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

Arthritis Rheum. 2001 Mar;44(3):682-92. doi: 10.1002/1529-0131(200103)44:3<682::AID-ANR118>3.0.CO;2-E.


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-y, 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 alpha) 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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arthritis / chemically induced*
  • Arthritis / genetics
  • Female
  • Genetic Predisposition to Disease
  • Intervertebral Disc / pathology
  • Joints / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Proteoglycans / genetics*
  • Spine / pathology
  • Spondylitis, Ankylosing / chemically induced*
  • Spondylitis, Ankylosing / genetics


  • Proteoglycans