Understanding progressive CNS autoimmunity using transgenic mouse models

Authors: Ignatius Arokia Doss, Prenitha Mercy
Advisor: Rangachari, Manu
Abstract: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) marked by neurodegeneration and accumulating disability over time. Over 100,000 people in Canada are affected by MS. Multiple factors could contribute to the worsening of the disease and yet the exact cause is still unknown. It is widely accepted that T and B lymphocytes cross the blood-brain barrier and invoke an inflammatory attack against CNS myelin. The role of T and B cells in CNS autoimmunity can be studied using an animal model called experimental autoimmune encephalomyelitis (EAE). In the first part of this thesis, I have used a transgenic mouse on a non-obese diabetic (NOD) background called 1C6 whose T cells possess specificity for a myelin-derived peptide, myelin oligodendrocyte glycoprotein 35-55 (MOG[35-55]). 1C6 CD4+ T cells from both male and female mice are differentiated into Th17 cells and are adoptively transferred into lymphocyte deficient NOD.Scid mice. Male 1C6 Th17 cells became highly pathogenic compared to the females and induced a severe progressive disease in the recipients. Th17 cells from both sexes exhibited phenotypic plasticity as measured by their expression of the classic Th1 cytokine IFN-©. However, male Th17 display increased production of IFN-© by male Th17 cells and this is correlated with disease severity in recipient mice. The use of four core genotype model has allowed us to segregate the effect of sex hormones and sex chromosomes in EAE. We uncovered an immune regulatory gene in the X chromosome called Jarid1c is found to be downregulated in both male Th17 cells that caused greater severity as well as in CD4+ T cells from the peripheral blood of men with MS. In the second part of the thesis, I utilized a transgenic mouse called IgH[MOG] on a NOD background whose B cells are specific for MOG protein. Upon immunization with MOG[35-55], IgH[MOG] mice displayed a rapid and lethal EAE, which is correlated to the inflammation and demyelination in the CNS of these mice. This is accompanied by the infiltration of B cells and T cells into the CNS. In IgH[MOG] mice, CNSinfiltrating CD4+ T cells became highly proinflammatory as measured by their production of IL-17 and GM-CSF in the CNS. Hence, our data provide insight into the contributions of Th17 T cell responses, male sex and B cells in chronic CNS autoimmunity. In the future, this work may permit us to identify targetable molecules and pathways for the treatment of MS.
Document Type: Thèse de doctorat
Issue Date: 2019
Open Access Date: 12 September 2019
Permalink: http://hdl.handle.net/20.500.11794/36448
Grantor: Université Laval
Collection:Thèses et mémoires

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