The Human T Cell Response to Myelin Oligodendrocyte Glycoprotein: A Multiple Sclerosis Family-Based Study

Abstract

Myelin oligodendrocyte glycoprotein (MOG) is an encephalitogenic myelin protein and a likely autoantigen in human multiple sclerosis (MS). In this work, we describe the fine specificity and cytokine profile of T cell clones (TCC) directed against MOG in three nuclear families, comprised of four individuals affected with MS and their HLA-identical siblings. TCC were generated from PBMC by limiting dilution against a mixture of eleven 20-mer overlapping peptides corresponding to the encephalitogenic extracellular domain of human MOG (aa 1–120). The frequency of MOG peptide-reactive T cells was surprisingly high (range, 1:400 to 1:3,000) and, unexpectedly, cloning efficiencies were highest at low seeding densities of 102 or 103 PBMC per well. A total of 235 MOG peptide-reactive TCC were produced, all of which were CD4+CD8−TCRαβ+TCRγδ−. All 11 MOG peptides were recognized by the TCC, and different epitopes of MOG appeared to be immunodominant in the HLA-identical siblings. The patterns of cytokine secretion by TCC from single individuals were generally similar. The healthy individuals exhibited Th2-, Th0-, and T regulatory cell 1-like cytokine profiles, whereas TCC from one sibling with MS had a striking Th1-like phenotype, producing high levels of IFN-γ and TNF-α, and low IL-4 levels. Thus, MOG-reactive T cells appear to constitute an important part of the natural T cell repertoire, a finding that could contribute to the development of autoimmunity to this protein.

Structural insight into the role of myelin basic protein in multiple sclerosis

“…The results interpret prior studies with a mechanism of action. The results indicate that myelin disintegration may be initiated in the cytosolic space, as opposed to the external extracellular surface, although the cause and course of demyelination remain unknown and myelin degradation could be occurring at both surfaces of myelin (19). And, finally, the results support the hypothesis that myelin structure in MS is similar to immature myelin, resulting in altered myelin stability.…”

Interferon‐β therapy reduces CD4+ and CD8+ T‐cell reactivity in multiple sclerosis

“…18,28,51 Bielekova et al found a correlation between MBP-specific Th1 cells and a more destructive disease process as detected by magnetic resonance imaging of the CNS. 52 In contrast to these reports, other studies failed to detect significant differences in the percentage of T cells secreting IFN-c, IL-2 and tumour necrosis factor-a between MS patients and healthy controls; 49 however, the percentage of T cells producing IFN-c was significantly correlated with the EDSS scores in female MS patients.…”

“…[8][9][10] Based on the difficulties they had in establishing MOG-reactive T-cell clones from IFN-b-treated MS patients, Koehler et al concluded that therapy with IFN-b might reduce the number of antigenspecific CD4 + T cells in the periphery. 28 The suppressive effect on T cells might be the result of interference with costimulatory pathways, as IFN-b treatment reduces the elevated levels of CD80-induced IL-2 production observed in relapsing-remitting MS patients. 57 This is in line with observations that IFN-b up-regulates the CD80-related protein B7-H1 and tolerogenic HLA-G molecules on monocytes, which might thereby restore a state of peripheral tolerance.…”

“…11,28 In pilot experiments, no reduction in CFSE intensity was observed in the CD4 + and CD8 + T-cell populations after the addition of IL-2 in the absence of antigenic stimulation, indicating that IL-2 alone did not bias the experimental outcome (data not shown).…”

Mechanisms of Anti-Proliferative Effect Produced by Mesenchymal Stem Cells in Patients With Multiple Sclerosis

“…4). При этом установлена выраженная об-ратная корреляция между концентрацией PGЕ 2 в ко-культурах МПК и МСК при культивиро-вании с рМОГ [1][2][3][4][5][6][7][8][9][10][11][12] Т-лимфоцитов на-блюдались при культивировании МПК в присут-ствии или МСК, или супернатантов клеточных культур, полученных при совместном культиви-ровании МПК и МСК с соответствующей высо-кой концентрацией PGЕ 2 в супернатантах. В то же время добавление к МПК супернатантов от МСК с низкой пороговой концентрацией PGЕ 2 не при-водило к супрессии митоген-индуцированной пролиферации Т-клеточных субпопуляций.…”