A search for genes influencing autoimmunity - focus on rheumatoid arthritis and multiple sclerosis

Abstract: The causes of autoimmune diseases are largely unknown today, but there is evidence supporting a substantial complex genetic influence on many of these diseases as well as environmental factors and chance. In this thesis I have tried to get one step closer to the genetic causes of two autoimmune diseases through their induced counterparts in mice, namely rheumatoid arthritis (RA) and multiple sclerosis (MS). We show that experimental autoimmune encephalomyelitis (EAE), the model for MS, is controlled by two major genes. One is found to reside on mouse chromosome 15 (eae2) and the other on chromosome 3 (eae3). These genes work together giving a more severe disease. After eliminating the stronger eae2 gene by congenic breeding, we were able to identify an additional genetic factor and several putative regions also influencing disease. Furthermore, we define one region on chromosome 3 (cia5) and one on chromosome 13 that affect susceptibility to collagen induced arthritis (CIA), a mouse model of RA. In this experiment we find that the linked region on chromosome 3 is almost identical to the region found in the first study. Since these experiments were performed on the same strain combination, it is possible that the underlying genetic factor is the same in both diseases. Furthermore we were able to identify four regions that control different aspects of CIA on chromosomes 6, 7, 8 and 10 in a different cross. An interesting observation is that most linked regions are homologous to regions in the rat genome that also have been linked to CIA. This implies a common genetic pathway that promotes autoimmunity across species.