High Immunogenicity of Intracellular Myelin Oligodendrocyte Glycoprotein Epitopes

Abstract

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS with associated axonal loss. There is strong evidence for an autoimmune pathogenesis driven by myelin-specific T cells. Myelin oligodendrocyte glycoprotein (MOG) induces a type of experimental autoimmune encephalomyelitis in animals which is very MS-like since there are demyelinating CNS lesions and axonal loss. This underscores the potential role of MOG in MS pathogenesis. We performed a T cell reactivity pattern analysis of MS patients at the onset of relapse or progression of neurological deficits and controls that were stratified for the genetic risk factor HLA-DRB1*1501. For the first time, we show that there is an HLA-DR-restricted promiscuous dominant epitope for CD4+ T cells within the transmembrane/intracellular part of MOG comprising aa 146–154 (FLCLQYRLR). Surprisingly, controls had broader T cell reactivity patterns toward MOG peptides compared with MS patients, and the transmembrane and intracellular parts of MOG were much more immunogenic compared with the extracellular part. Measurements of in vitro binding affinities revealed that HLA-DRB1*1501 molecules bound MOG 146–154 with intermediate and HLA-DRB1*0401 molecules with weak affinities. The binding of MOG 146–154 was comparable or better than myelin basic protein 85–99, which is the dominant myelin basic protein epitope in context with HLA-DRB1*1501 molecules in MS patients. This is the first study in which the data underscore the need to investigate the pathogenic or regulatory role of the transmembrane and intracellular part of MOG for MS in more detail.

A sequence variation in the MOG gene is involved in multiple sclerosis susceptibility in Italy

“…However more recent data show that the intracellular part of MOG is much more immunogenic than the extracellular part. 44 In particular, there is a dominant MOG epitope recognized by CD4 þ T cells within the intracellular part of MOG comprising amino acids immediately flanking the 142 residue. The reported experiments were performed only with the more frequent V142 sequence.…”

Differential Processing of Autoantigens in Lysosomes from Human Monocyte-Derived and Peripheral Blood Dendritic Cells

“…Human recombinant MOG was expressed as previously described (22). Briefly, the DNA sequence encoding the extracellular domain of mature human MOG (including four N-terminal amino acids of the transmembrane domain) was PCR amplified and subcloned into pQ60 (Qiagen).…”

A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis

“…As IFN-γ is still the most commonly measured Th1 cytokine (Hellings et al, 2001;Vergelli et al, 2001;Weissert et al, 2002) and has been shown to be involved in MS pathogenesis (Panitch et al, 1987;Woodroofe and Cuzner, 1993), we limited our results presented here to IFN-γ production by myelin-specific T cells. To avoid bias, analysis of the flow cytometrybased assay was performed without the evaluator knowing the patients' clinical status.…”