Localization of non-Mhc collagen-induced arthritis susceptibility loci in DBAy1j mice (rheumatoidygenome scanycollagen-induced arthritis)

One approach to understanding common human diseases is to determine the genetic defects responsible for similar diseases in animal models and place those defective genes in their corresponding biochemical pathways. Our laboratory is working with an animal model for human rheumatoid arthritis called collagen-induced arthritis (CIA). We are particularly interested in determining the location of disease-predisposing loci. To that end, we performed experiments to localize susceptibility loci for CIA in an F2 cross between the highly susceptible mouse strain DBAy1j and the highly resistant mouse strain SWRyj. Specifically, a quantitative trait locus analysis was performed to localize regions of the mouse genome responsible for susceptibilityyseverity to CIA. One susceptibility locus, Cia1 in the major histocompatibility locus, had been identified previously. Two additional loci were detected in our analysis that contribute to CIA severity (Cia2, Cia3) on chromosomes 2 and 6. A third locus was detected that contributes to the age of onset of the disease. This locus (Cia4) was located on chromosome 2 and was linked to the same region as Cia2. Determining the identity of these loci may provide insights into the etiology of human rheumatoid arthritis. One approach to solving the complex interactions of susceptibility genes for a particular human disease is to identify genes in an animal model for a similar disorder and then assess the relevance of those genes by looking at homologous genes or their pathways in humans. A number of rodent animal models exist for a variety of human diseases, such as diabetes, hypertension, systemic lupus erythrematosus, and rheumatoid arthritis. The genes predisposing to disease in the animal model may not be orthologous to the loci involved in the human pathologies. However, understanding the physiological mechanisms that lead to the disease in animals may provide insights into the etiology of their human counterparts. The NOD mouse has provided new insights for diabetes (1), the NZM2410 mouse has provided insights for systemic lupus erythrematosus (2, 3), and the stroke-prone spontaneously hypertensive rat (SHRSP) has provided insights for hypertension (4, 5). Our laboratory has been studying collagen-induced arthritis (CIA), a mouse animal model for human rheumatoid arthritis (6). Autoimmune reactivity to type II collagen (CII) was first experimentally induced in the rat by Trentham et al. in 1977 (7). Intradermal injection of CII in complete Freund’s adjuvant (CFA) resulted in an inflammatory polyarthritis with characteristics similar to rheumatoid arthritis in man. A mouse model of CIA subsequently was established by Courtenay et al. (8). Most rodent studies immunize the animals with heterologous CII (e.g., bovine or chicken CII), which presents a pathology characterized as an arthritis that develops ‘‘explosively’’ 6–10 weeks after injection and never relapses after remission. Microscopic examination of the joints of diseased animals reveals many features that are similar to rheumatoid arthritis, including lymphocytic infiltration and synovial membrane hypertrophy. The genetics of CIA has been under intense investigation for a number of years. Genetic crosses between susceptible and resistant inbred mouse strains have demonstrated that CIA is inherited in most inbred strains as a polygenic, dominant trait (9, 10). Several investigators have explored the role of the murine major histocompatibility complex (Mhc or H-2) in CIA development by immunization of congenic and inbred strains with heterologous and homologous CII (11–14). The results from these studies established that specific Mhc haplotypes are required for CIA susceptibility, namely H-2q and H-2r. Specifically, Wooley et al. (15) used recombinant inbred strains to map susceptibility to CIA within the I region of the Mhc. In this current study, the Mhc is given the CIA susceptibility locus name Cia1. Evidence localizing susceptibility to the b1 domain of the H2-Ab gene was described later (16). Although susceptibility to CIA has been linked to H-2 inheritance, non-Mhc genes clearly influence the incidence and severity of CIA. This is demonstrated by the difference in the frequency of CIA in the H-2q strains DBAy1j (100%), B10.Q (84%), NFRyN (50%), B10.G (41%) and SWRyj (0%) (12, 14). Of interest, SWRyj mice are completely resistant to CIA induction with both heterologous and homologous CII, although they have the permissive H-2 haplotype. The underlying mechanisms responsible for their resistance have been under investigation for quite some time, with two principle loci being implicated in the resistance of SWRyj to CIA induction, complement C5 (Hc) and the T cell receptor beta locus (Tcrb) (17–21). The contribution of these loci to CIA susceptibility is still not clear and has been under debate (19, 20, 22). Further evidence of non-Mhc loci contributing to the severity of CIA was provided by Remmers et al. (23). They performed a genome scan to localize susceptibility loci for CIA in (DA 3 F344)F2 susceptible rats. In addition to the rat Mhc, five additional susceptibility loci were localized to five separate chromosomes (chromosomes 1, 4, 7, 8, and 10). Recently, Jirholt et al. (24) described two additional susceptibility loci for CIA in (B10.RII 3 RIIISyj)F2 arthritic mice. These loci were located on chromosomes 3 and 13. Given the disease heterogeneity and Mhc variability, we argue that mice of the H-2q and H-2r haplotypes represent different collections of polymorphism leading to CIA suscepThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. §1734 solely to indicate this fact. PNAS is available online at www.pnas.org. Abbreviations: CIA, collagen-induced arthritis; CII, type II collagen; CFA, complete Freund’s adjuvant; QTL, quantitative trait locus; lod, logarithm of odds. †To whom reprint requests should be addressed at current address: CuraGen Corporation, 12085 Research Drive, Alachua, FL 32615. e-mail: [email protected].