Definition of genetic and pathogenic mechanisms regulating neuroinflammation

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.

List of scientific papers

I. Amennai Daniel Beyeen, Milena Z. Adzemovic, Johan Öckinger, Pernilla Stridh, Kristina Becanovic, Hannes Laaksonen, Hans Lassmann, Robert A. Harris, Jan Hillert, Lars Alfredsson, Elisabeth G. Celius, Hanne F. Harbo, Ingrid Kockum, Maja Jagodic and Tomas Olsson. IL22RA2 associates with multiple sclerosis and macrophage effector mechanisms in experimental neuroinflammation. Journal of Immunology. [Accepted]
https://doi.org/10.4049/jimmunol.1001392

II. Maja Jagodic, Celine Colacios, Rita Nohra, Anne S. Dejean, Amennai Daniel Beyeen, Mohsen Khademi, Audrey Casemayou, Lucille Lamouroux, Christine Duthoit, Olivier Papapietro, Louise Sjöholm, Isabelle Bernard, Dominique Lagrange, Ingrid Dahlman, Frida Lundmark, Annette B. Oturai, Helle B. Soendergaard, Anu Kemppinen, Janna Saarela, Pentti J. Tienari, Hanne F. Harbo, Anne Spurkland, Sreeram V. Ramagopalan, Dessa A. Sadovnick, George C. Ebers, Maria Seddighzadeh, Lars Klareskog, Lars Alfredsson, Leonid Padyukov, Jan Hillert, Michel Clanet, Gilles Edan, Bertrand Fontaine, Gilbert J. Fournié, Ingrid Kockum1, Abdelhadi Saoudi and Tomas Olsson. A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis. Science Translational Medicine. 2009 9 Dec: 1(10):10ra21.
https://doi.org/10.1126/scitranslmed.3000278

III. Amennai Daniel Beyeen, Alan Gillett, Melanie Thessen Hedreul, Steffen Möller, Tomas Olsson and Maja Jagodic. Epistasis between genetic variants in Raet1l and Klrk1 determines NK cell regulation of experimental neuroinflammation. [Manuscript]

IV. Alexander Huberle* and Amennai Daniel Beyeen*, Johan Öckinger, Miriam Ayturan, Maja Jagodic, Katrien L. de Graaf, Nicolas Fissolo, Monica Marta, Peter Olofsson, Malin Hultqvist, Rikard Holmdahl, Tomas Olsson and Robert Weissert. Advanced Intercross Line Mapping Suggests That Ncf1 (Ean6) Regulates Severity in an Animal Model of Guillain-­‐Barré Syndrome. Journal of Immunology. 2009;182;4432-­‐4438. *These authors contributed equally.
https://doi.org/10.4049/jimmunol.0803847