Genetic regulation of, and autoimmunity in, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis and multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) with inflammation and plaques of demyelination. This thesis examines the genetic and immunological requirements or rat experiment autoimmune encephalomyelitis (EAE), an animal model of MS, to display both inflammatory and demyelinated CNS lesions with chronic and/or relapsing-remitting disease courses. Immunization of DA and LEW.AV 1 rats with the recombinant extracellular part (amino acids 1-125) of the minor myelin component myelin oligodendrocyte glycoprotein (rMOG) in adjuvant leads to the expansion of MOG-specific T cells and anti-MOG antibodies and focal CNS plaques of monocyte-macrophage and T cell infiltration, accompanied by demyelination.

Screening of a panel of major histocompatibility complex (MHC) congenic LEW rats with a constant immunization protocol revealed that the MHC haplotype determined the degree of disease susceptibility, the clinical course, the cellular composition of CNS lesions and the recruitment of MOG-specific T- and B-cells. Titration of the immunization protocol demonstrated that the MHC determined the threshold for disease induction, paralleled by the appearance of anti-MOG antibodies. Use of intra-MHC recombinant rats genetically mapped major MHC effects to the MHC class II. Non-MHC genes determined T cell effector functions and could abrogate disease in MHC RT.AV1 rats with PVG and ACI backgrounds. In a (DA x ACI) F2 intercross, microsatellite-based genome screening identified a locus on rat chromosome (RNO) 18 linked to demyelination. Regulating loci previously identified in experimental arthritis models were mapped to RNO 10 and 12.

MOG-peptide reactive effector lymphocytes were enumerated as interferon gamma (IFN[gamma])- secreting peripheral blood lymphocytes. MOG peptides 38-60, 63-87, 76-100, 89-113, 162-178 and 168-182 induced more (IFN[gamma] secreting lymphocytes than background levels of (IFN[gamma])- secreting lymphocytes in DR2(15)+ MS patients, but not in DR2(15)+ healthy controls. MOG peptide 63-87 induced a weak proliferative response in a subset of MS patients, which was blocked by anti-DQ/DR/DP antibodies. Higher numbers of spontaneously IFN[gamma] mRNA expressing CD4+ or CD8+ peripheral blood lymphocytes were detected by combined in situ hybridization - immunocytochemistry in another group of MS patients compared to healthy controls. Both CD4+ and CD8+ IFN[gamma] mRNA expressing cells were enriched in the cerebrospinal fluid as compared to the peripheral blood of MS patients.

In conclusion, there are activated CD4+ IFN[gamma]-producing blood and CSF lymphocytes in MS patients. Some of the lymphocytes are MOG-specific, recognizing several MOG epitopes. Depending on MHC haplotype and non-MHC genes, rMOG-immunization results in focal inflammation and demyelination in rats, imitating MS. Major MHC influences were genetically mapped to MHC class 11, while a non-MHC locus regulating demyelination was mapped to RNO 18.