Th1 and Th2 cytokines regulate proteoglycan-specific autoantibody isotypes and arthritis

BALB/c mice immunized with human cartilage proteoglycan (PG) develop arthritis accompanied by the production of autoantibodies to mouse cartilage PG. To determine whether the autoantibody isotype contributes to the onset and severity of arthritis, PG-specific serum IgG1 (Th2, IL-4-cytokine-supporting) and IgG2a (Th1, IFN-γ-controlling) concentrations were monitored during immunization with PG in IL-4-deficient and IFN-γ-deficient mice. Paradoxically, despite elevated IFN-γ, the PG-specific IgG1 isotype was significantly higher than the PG-specific IgG2a response, and the PG-specific IgG1 isotype was independent of IL-4. In contrast, the serum concentration of PG-specific IgG2a isotype was six times higher in IL-4-deficient mice than in wild-type controls. Moreover, the high concentration of PG-specific IgG2a isotype in IL-4-deficient mice corresponded to an increased severity of arthritis. The concentration of PG-specific IgG2a isotype was lower in IFN-γ-deficient mice than in wild-type mice, and the incidence and severity of arthritis also were significantly lower. Concentrations of PG-specific IgG2a isotype autoantibody correlated with the onset and severity of arthritis, suggesting a pathological role of this isotype, probably locally in the joint.     

Th1 and Th2 cytokines regulate proteoglycan-specific autoantibody isotypes and arthritis

BALB/c mice immunized with human cartilage proteoglycan (PG) develop arthritis accompanied by the production of autoantibodies to mouse cartilage PG. To determine whether the autoantibody isotype contributes to the onset and severity of arthritis, PG-specific serum IgG1 (Th2, IL-4-cytokine-supporting) and IgG2a (Th1, IFN-gamma-controlling) concentrations were monitored during immunization with PG in IL-4-deficient and IFN-gamma-deficient mice. Paradoxically, despite elevated IFN-gamma, the PG-specific IgG1 isotype was significantly higher than the PG-specific IgG2a response, and the PG-specific IgG1 isotype was independent of IL-4. In contrast, the serum concentration of PG-specific IgG2a isotype was six times higher in IL-4-deficient mice than in wild-type controls. Moreover, the high concentration of PG-specific IgG2a isotype in IL-4-deficient mice corresponded to an increased severity of arthritis. The concentration of PG-specific IgG2a isotype was lower in IFN-gamma-deficient mice than in wild-type mice, and the incidence and severity of arthritis also were significantly lower. Concentrations of PG-specific IgG2a isotype autoantibody correlated with the onset and severity of arthritis, suggesting a pathological role of this isotype, probably locally in the joint.     

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

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 F(2) 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 F(2) hybrid mice. For pathophysiological analyses, we measured pro- and anti-inflammatory cytokines (IL-1, IL-6, TNF-alpha, IFN-gamma, 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-gamma levels differed significantly between arthritic and nonarthritic animals in both CIA and PGIA populations. High levels of TNF-alpha, IFN-gamma, IL-2, and Ab production were detected in F(2) hybrids with CIA, whereas T cell proliferation, IL-2 and IFN-gamma 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.     

Passing the message on: inheritance of epigenetic traits

Epigenetic modifiers play an important role in genome organization, stability and the control of gene expression. Three research groups that are exploring the transfer of epigenetic information between generations have recently published papers. Mary Alleman et al. have shown that RNA-directed chromatin changes mediate paramutation in maize, and Minoo Rassoulzadegan et al. have demonstrated that RNA also plays a role in paramutation in mice. A new aspect of epigenetic regulation has been revealed by Jean Molinier et al. - they have demonstrated that the memory of exposure to stress is transferred through several generations.