Immunogenetics and treatment of experimental autoimmune encephalomyelitis

Sammanfattning: Experimental autoimmune encephalomyelities (EAE) is a model of multiple sclerosis (MS). This experimental central nervous system (CNS) disease can be induced in rats by immunization with components of the CNS myelin sheath. EAE actively induced with myelin-basic-protein (MBP) is characterized by T cell infiltration of the CNS and typically leads to a monophasic disease course in Lewis (LEW) rats. We showed that in LEW rats MBP and MBP peptide immunizations result in preferential recruitment of TCRBV8S2+ T cells. This preferential T cell receptor (TCR) recruitment has its source in a multistep molecular mimicry event and is strictly dependent on the MHC and heterologous antigen. We used this model to assess the therapeutical potential of vaccination with naked DNA. Vaccination with DNA encoding the dominant T cell epitope MBPGP63-88 can suppress disease. Myelin oligodendrocyte glycoprotein (MOG) is a minor component of the myelin sheath. Unlike MBP which is hidden in the myelin sheath, MOG is exposed on its surface and is therefore easy accessible for antibody binding. Active immunization with the extracellular part of MOG (rMOG aa1-125) leads to different CNS specific immune effector mechanisms compared to MBP. While immunization with MBP results in purely inflammatory, monophasic disease, use of MOG cae result in a demyelinating chronic disease. We analyzed the influence of the major histocompatibility complex (MHC) haplotype on disease, pathology of CNS lesions and immune responses in this new model. The MHC haplotype does not exert an all or none effect on disease susceptibility but determines the degree of disease susceptibility, recruitment of MOG-specific immunocompetent cells, clinical course and CNS pathology in a hierarchical and allele-specific manner. The major regulatory region mapped to the MHC class II genes, but also MHC class I and class III or genes further downstream influenced disease. Moreover non-MHC genes could overcome MHC susceptibility effects. To understand the molecular basis for the observed strong MHC influences we systematically measured immunogenicity, encephalitogenicity and MHC class II peptide binding in different rat MHC haplotypes. Using overlapping synthetic peptides covering MOG 1-125 we found that immunodominance of T cell determinants was purely MHC class II dependent. Surprisingly, immunogenicity correlated only partly with encephalitogenicity. No disease ensued in resistant haplotypes despite the presence of immunogenic epitopes. In susceptible haplotypes the region between MOG 91-114 contained the main encephalitogenic determinants. Beside a T cell determinant MOG 91-108 also contains a linear B cell determinant, suggesting a role for B cell mediated immunity in encephalitogenicity. Binding patterns and the degree of promiscuity in peptide binding varied greatly between different haplotypes, with susceptible haplotypes showing higher promiscuity. MHC haplotype regulated peptide specific production of IFN-[gamma] did not correlate to MOG peptide encephalitogenicity. Such T cell responses can instead be argued to modulate disease, perhaps by influencing antigen presentation after induction of MHC expression in the periphery or in the CNS. In summary these studies demonstrate in two EAE models the dependence of MHC gene products, background genes and antigen on the clinical outcome, lesion development and immune responses. There is a high complexity of MHC driven T- and B cell determinant-selection, TCR shaping and tuning. Depending on the antigen, great differences in the molecular pathways that lead to disease manifestation come into action.