Definition of genetic and pathogenic mechanisms regulating neuroinflammation

Sammanfattning: Although complex inflammatory diseases affect 5% of the population we still do not understand fully the underlying disease triggers and mechanisms. This partly explains why current treatments are not curative but only modify disease. These diseases arise from combined genetic, environmental and unknown effects. In this thesis, I have focused on identifying the genetic factors that regulate complex disease in experimental models. The rationale is that these genetic determinants will provide insight into the conserved mechanisms also important for human disease. These mechanisms can then be targeted therapeutically. I have worked with the neuroinflammatory diseases multiple sclerosis (MS) and Guillain-­?Barré syndrome (GBS) and their respective animal models, experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). To identify risk genes in an unbiased phenotype-­?driven manner, we established intercrosses and recombinant lines between rat strains with opposing susceptibilities to EAE and EAN. Linkage analyses and functional studies in rat lines then successfully positioned five genes that regulate experimental neuroinflammation, namely Il22ra2, Vav1, Raet1, Klrk1 and Ncf1. IL22RA2 and VAV1 were also translated as risk genes in MS cohorts. More importantly, however, the five genes targeted immune mechanisms and events that correlated well with disease. In our hands, Il22ra2 regulated macrophage activation, Vav1 controlled effector T cell activity and regulatory T cell proportions, Raet1 and Klrk1 displayed a gene-­?gene interaction that modified NK cell activity and Ncf1 controlled oxidative burst from mononuclear cells. All these mechanisms also have described roles in both MS and GBS. By finding genetic determinants of distinct pathogenic mechanisms we may both discover novel targets for treatment and also more accurately define which current therapies are more suitable for different patients.