ABSTRACT
PURPOSE: Recently, genomewide association analysis has revealed that the Tumor Necrosis Factor Receptor-associated factor 1-Complement 5 (TRAF1-C5) containing locus on chromosome 9 was associated with an increased risk for RA. Studies in model systems suggested that either gain- or loss-of-function TRAF1 mutations have immune effects that could plausibly lead to or exacerbate the arthritis phenotype. KRN/I-A(g7) (KxB/N) is a genetic mouse model of inflammatory arthritis. We aimed to assess the impact of TRAF1 deficiency on KRN/I-A(g7) mice. METHODS: We have bred KRN/I-A(g7) mice onto a TRAF1-deficient background and followed cohorts for the spontaneous appearance of arthritis. We have also transferred KxB/N serum to B6.I-A(g7) TRAF1KO recipients. In addition, systemic autoimmunity was induced through cGVH by injecting bm12 splenocytes into TRAF1KO recipient mice. RESULTS: TRAF1-deficient KRN/I-A(g7) mice spontaneously developed severe, progressive arthritis, comparable to that seen in TRAF1-intact KRN/I-A(g7) mice. However, the anti-GPI antibody titer was significantly lower in the former group. Interestingly, the TRAF1KO mice that had background levels of anti-GPI antibodies still showed severe arthritis, although with a brief delay compared to TRAF1 sufficient mice. In addition, TRAF1KO mice were fully susceptible to passive, serum transfer experiments. In another model of autoimmunity, TRAF1KO had no effect on cGVH autoantibodies production; nor was the response to an exogenous antigen impaired. CONCLUSION: The pathogenesis of spontaneous KRN/I-A(g7) arthritis can largely proceed by TRAF1-independent pathways. The production of anti-GPI autoantibody, but not other autoantibody or antibody responses, was markedly impaired by TRAF1 deficiency. The spontaneous arthritis model in KRN mice appears to be much less antibody dependent than previously believed.
Subject(s)
Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Autoimmune Diseases/immunology , TNF Receptor-Associated Factor 1/immunology , Animals , Antibody Formation/drug effects , Arthritis, Experimental/genetics , Arthritis, Rheumatoid/genetics , Autoantibodies/blood , Autoimmune Diseases/genetics , Glucose-6-Phosphate Isomerase/immunology , Histocompatibility Antigens Class II/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Risk , TNF Receptor-Associated Factor 1/geneticsABSTRACT
BACKGROUND: KRN/I-A(g7) (KxB/N) is a mouse model of inflammatory arthritis, which resembles human rheumatoid arthritis. Arthritis in these animals is caused by autoreactivity to a ubiquitously expressed autoantigen, glucose-6 phosphate isomerase. Tolerance is broken at both the T cell and B cell level. The sera from KRN/I-A(g7) mice can induce mouse arthritis in healthy mice. Complement components of the alternative complement pathway, including C3, have been shown to be required in induction of mouse arthritis by serum transfer. METHODS: We have bred KRN/I-A(g7) mice onto a C3-deficient background and followed cohorts for the spontaneous appearance of arthritis. We have also transferred KxB/N serum to B6.I-A ( g7 ) recipients. RESULTS: C3-deficient KRN/I-A(g7) mice spontaneously developed severe, destructive arthritis, comparable to that seen in C3-intact KRN/I-A(g7) mice. However, serum transfer experiments confirmed the strong requirement for C3 in the passive model. CONCLUSION: The pathogenesis of spontaneous KRN/I-A(g7) arthritis can largely proceed by complement-independent pathways and must have pathology effector mechanisms in addition to those seen in the passive serum transfer model.
Subject(s)
Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/immunology , Autoantigens/immunology , Glucose-6-Phosphate Isomerase/immunology , Histocompatibility Antigens Class II/metabolism , Animals , Arthritis, Rheumatoid/physiopathology , Autoantibodies/blood , Complement Activation/genetics , Complement C3/genetics , Disease Models, Animal , Genetic Predisposition to Disease , Histocompatibility Antigens Class II/genetics , Humans , Immunization, Passive , Mice , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
Systemic lupus erythematosus is characterized by loss of tolerance to DNA and other nuclear Ags. To understand the role of T cells in the breaking of tolerance, an anti-DNA site-specific transgenic model of spontaneous lupus, B6x56R, was studied. T cells were eliminated by crossing B6x56R with CD4(-/)(-) or TCRbeta(-/-)delta(-/-) mice, and the effects on anti-dsDNA serum levels, numbers of anti-dsDNA Ab-secreting cells, and isotypes of anti-dsDNA were analyzed. In addition, the development and activation of B cells in these mice were examined. Surprisingly, the presence of T cells made little difference in the development and character of the serum anti-dsDNA Ab in B6x56R mice. At 1 mo of age, anti-dsDNA Abs were somewhat lower in mice deficient in alphabeta and gammadelta T cells. Levels of Abs later were not affected by T cells, nor was autoantibody class switching. B cell activation was somewhat diminished in T cell-deficient mice. Thus, in the B6 background, the presence of an anti-dsDNA transgene led the production of autoantibodies with a specificity and isotype characteristic of murine systemic lupus erythematosus with little influence from T cells. TLR9 also did not appear to play a role. Although we do not yet understand the mechanism of this failure of immunoregulation, these results suggest that similar processes may influence autoimmunity associated with clinical disease.