Reduced ROS production triggers arthritis / The role of T cells in arthritis pathogenesis

Sammanfattning: The aim of this thesis is to defend a novel mechanism that triggers arthritis susceptibility in both rats and mice through reduced production of reactive oxygen species (ROS), but also to introduce a novel model for chronic relapsing arthritis. Five papers are included, all of which employ animal models for rheumatoid arthritis and one that also uses animal models for multiple sclerosis. Paper I aimed at identifying strong dominant loci operating early in PIA by linkage analysis of a large F2 backcross. We identified eight dominant QTLs regulating arthritis traits, of which Pia4 was the strongest in suppressing arthritis. Paper II aimed at cloning the gene responsible for the strong arthritis-suppressive effect of Pia4. Ncf1 was positionally identified as the only gene within a minimal Pia4-fragment with polymorphisms inside the coding region that differed between parental strains. Paper III aimed at showing that the arthritis-regulatory effect of Ncf1 is not species-specific. We showed that Ncf1-mutant mice were more susceptible to arthritis as well as to MOG protein-induced EAE than heterozygous littermate controls. Paper IV aimed at characterizing the immune response in PIA. Through several cell transfer experiments, we could conclude that T cell antigens must be involved in PIA, since arthritis transferred by T cells was restricted by MHC class II DQ and DR molecules. Paper V aimed at characterizing the chronic relapsing arthritis induced by adoptive transfer of PIA. High levels of COMP, AGP and IgG2b in blood at the chronic phase suggested cartilage destruction, systemic inflammation and Th1-mediated antibody production, respectively. Also, Methotrexate, anti-IFN-? or anti-TNF-? treatment with Etanercept ameliorated arthritis severity at the chronic stage.