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

Abstract

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.

HLA-DQB1*0602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice

“…Northern blot analysis, in situ hybridization, immunochemistry, and immunoelectron microscopy (16,17) indicated that MOBP is expressed exclusively in CNS white matter and more particularly throughout compact myelin, predominantly at the major dense lines of myelin (16). The encephalitogenic potential of MOBP was demonstrated in H-2 b (18) and H-2 s (19,20) mice, and two separate studies of proliferative response to MOBP peptides (pMOBP) by PBL from MS patients and controls indicated that MOBP65-87 was the region most frequently recognized by MS patients T cells (18). Another study indicated that PBL obtained from relapsing/remitting MS patients mount a proliferative response to human MOBP, especially at aa 21-39 (21).…”

Bispecificity for Myelin and Neuronal Self-Antigens Is a Common Feature of CD4 T Cells in C57BL/6 Mice

“…The binding ability of overlapping 9-aa segments of NF-M was estimated as the sum of scores for the four pockets. Previous calculations with this in-house computer program successfully predicted minimal core epitopes, all of which scored 25 or lower (46,54,55). Initial model structures of the I-A b peptide-binding domain in complex with 12-aa peptides that include the predicted core epitopes were constructed based on the experimental structure.…”

The inflammatory perspective of depression in the context of chronic medical conditions

“…Chronically active plaques present demyelination and axonal injury, with reactive astrocytes and immunoglobulin deposition [137]. At a cellular and molecular level, several studies have showed that T cells from MS patients are able to recognize different myelin protein targets, including myelin basic protein (MBP) [138,139], proteolipid protein (PLP) [140], myelin oligodendrocyte glycoprotein (MOG) [141]and myelin-associated oligodendrocyte basic protein (MOBP) [142]. These patients also present auto-reactive CD8+ T cell [143].…”