Combined autoimmune models of arthritis reveal shared and independent qualitative (binary) and quantitative trait loci

Vyacheslav A. Adarichev, Juan C. Valdez, Tamás Bárdos, Alison Finnegan, Katalin Mikecz, Tibor T. Glant

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Abstract

Collagen-induced arthritis (CIA) and proteoglycan-induced arthritis (PGIA) are murine models for rheumatoid arthritis both in terms of their pathology and genetics. Using the F2 hybrids of the CIA-susceptible, but PGIA-resistant DBA/1 mice, and the CIA-resistant, but PGIA-susceptible BALB/c mice, our goals were to 1) identify both model-specific and shared loci that confer disease susceptibility, 2) determine whether any pathophysiological parameters could be used as markers that distinguish between nonarthritic and arthritic mice, and 3) analyze whether any immune subtraits showed colocalization with arthritis-related loci. To identify chromosomal loci, we performed a genome scan on 939 F2 hybrid mice. For pathophysiological analyses, we measured pro- and anti-inflammatory cytokines (IL-1, IL-6, TNF-α, 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. In addition to multiple CIA- and PGIA-related loci identified in previous studies, we have identified nine new CIA- and eight new PGIA-linked loci. Comprehensive statistical analysis demonstrated that IL-2 production, T cell proliferation, and IFN-γ levels differed significantly between arthritic and nonarthritic animals in both CIA and PGIA populations. High levels of TNF-α, IFN-γ, IL-2, and Ab production were detected in F2 hybrids with CIA, whereas T cell proliferation, IL-2 and IFN-γ production, and a shift to IgG2a isotype were more characteristic of PGIA. Quantitative trait loci analysis demonstrated colocalization of numerous immune subtraits with arthritis-related traits. Quantitative trait loci on chromosomes 5, 10, 17, 18, and X were found to control arthritis in both models.

Original languageEnglish
Pages (from-to)2283-2292
Number of pages10
JournalJournal of Immunology
Volume170
Issue number5
DOIs
Publication statusPublished - Mar 1 2003

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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