate autoimmune diabetes and experimental autoim mune encephalomyelitis in mice and multiple sclerosis in humans, Conclusion. Sex chromosomes and Cia7 play an important role in regulating C IA. in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role i n several forms of autoimmune disease, including rheumatoid arthritis.