Itzhack Mendel

The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease.

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) characterized by primary demyelination, is believed to result from an autoimmune attack against myelin components. In view of their ability to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS, the quantitatively major myelin proteins — myelin basic protein (MBP) and proteolipid protein (PLP) — have been extensively studied as the relevant primary antigens in MS, and therapeutic approaches have been targeted to counteract autoimmune reactivity to MBP and PLP. Accordingly, copolymer 1, a random synthetic amino acid copolymer cross-reactive with MBP and highly protective against the induction of EAE with MBP or PLP, is now being extensively tested in clinical studies as a therapeutic agent for MS. However, increasing evidence suggests that autoimmune reactivity against other CNS-specific myelin proteins could also be involved in the pathogenesis of MS. In this context, we have demonstrated that peripheral blood lymphocytes from patients with MS respond predominantly to myelin oligodendrocyte glycoprotein (MOG) rather than to MBP or PLP, suggesting an important role for cell reactivity against MOG in the pathogenesis of MS. We have demonstrated that T-cell reactivity to MOG can also be pathogenic by inducing neurological disease in H-2u and H-2b mice with the same peptide of MOG, pMOG 35–55. Most interestingly, the expression of the disease differed with the different MHC backgrounds. Induction of a differentially expressed disease in different strains of mice with the same myelin antigen makes this new model particularly relevant to MS, where different expression of the disease is seen in different patients. Therefore, notwithstanding the importance of the autoimmune reactivity to MBP and PLP in MS, the potentially pathogenic autoimmune reactivity to MOG must now also be taken into consideration in therapeutic approaches to MS. In this context, we have investigated the possible effect of copolymer 1 treatment on autoimmune reactivity to MOG and on the development of EAE induced by MOG. Copolymer 1 was found to inhibit the binding of MOG peptides to MHC molecules, as well as the proliferation of MOG-reactive T cells, in a dose-dependent manner. In parallel, injection of copolymer 1 concomitantly with the encephalitogenic MOG peptide exerted a strong protective effect against the development of EAE. These preliminary data on the effect of copolymer 1 on the autoimmune response to MOG in mice indicate that copolymer 1 may also be effective in cases of MS where the autoimmune response to MOG prevails, and should therefore be further investigated in this context.

The central nervous sytem-specific myelin oligodendrocytic basic protein (MOBP) is encephalitogenic and a potential target antigen in multiple sclerosis (MS)

Uncovering primary target antigens in multiple sclerosis (MS) is of major significance for understanding the etiology and pathophysiology of the disease, and for designing immunospecific therapy. In this study, a synthetic peptide representing a predicted T cell epitope on myelin oligodendrocytic basic protein (MOBP) was found to be encephalitogenic in C3H.SW mice, inducing experimental autoimmune encephalomyelitis with an abrupt onset. Two separate preliminary studies with MOBP peptides indicated that autoreactivity to MOBP occurs in MS. These data strongly suggest that MOBP is a highly relevant target in MS and further point to the complexity of antigen specificities in MS.

The Myelin-Associated Oligodendrocytic Basic Protein Region MOBP15–36 Encompasses the Immunodominant Major Encephalitogenic Epitope(s) for SJL/J Mice and Predicted Epitope(s) for Multiple Sclerosis-Associated HLA-DRB1*1501

Autoimmune response to the myelin-associated oligodendrocytic basic protein (MOBP), a CNS-specific myelin constituent, was recently suggested to play a role in the pathogenesis of multiple sclerosis (MS). The pathogenic autoimmune response to MOBP and the associated pathology in the CNS have not yet been fully investigated. In this study, we have characterized the clinical manifestations, pathology, T cell epitope-specificity, and TCRs associated with experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with recombinant mouse MOBP (long isoform, 170 aa). Analysis of encephalitogenic MOBP-reactive T cells for reactivity to overlapping MOBP peptides defined MOBP15–36 as their major immunodominant epitope. Accordingly, MOBP15–36 was demonstrated to be the major encephalitogenic MOBP epitope for SJL/J mice, inducing severe/chronic clinical EAE associated with intense perivascular and parenchymal infiltrations, widespread demyelination, axonal loss, and remarkable optic neuritis. Molecular modeling of the interaction of I-As with MOBP15–36, together with analysis of the MOBP15–36-specific T cell response to truncated peptides, suggests MOBP20–28 as the core sequence for I-As-restricted recognition of the encephalitogenic region MOBP15–36. Although highly focused in their epitope specificity, the encephalitogenic MOBP-reactive T cells displayed a widespread usage of TCR Vβ genes. These results would therefore favor epitope-directed, rather than TCR-targeted, approaches to therapy of MOBP-associated pathogenic autoimmunity. Localization by molecular modeling of a potential HLA-DRB1*1501-associated MOBP epitope within the encephalitogenic MOBP15–36 sequence suggests the potential relevance of T cell reactivity against MOBP15–36 to MS. The reactivity to MOBP15–36 detected in MS shown here and in another study further emphasizes the potential significance of this epitope for MS.

Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): Prime role of MOG44F in selection and control of MOG-reactive T cells in H-2b mice

Myelin oligodendrocyte glycoprotein (MOG) is an important myelin target antigen, and MOG‐induced EAE is now a widely used model for multiple sclerosis. Clonal dissection revealed that MOG‐induced EAE in H‐2b mice is associated with activation of an unexpectedly large number of T cell clones reactive against the encephalitogenic epitope MOG35–55. These clones expressed extremely diverse TCR with no obvious CDR3α/CDR3β motif(s). Despite extensive TCR diversity, the cells required MOG40–48 as their common core epitope and shared MOG44F as their major TCR contact. Fine epitope‐specificity analysis with progressively truncated peptides suggested that the extensive TCR heterogeneity is mostly related to differential recognition of multiple overlapping epitopes nested within MOG37–52, each comprised of a MOG40–48 core flanked at the N‐ and/or the C‐terminus by a variable number of residues important for interaction with different TCR. Abrogation of both the encephalitogenic potential of MOG and T cell reactivity against MOG by a single mutation (MOG44F/MOG44A), together with effective down‐regulation of MOG‐induced EAE by MOG37–44A–52, confirmed in vivo the primary role for MOG44F in the selection/activation of MOG‐reactive T cells. We suggest that such a highly focused T cell autoreactivity could be a selective force that offsets the extensive TCR diversity to facilitate a more “centralized control” of pathogenic MOG‐related T cell autoimmunity.

Experimental autoimmune encephalomyelitis induced in B6.C-H-2bm12 mice by myelin oligodendrocyte glycoprotein: effect of MHC class II mutation on immunodominant epitope selection and fine epitope specificity of encephalitogenic T cells.

The effect of the bm12 mutation on susceptibility to MOG-induced EAE, TCR repertoire and fine epitope specificity of the encephalitogenic T-cells, was assessed. prMOG35-55 was encephalitogenic for H-2bm12 and H-2b mice. Despite only minor differences in TCRVbeta expression and fine epitope specificity, H-2bm12/ and H-2b/prMOG35-55-specific T-cells failed to recognize Ab/prMOG35-55 and Abm12/prMOG35-55, respectively. rhMOG-induced EAE was milder in H-2bm12 mice, possibly as a result of co-dominant responses to prMOG35-55 and to the non-encephalitogenic pMOG94-116, rather than a single dominant response to prMOG35-55 in H-2b mice.