Genetic and immunological regulation of neuroinflammation

Multiple Sclerosis (MS) affects young adults and is characterized by chronic inflammation and demyelination in the central nervous system that leads to progressive worsening of disease. The cause of MS is incompletely understood and there is a need for more specific and effective treatments.

This thesis aimed to characterize genetically controlled pathogenic mechanisms in the model of MS, experimental autoimmune encephalomyelitis (EAE), and to translate findings from experimental models to human disease.

We demonstrated that genetic risk factors and pathogenic mechanisms in EAE are similar to those of MS. The EAE-susceptible strain had increased expression of MS candidate genes Il2ra and Il7r among others and upregulation of MS-associated immunological pathways such as TH1 and TH17. Expression of Il18r1 was increased in both the susceptible strain and in periphery and cerebrospinal fluid of MS patients. This might contribute pathogenically to disease through T cell differentiation and activation. Clinically isolated syndrome (CIS) patients had elevated IL18R1 expression, thus it could potentially serve as an early disease biomarker.

Using an expression quantitative trait loci (eQTL) approach we detected numerous cis-regulated positional candidate genes for EAE and defined several disease correlated gene networks enriched for pathways involved in cell-mediated immune mechanisms of relevance for both EAE and MS. Mfsd4 was identified as a candidate gene for Eae34 which conferred a functional effect on T cell proliferation and activation. The importance of autophagy related genes in the pathogenesis of neuroinflammation was investigated. Atg7 expression was higher in the EAE-resistant strain and in MS patients it associated with remission and less severe symptoms.

Results presented in this thesis collectively demonstrate genetic regulation of known and novel mechanisms in EAE and MS and point to causal pathogenic

List of scientific papers

I. Melanie Thessen Hedreul, Alan Gillett, Tomas Olsson, Maja Jagodic and Robert A. Harris. Characterization of Multiple Sclerosis candidate gene expression kinetics in rat experimental autoimmune encephalomyelitis. Journal of Neuroimmunology. 2009;210(1-2):30-9.
https://doi.org/10.1016/j.jneuroim.2009.02.010

II. Alan Gillett, Melanie Thessen Hedreul, Mohsen Khademi, Alexander Espinosa, Amennai Daniel Beyeen, Maja Jagodic, Ingrid Kockum, Robert A. Harris and Tomas Olsson. Interleukin 18 Receptor 1 expression distinguishes patients with multiple sclerosis. Multiple Sclerosis. 2010;16(9):1056-65.
https://doi.org/10.1177/1352458510364634

III. Melanie Thessen Hedreul, Steffen Möller, Pernilla Stridh, Rasmus Berglund, Andre Ortlieb Guerreiro-Cacais, Ann-Kristin Grimm, Yask Gupta, Johan Öckinger, Alan Gillett, Amennai Daniel Beyeen, Margarita Diez, Tomas Olsson and Maja Jagodic. Genome-wide expression profiling in experimental autoimmune encephalomyelitis highlights a gene network enriched for T cell functions and Mfsd4 as a candidate gene regulating autoimmunity. [Submitted]

IV. Melanie Thessen Hedreul, Rasmus Berglund, Jenny Link, Roham Parsa, Juliane Becher, Petra Bergman, Mohsen Khademi, Francesco Cecconi, Jan Hillert, Ingrid Kockum, Maja Jagodic and Tomas Olsson. Expression of the autophagy related gene Atg7 is genetically regulated in experimental autoimmune encephalomyelitis and altered in patients with multiple sclerosis. [Manuscript]