Variations in susceptibility to proteoglycan-induced arthritis and spondylitis among C3H substrains of mice: Evidence of genetically acquired resistance to autoimmune disease

Abstract

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.

Sex effect on clinical and immunologic quantitative trait loci in a murine model of rheumatoid arthritis

“…There is strong genetic linkage between the MHC and autoimmune/arthritic processes (37); however, having the "right" combination of MHC alleles is not sufficient for the induction of an autoimmune disease (29,35,44,53). In order to exclude the MHC effect on disease development and severity in a mixed (F 2 ) genetic background, we intercrossed PGIA-susceptible BALB/c females with arthritis-resistant DBA/2 males, both strains carrying the same H-2 d haplotype.…”

“…Antibodies to the immunizing (human) and mouse (self) cartilage PGs were determined by enzymelinked immunosorbent assay (ELISA) as described elsewhere (38,44). Briefly, 96-well Maxisorp plates (Nunc International, Hanover Park, IL) were coated with either chondroitinase ABC-digested human (for heteroantibodies) or native mouse (for autoantibodies) cartilage PGs (0.1 g of antigen protein/ well).…”

Interleukin‐4 regulates proteoglycan‐induced arthritis by specifically suppressing the innate immune response

“…BALB/c and C3H mice are susceptible to PGIA (14,15). Female wild-type (WT) BALB/c mice were purchased from The Jackson Laboratory (Bar Harbor, ME).…”

The pathogenesis of ankylosing spondylitis

“…The entheses, anterior uveal tract, aorta, and aortic valve all contain aggrecan or homologous proteins such as versican that provide for cyclic compression and relaxation. Immunity to aggrecan in BALB/c mice induces spondylitis and peripheral arthritis, 45 and the immunoreactive G1 domain is the major proteolytic degradation product of the proteoglycan. One explanation for these findings is that fibrocartilaginous entheseal microtrauma or local inflammatory processes secondary to infection in the immunogenetically predisposed patient may lead to an autoimmune reaction against newly exposed antigens that are also expressed at extraarticular sites typical of AS.…”