Immune Tolerance to Myelin Proteins

Abstract

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. It is believed to be an autoimmune disease arising from a breakdown of immune tolerance in T cells specific for myelin antigens. The heterogeneity in clinical signs and pathology observed in MS patients suggests a complex pathogenesis in which the specificity of the pathogenic T cells and the tolerance mechanisms that are compromised vary among individual patients. In this review, we summarize some of the features of the diverse immune pathology observed in MS and the animal models used to study this disease. We then describe the current state of knowledge regarding the expression of the major myelin protein antigens believed to be targeted in MS and the mechanisms of immune tolerance that operate on T cells that recognize these antigens.

5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

“…The Th1 CD4 ϩ T cells reactive to myelin produce the proinflammatory cytokines (IFN-␥ and TNF-␣) that are crucial in orchestrating an immunopathological cascade, mediating the damage to the myelin sheath and eventually the axon (4,34,35). In this study, we present data showing AICAR as a novel immunomodulatory agent with beneficial effects on EAE disease.…”

“…The etiology of MS remains unknown, but the composition of plaques, immunogenetic background response to immunomodulation, and data from animal models suggest that it is an autoimmune disease mediated by myelin-specific CD4 ϩ and CD8 ϩ T cells (3,4). Already, chemotherapy using immunosuppressive drugs such as mitoxanthrone and cyclophosphamide or immunotherapy using immunomodulatory drugs such as IFN-␤, glatiramer acetate, and statins are being used or are in clinical studies for the treatment of MS (5)(6)(7).…”

Coronin 1-Mediated Naive T Cell Survival Is Essential for the Development of Autoimmune Encephalomyelitis

“…34). It is believed that those autoreactive T cells are present in the peripheral naive T cell pool in a state of ignorance (35). However, under certain circumstances, these cells can become activated and differentiate into effector T cells that then acquire access to the CNS.…”

Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs

“…We therefore hypothesized that one approach to the induction of peripheral control of autoreactive lymphocytes is the ectopic expression of autoantigen in the liver. To test our hypothesis, we used an animal model for the human neuroinflammatory disease multiple sclerosis, EAE, which is marked by CD4 + T cell-mediated inflammation of the central nervous system and ascending paralysis (21,22). EAE was induced in susceptible B10.PL mice by autoimmunization to myelin basic protein (MBP) (21,22).…”

“…To test our hypothesis, we used an animal model for the human neuroinflammatory disease multiple sclerosis, EAE, which is marked by CD4 + T cell-mediated inflammation of the central nervous system and ascending paralysis (21,22). EAE was induced in susceptible B10.PL mice by autoimmunization to myelin basic protein (MBP) (21,22). In B10.PL mice, which carry the H-2 u MHC haplotype, the encephalitogenic epitope of MBP is the aminoterminal acetylated nonameric peptide Ac1-9.…”