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MOG transmembrane and cytoplasmic domains contain highly stimulatory T-cell epitopes in MS.

Varrin-Doyer M, Shetty A, Spencer CM, Schulze-Topphoff U, Weber MS, Bernard CC, Forsthuber T, Cree BA, Slavin AJ, Zamvil SS - Neurol Neuroimmunol Neuroinflamm (2014)

Bottom Line: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS.T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC.Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Program in Immunology (M.V.-D., A.S., C.M.S., U.S.-T., B.A.C.C., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia; Department of Immunology (T.F.), University of Texas at San Antonio; and Boehringer Ingelheim (A.J.S.), Ridgefield, CT.

ABSTRACT

Objective: Recently, we reported that the 218 amino acid murine full-length myelin oligodendrocyte glycoprotein (MOG) contains novel T-cell epitopes p119-132, p181-195, and p186-200, located within its transmembrane and cytoplasmic domains, and that p119-132 is its immunodominant encephalitogenic T-cell epitope in mice. Here, we investigated whether the corresponding human MOG sequences contain T-cell epitopes in patients with multiple sclerosis (MS) and healthy controls (HC).

Methods: Peripheral blood T cells from patients with MS and HC were examined for proliferation to MOG p119-130, p181-195, p186-200, and p35-55 by fluorescence-activated cell sorting analysis using carboxylfluorescein diacetate succinimidyl ester dilution assay. Intracellular production of proinflammatory cytokines was analyzed by flow cytometry.

Results: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS. T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC. Further, MOG p119-130-specific T cells exhibited Th17 polarization, suggesting this T-cell epitope may be relevant to MS pathogenesis.

Conclusions: Transmembrane and cytoplasmic MOG domains contain potent T-cell epitopes in MS. Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

No MeSH data available.


Related in: MedlinePlus

T cells from patients with multiple sclerosis recognize MOG p119-130 and are HLA-DR restricted(A) Peripheral blood mononuclear cells (PBMC) from 12 patients with multiple sclerosis (MS) and 12 healthy controls (HC) were examined by carboxylfluorescein diacetate succinimidyl ester (CFSE) dilution assay for proliferation to myelin oligodendrocyte glycoprotein (MOG) p35-55, p119-130, p181-195, and p186-200 (10 μg/mL) after 10 days of culture. CFSE was measured in CD3+CD4+ T cells by flow cytometry and quantified by cell division index (CDI). Horizontal lines indicate median values. (B) CFSE-labeled PBMC were cultured for 10 days in the presence of antigens alone or in combination with anti–HLA-DR, -anti–HLA-DQ, anti–-HLA-DP, or isotype control antibodies. T-cell proliferative responses were evaluated by analysis of CFSE dilution. *p < 0.05, **p < 0.01, Mann–Whitney U test.
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Figure 1: T cells from patients with multiple sclerosis recognize MOG p119-130 and are HLA-DR restricted(A) Peripheral blood mononuclear cells (PBMC) from 12 patients with multiple sclerosis (MS) and 12 healthy controls (HC) were examined by carboxylfluorescein diacetate succinimidyl ester (CFSE) dilution assay for proliferation to myelin oligodendrocyte glycoprotein (MOG) p35-55, p119-130, p181-195, and p186-200 (10 μg/mL) after 10 days of culture. CFSE was measured in CD3+CD4+ T cells by flow cytometry and quantified by cell division index (CDI). Horizontal lines indicate median values. (B) CFSE-labeled PBMC were cultured for 10 days in the presence of antigens alone or in combination with anti–HLA-DR, -anti–HLA-DQ, anti–-HLA-DP, or isotype control antibodies. T-cell proliferative responses were evaluated by analysis of CFSE dilution. *p < 0.05, **p < 0.01, Mann–Whitney U test.

Mentions: Peripheral blood CD4+ T cells from patients with MS and HC were examined for their capability to respond to human MOG peptides p119-130, p181-195, and p186-200. Proliferation was measured by CFSE dilution assay. As shown in figure 1A, CD4+ T cells from untreated patients with MS and HC proliferated in response to human MOG p119-130, p181-195, and p186-200 more strongly than to MOG p35-55. Further, T-cell proliferation to p119-130, p181-195, and p186-200 was significantly greater than to p35-55 (p = 0.0051, p = 0.0304, and p = 0.0007, respectively) in patients with MS. Proliferative responses to MOG p119-130 and p186-200 were most robust, and, in comparison, T cells from patients with MS proliferated significantly more to these determinants than T cells from HC. In contrast, no significant differences in proliferation to p181-195 were observed between patients with MS and HC.


MOG transmembrane and cytoplasmic domains contain highly stimulatory T-cell epitopes in MS.

Varrin-Doyer M, Shetty A, Spencer CM, Schulze-Topphoff U, Weber MS, Bernard CC, Forsthuber T, Cree BA, Slavin AJ, Zamvil SS - Neurol Neuroimmunol Neuroinflamm (2014)

T cells from patients with multiple sclerosis recognize MOG p119-130 and are HLA-DR restricted(A) Peripheral blood mononuclear cells (PBMC) from 12 patients with multiple sclerosis (MS) and 12 healthy controls (HC) were examined by carboxylfluorescein diacetate succinimidyl ester (CFSE) dilution assay for proliferation to myelin oligodendrocyte glycoprotein (MOG) p35-55, p119-130, p181-195, and p186-200 (10 μg/mL) after 10 days of culture. CFSE was measured in CD3+CD4+ T cells by flow cytometry and quantified by cell division index (CDI). Horizontal lines indicate median values. (B) CFSE-labeled PBMC were cultured for 10 days in the presence of antigens alone or in combination with anti–HLA-DR, -anti–HLA-DQ, anti–-HLA-DP, or isotype control antibodies. T-cell proliferative responses were evaluated by analysis of CFSE dilution. *p < 0.05, **p < 0.01, Mann–Whitney U test.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4202926&req=5

Figure 1: T cells from patients with multiple sclerosis recognize MOG p119-130 and are HLA-DR restricted(A) Peripheral blood mononuclear cells (PBMC) from 12 patients with multiple sclerosis (MS) and 12 healthy controls (HC) were examined by carboxylfluorescein diacetate succinimidyl ester (CFSE) dilution assay for proliferation to myelin oligodendrocyte glycoprotein (MOG) p35-55, p119-130, p181-195, and p186-200 (10 μg/mL) after 10 days of culture. CFSE was measured in CD3+CD4+ T cells by flow cytometry and quantified by cell division index (CDI). Horizontal lines indicate median values. (B) CFSE-labeled PBMC were cultured for 10 days in the presence of antigens alone or in combination with anti–HLA-DR, -anti–HLA-DQ, anti–-HLA-DP, or isotype control antibodies. T-cell proliferative responses were evaluated by analysis of CFSE dilution. *p < 0.05, **p < 0.01, Mann–Whitney U test.
Mentions: Peripheral blood CD4+ T cells from patients with MS and HC were examined for their capability to respond to human MOG peptides p119-130, p181-195, and p186-200. Proliferation was measured by CFSE dilution assay. As shown in figure 1A, CD4+ T cells from untreated patients with MS and HC proliferated in response to human MOG p119-130, p181-195, and p186-200 more strongly than to MOG p35-55. Further, T-cell proliferation to p119-130, p181-195, and p186-200 was significantly greater than to p35-55 (p = 0.0051, p = 0.0304, and p = 0.0007, respectively) in patients with MS. Proliferative responses to MOG p119-130 and p186-200 were most robust, and, in comparison, T cells from patients with MS proliferated significantly more to these determinants than T cells from HC. In contrast, no significant differences in proliferation to p181-195 were observed between patients with MS and HC.

Bottom Line: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS.T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC.Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Program in Immunology (M.V.-D., A.S., C.M.S., U.S.-T., B.A.C.C., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia; Department of Immunology (T.F.), University of Texas at San Antonio; and Boehringer Ingelheim (A.J.S.), Ridgefield, CT.

ABSTRACT

Objective: Recently, we reported that the 218 amino acid murine full-length myelin oligodendrocyte glycoprotein (MOG) contains novel T-cell epitopes p119-132, p181-195, and p186-200, located within its transmembrane and cytoplasmic domains, and that p119-132 is its immunodominant encephalitogenic T-cell epitope in mice. Here, we investigated whether the corresponding human MOG sequences contain T-cell epitopes in patients with multiple sclerosis (MS) and healthy controls (HC).

Methods: Peripheral blood T cells from patients with MS and HC were examined for proliferation to MOG p119-130, p181-195, p186-200, and p35-55 by fluorescence-activated cell sorting analysis using carboxylfluorescein diacetate succinimidyl ester dilution assay. Intracellular production of proinflammatory cytokines was analyzed by flow cytometry.

Results: MOG p119-130, p181-195, and p186-200 elicited significantly greater T-cell responses than p35-55 in patients with MS. T cells from patients with MS proliferated significantly more strongly to MOG p119-130 and p186-200 than did T cells from HC. Further, MOG p119-130-specific T cells exhibited Th17 polarization, suggesting this T-cell epitope may be relevant to MS pathogenesis.

Conclusions: Transmembrane and cytoplasmic MOG domains contain potent T-cell epitopes in MS. Recognition of these determinants is important when evaluating T-cell responses to MOG in MS and may have implications for development of myelin antigen-based therapeutics.

No MeSH data available.


Related in: MedlinePlus