Identification of Arthritis Regulating Genes in Rats

Sammanfattning: The immune response is designed to protect the body from harmful microbial invasions. However, when the immune system attacks itself instead, an autoimmune reaction starts that damage our own cells, tissues and organs. Despite decades of research concerning the etiology of autoimmune diseases the molecular mechanisms of these disorders are poorly understood as they are complex and influenced by both inherited factors and environment. One of the most prevalent autoimmune diseases is Rheumatoid Arthritis (RA). In this thesis I present results concerning how animal models for RA were used to investigate the genetic predisposition of arthritis. By genetic segregation experiments between arthritis resistant and susceptible rat strains we have identified several chromosomal regions (Pia 1-15), including MHC, which strongly regulates the development of arthritis in rats. To characterize arthritis we use clinical phenotypes like maximal disease severity and onset of disease as well as other disease sub-phenotypes like the acute phase response, cartilage destruction and cell surface markers on lymphocytes to support linkage analysis and positional cloning of the arthritis regulating genes. Hence, through genetic mapping and reverse genetics we have identified one of the major genes that regulate arthritis severity in rats. The identified gene, Ncf1, is involved in production of radical oxygen species (ROS) in phagocyting cells. Besides the fact that this was the first case of a single gene shown to be of importance in arthritis, that had been positionally cloned, it also indicated the importance of free radicals in autoimmune disease. It is shown that low levels of free radicals are involved in causing severe arthritis. As this contradicts the general idea of high concentrations of free radicals being involved in tissue destruction, we postulate a role of free radicals in the priming of autoreactive T cells in secondary lymphoid organs. Through analysis of Ncf1 deficient mice we also show that ROS not only are an important regulator of arthritis and EAE (experimental allergic encephalomyelitis), but also indicate that the effect of ROS in autoimmunity might be connected to antigen presenting or processing. Furthermore, we also introduce a new therapeutic approach aimed at activation of free radicals that suppresses experimental autoimmunity. Conclusively, the identification of arthritis regulating genes will provide major impact in understanding RA, and for treatment of the disease. Also, an increased knowledge regarding the genetic predisposition to arthritis will provide potential targets for future pharmaceutical drug development.