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,
*
Section of Biochemistry and Molecular Biology, Departments of Biochemistry and Orthopedic Surgery,
Department of Immunology/Microbiology, and
Department of Internal Medicine (Section of Rheumatology), Rush University at Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612
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-
, 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 x C57BL/6 F2 intercross
reduced the detection of several previously identified QTLs to
suggestive levels, indicating a masking effect of unmatched
MHCs.
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