BBB seminar: Rikard Holmdahl
From disease to genes and back – following an oxidation path
Medical Inflammation Research, Karolinska Institutet, Stockholm, Sweden
To resolve the pathogenic mechanisms of chronic inflammatory disease like rheumatoid arthritis (RA) we need to identify the causative genetic and environmental factors. This has, however, proven to be complex, with many factors and genes interacting. Animal models offer a possibility to not only to identify underlying genes but also to understand their role. We have used inbred mouse and rat strains to identify genes controlling models for RA. Using a cross between the disease susceptible inbred rat strain DA and the resistant E3 strain we identified more than 20 loci (locations on chromosomes controlling disease susceptibility). One of the major loci was positionally cloned and the underlying gene was Ncf1 (which encodes neutrophil cytosolic factor 1, a component of the NADPH oxidase complex). Surprisingly the DA allele of Ncf1 that allowed a lower oxidative burst by the NADPH oxidase complex (which is controlling the induced oxidative burst in phagocytes), predisposed to more severe arthritis and also increased autoimmunity. This discovery of the Ncf1 polymorphism (genetic variability) led us to propose a pathway in which oxygen radicals modify antigen presentation, resulting in activation of autoreactive T cells. Another Ncf1 mutation was identified in the mouse that showed similar effects as the natural polymorphism in the rat. Mice with the deficient Ncf1 allele were found to be more susceptible to arthritis, confirming the observations in the rat. Interestingly, the immune response to CII (type II collagen) was enhanced by the Ncf1 deficiency, linking the Ncf1 pathway to the adaptive immune response. Oxidation of T cell membranes seems to be a key event in the pathogenic mechanism as reduction of T cell membranes leads to increased activation and the capacity to induce arthritis in rats. On the basis of these findings a new type of therapy has been developed using agents that activate the NADPH oxidase complex, i.e. oxidants.
Taken together we found that oxygen radicals could also be of importance to dampen the immune response and inflammatory diseases, in complete contrast to the current dogma that antioxidants promote health.
Host: Rolf Kåre Reed <firstname.lastname@example.org>, Department of Biomedicine