Pathogenesis of myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in DBA/1 mice

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human autoimmune disease, multiple sclerosis (MS). MS is prevalent among the Caucasian population and linkage analysis studies have indicated that the presence of certain MHC class II genes can increase the risk of manifesting MS. Due to the limitations of MS patient materials, EAE has provided a tool for studying the mechanisms behind the initiation, progression and remission of MS and consequently providing information on how the immune system functions in MS.

In this study, myelin oligodendrocyte glycoprotein (MOG) was used with adjuvant to induce EAE in the DBA/ 1 mouse strain. We established DBA/ 1 (H2q) mice as highly susceptible to MOG-induced EAE after screening several different MHC class II congenic mice. In additon, we also established the mildest immunization protocol to date using less or even omitting adjuvant components such as Mycobacterium tuberculosis (MT) and pertussis toxin (PT).

Investigation of CD4 cell deficient mice (CD4-/-) and CD8 cell deficient mice (CD8-/-), as well as of wild type DBA/ 1 mice depleted of either CD4+ T cells or CD8+ T cells, highlighted the role of CD8+ T cells in MOG-induced EAE. Co-administration of PT appeared to alter EAE susceptibility by Increasing clinical severity when MOG peptide was used. Hence use of PT for the induction of EAE in mouse strains should be re-assessed as appropriate animal models of MS as the immunological mechanisms are skewed due to the action of PT.

The role of B cells was investigated using µMT and xid (lacking a B cell subpopulation) mice immunized with MOG. Both µMT and xid mice developed MOG-EAE but with decreased clinical severity as well as less demyelination in the CNS. It can therefore be concluded that B cells do not have a primary role in disease initiation, but contribute to severity of pathogenesis.

We next investigated the role of Fc receptors (FcRs), since FcRs link the cellular and the humoral branches of the immune system. FcR-gamma and Fc-gammaRII deficient mice were immunized with MOG. FcR-gamma deficient mice were protected from disease while Fc-gammaRII deficient mice had enhanced disease. Thus the role of FcRs in either enhancing or downregulating cell activation is an important mechanism in disease development.

This thesis presents the DBA/ 1 mouse strain as a new animal model of EAE. Using different gene-deleted mice on the DBA/ 1 background has identified the different roles of T cell subsets, B cells and FcRs in the pathogenesis of EAE. Clearly to provide an entire picture of how EAE is initiated, an overall view of the interactions within the immune system is required. Comprehending the mechanisms involved in EAE may provide further insight into the human disease, MS.