The Role of Reactive Oxygen Species in Animal Models of Autoimmunity

Sammanfattning: Reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase complex are important in the killing of invading pathogens. Lately, a role of ROS has been suggested in regulation of the immune system. This was further highlighted when the Ncf1 gene, encoding a subunit of the NADPH oxidase complex, was found to regulate arthritis severity in rats. Interestingly, the fact that increased arthritis susceptibility was mediated by a lowered ROS production diverged from the general dogma that ROS in general promotes inflammation. The studies included in this thesis aimed to further investigate and characterize the influence of Ncf1 and ROS in autoimmune diseases such as arthritis and encephalomyelitis. By using animal models of the human Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS), we could confirm the importance of decreased ROS production in development of autoimmunity. This was validated by identification of a mouse Ncf1 mutation that also decreased ROS production and resulted in enhanced arthritis. In addition, we found that T cell reactivity was altered in animals with impaired ROS production, presumably through interaction with antigen presenting cells. We found that the redox level on T cell membranes was the determinant for arthritogenicity. Interestingly, we could also reverse the genetic effect by administrate NADPH oxidase activating oils into rats, thereby preventing and ameliorating disease. This is promising as these findings provide a novel pathway to target therapeutically in complex inflammatory diseases. In summary, this thesis describes a pathway in the pathology of arthritis and encephalomyelitis that reveals a new way to treat autoimmunity.