A genome scan using a novel genetic cross identifies new susceptibility loci and traits in a mouse model of rheumatoid arthritis

Proteoglycan-induced arthritis (PGIA) is a murine model for rheumatoid arth ritis (RA) both in terms of its pathology and its genetics, PGIA can only b e induced in susceptible mouse strains and their F-2 progeny, Using the F-2 hybrids resulting from an F-1 intercross of a newly identified susceptible (C3H/HeJCr) and an established resistant (C57BL/6) strain of mouse, our go als were to: 1) identify the strain-specific loci that confer PGIA suscepti bility, 2) determine whether any pathophysiological parameters could be use d 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 F-2 hybrids. For pathophysiological analyses, we measured pro- and antiinflammatory cyt okines such as IL-1, IL-6, IFN-gamma, IL-4, IL-10, IL-12, Ag-specific T cel l proliferation and IL-2 production, serum IgG1 and IgG2 levels of bath aut o- 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 eith er disease onset or severity, Comprehensive statistical analysis demonstrat ed that while soluble CD44, IL-6, and IgG1 vs IgG2 heteroantibody levels di ffered significantly between the arthritic and nonarthritic groups, only Ab -related parameters colocalized with the QTLs, Importantly, the mixed haplo type (H-2(b) and H-2(k)) of the C3H x C57BL/6 F-2 intercross reduced the de tection of several previously identified QTLs to suggestive levels, indicat ing a masking effect of unmatched MHCs.