Proteoglycan-induced arthritis (PGIA) is a murine model for rheumatoid arthritis (RA) both in terms of its pathology and its genetics. PGIA can only be induced in susceptible mouse strains and their F2 progeny. Using the F2 hybrids resulting from an F1 intercross of a newly identified susceptible (C3H/HeJCr) and an established resistant (C57BL/6) strain of mouse, our goals were to: 1) identify the strain-specific loci that confer PGIA susceptibility, 2) determine whether any pathophysiological parameters could be used as markers that distinguish between nonarthritic and arthritic mice, and 3) analyze the effect of the MHC haplotype on quantitative trait loci (QTL) detection. To identify QTLs, we performed a genome scan on the F2 hybrids. For pathophysiological analyses, we measured pro- and antiinflammatory cytokines such as IL-1, IL-6, IFN-γ, IL-4, IL-10, IL-12, Ag-specific T cell proliferation and IL-2 production, serum IgG1 and IgG2 levels of both auto- and heteroantibodies, and soluble CD44. We have identified four new PGIA-linked QTLs (Pgia13 through Pgia16) and confirmed two (Pgia5, Pgia10) from our previous study. All new MHC-independent QTLs were associated with either disease onset or severity. Comprehensive statistical analysis demonstrated that while soluble CD44, IL-6, and IgG1 vs IgG2 heteroantibody levels differed significantly between the arthritic and nonarthritic groups, only Ab-related parameters colocalized with the QTLs. Importantly, the mixed haplotype (H-2b and H-2k) of the C3H × C57BL/6 F2 intercross reduced the detection of several previously identified QTLs to suggestive levels, indicating a masking effect of unmatched MHCs.

Objective. Proteoglycan-induced arthritis (PGIA) is a murine model of rheumatoid arthritis (RA), both in terms of its pathology and its genetics. PGIA can only be induced in susceptible murine strains and their F 2 progeny. As with RA, the genetics are complex, containing both major histocompatibility complex (MHC)-related and non-MHC-related components. Our goal was to identify the underlying non-MHC-related loci that confer PGIA susceptibility.Methods. We used 106 polymorphic markers to perform simple sequence-length polymorphism analysis on F 2 hybrids of susceptible (BALB/c) and nonsusceptible (DBA/2) strains of mice. Because both strains of mice share the H2 d haplotype, this cross permits identification and analysis of non-MHC-related genes.Results. We identified a total of 12 separate quantitative trait loci (QTL) associated with PGIA, which we have named Pgia1 through Pgia12. QTLs associated with the inflammatory symptoms of PGIA were linked to chromosomes 7, 9, 15 (2 separate loci), 16, and 19. QTLs associated with autoantibody production were identified on chromosomes 1, 2, 7, 8, 10, 11, 16, and 18. QTLs on chromosomes 7 and 16 showed linkage to both inflammation and autoantibody production, suggesting a shared regulatory component in arthritis induction. The first inflammation QTL on chromosome 15 and the autoantibody QTL on chromosome 7 originate from the DBA/2 background, which indicates that as in RA, susceptibility genes can originate from heterogeneous backgrounds.Conclusion. These data demonstrate the complexity of PGIA, where QTLs may be involved in multiple traits or even originate from a genetic background previously determined to be resistant.

Objective To identify and screen the level of arthritis susceptibility in C3H murine strains known to be resistant to proteoglycan (aggrecan)–induced arthritis, and to measure and correlate various immunologic and inflammatory parameters with susceptibility to either arthritis or spondylitis in various C3H substrains. Methods Mice of 10 C3H substrains (subcolonies) were immunized with cartilage proteoglycan (aggrecan) for induction of arthritis. Animals were assessed for clinical symptoms, and the peripheral joints and spine were studied by histologic methods. Proteoglycan‐specific T cell responses (T cell proliferation and production of interleukin‐2 [IL‐2], interferon‐γ, and IL‐4) and the B cell response to lipopolysaccharide (LPS) were measured in spleen cell cultures. Serum levels of heteroantibodies and autoantibodies as well as various cytokines (IL‐6, IL‐10, IL‐12, and tumor necrosis factor α) and soluble CD44 were determined by enzyme‐linked immunosorbent assay. Results Immunization with cartilage proteoglycan induced severe arthritis in the C3H/HeJCr substrain (95–100% incidence), whereas the original parent mice of the C3H/HeJ colony were resistant to proteoglycan (aggrecan)–induced arthritis. Furthermore, the progressive polyarthritis that is characteristic in susceptible C3H/HeJCr mice was accompanied by progressive inflammation around the spine. In subsequent experiments, 10 different C3H colonies with largely identical genetic backgrounds (all originating from the National Institutes of Health or Jackson Laboratory) exhibited extreme differences in susceptibility. Although none of the laboratory findings, including LPS hyporesponsiveness, immunologic parameters, and inflammatory markers, showed a correlation with susceptibility or resistance in the C3H/HeJCr and C3H/HeJ substrains, respectively, significant differences were found when all arthritic C3H mice were compared with all nonarthritic animals, regardless of their substrain origin. Conclusion Because many of the C3H substrains lost arthritis susceptibility or acquired resistance, our results suggest that a preferred site for a mutation(s) in a gene(s) in a relatively upstream position of the inflammatory cascade is present. This is the first autoimmune model that exhibits extreme differences in arthritis susceptibility in the same murine strain, and is therefore a valuable tool for identification of arthritis‐susceptible (or arthritis‐suppressive) genes.

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