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May 2020; 7 (3) ArticleOpen Access

Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS

Darius Häusler, Zivar Hajiyeva, Jan W. Traub, Scott S. Zamvil, Patrice H. Lalive, Wolfgang Brück, Martin S. Weber
First published March 17, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000698
Darius Häusler
From the Institute of Neuropathology (D.H., J.W.T., W.B., M.S.W.), University Medical Center; Department of Neurology (Z.H., J.W.T., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (S.S.Z.), University of California, San Francisco; Division of Neurology (P.H.L.), Department of Neurosciences, Hospital and University of Geneva; and Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, Geneva, Switzerland.
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Zivar Hajiyeva
From the Institute of Neuropathology (D.H., J.W.T., W.B., M.S.W.), University Medical Center; Department of Neurology (Z.H., J.W.T., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (S.S.Z.), University of California, San Francisco; Division of Neurology (P.H.L.), Department of Neurosciences, Hospital and University of Geneva; and Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, Geneva, Switzerland.
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Jan W. Traub
From the Institute of Neuropathology (D.H., J.W.T., W.B., M.S.W.), University Medical Center; Department of Neurology (Z.H., J.W.T., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (S.S.Z.), University of California, San Francisco; Division of Neurology (P.H.L.), Department of Neurosciences, Hospital and University of Geneva; and Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, Geneva, Switzerland.
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Scott S. Zamvil
From the Institute of Neuropathology (D.H., J.W.T., W.B., M.S.W.), University Medical Center; Department of Neurology (Z.H., J.W.T., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (S.S.Z.), University of California, San Francisco; Division of Neurology (P.H.L.), Department of Neurosciences, Hospital and University of Geneva; and Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, Geneva, Switzerland.
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Patrice H. Lalive
From the Institute of Neuropathology (D.H., J.W.T., W.B., M.S.W.), University Medical Center; Department of Neurology (Z.H., J.W.T., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (S.S.Z.), University of California, San Francisco; Division of Neurology (P.H.L.), Department of Neurosciences, Hospital and University of Geneva; and Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, Geneva, Switzerland.
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Wolfgang Brück
From the Institute of Neuropathology (D.H., J.W.T., W.B., M.S.W.), University Medical Center; Department of Neurology (Z.H., J.W.T., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (S.S.Z.), University of California, San Francisco; Division of Neurology (P.H.L.), Department of Neurosciences, Hospital and University of Geneva; and Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, Geneva, Switzerland.
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Martin S. Weber
From the Institute of Neuropathology (D.H., J.W.T., W.B., M.S.W.), University Medical Center; Department of Neurology (Z.H., J.W.T., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (S.S.Z.), University of California, San Francisco; Division of Neurology (P.H.L.), Department of Neurosciences, Hospital and University of Geneva; and Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, Geneva, Switzerland.
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Citation
Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS
Darius Häusler, Zivar Hajiyeva, Jan W. Traub, Scott S. Zamvil, Patrice H. Lalive, Wolfgang Brück, Martin S. Weber
Neurol Neuroimmunol Neuroinflamm May 2020, 7 (3) e698; DOI: 10.1212/NXI.0000000000000698

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    Figure 1 GA treatment alters the composition of leukocytes in patients with MS

    Peripheral blood samples were taken from control (n = 18) and glatiramer acetate–treated (GA; n = 20) patients with MS. (A) Leukocyte counts and (B) neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were measured in routine clinical laboratory blood counts if available (*p < 0.05; unpaired t test). Next, peripheral blood mononuclear cells (PBMCs) were isolated from the samples. (C) Cell frequencies of CD4+ T cells (TC), CD8+ TC, CD14+ monocytes (Mo), and CD19+ B cells (BC) were determined using flow cytometry (ns; unpaired t test). (D) CD4+, CD8+ TC, CD14+ Mo and BC of patients with MS at 2 time points during GA medication; line connects an individual patient (n = 5; *p < 0.05; Wilcoxon matched-pairs signed-rank test). (E and F) Fold changes of the horizontal and longitudinal cell frequency changes. GA = glatiramer acetate.

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    Figure 2 GA therapy changes the phenotype of human B cells in patients with MS

    Human peripheral blood mononuclear cells (PBMCs) were isolated from glatiramer acetate (GA; n = 20) or non-GA (control; n = 18) treated patients with MS. In addition, 6 patients were analyzed longitudinally on GA treatment. Red circles represent GA treatment, squares control treatment. (A) Mean frequency ± SEM of B-cell subpopulations defined as follows: transitional B cells (CD24high CD38high; transitional), mature B cells (CD24var CD38low; mature), antigen-activated B cells (CD27+; ag-activated), memory B cells (CD27var CD38−; memory), and plasmablasts (CD20− CD27+ CD38+; *p < 0.05; unpaired t test). (B) B-cell subset frequencies of patients with MS at 2 time points during GA therapy; line connects an individual patient (n = 6; *p < 0.05; Wilcoxon matched-pairs signed-rank test). (C) The individual patients' frequencies of BC subsets were correlated with the duration of GA treatment (*p < 0.05; linear regression). (D) MFI ± SEM of activation molecules expressed on B cells (ns; unpaired t test). (E) B-cell activation marker expression of patients with MS at 2 time points during GA therapy; line connects an individual patient (n = 6; *p < 0.05; Wilcoxon matched-pairs signed-rank test). (F) Mean MFI of molecules involved in antigen presentation expressed on B cells (*p < 0.05; unpaired t test). (G) Expression of molecules involved in antigen presentation of patients with MS at 2 time points during GA medication; line connects an individual patient (ns; Wilcoxon matched-pairs signed-rank test). (H) Shown is the frequency of positive cells regarding the respective cytokine (tumor necrosis factor [TNF], interleukin [IL]-6, and IL-10; mean ± SEM; ns; unpaired t test). (I) TNF, IL-6, and IL-10-positive B cells of patients with MS at 2 time points during GA medication; line connects an individual patient (*p < 0.05; Wilcoxon matched-pairs signed-rank test). GA = glatiramer acetate.

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    Figure 3 GA upregulates MHC Class II expression on B cells

    (A) Naive mice received a daily SC injection of 150 μg GA. On day 10 post-treatment onset, splenic B cells were isolated and analyzed (B and C) for expression of activation markers, (D–F) costimulatory molecules, and (G) the antigen-presenting molecule MHC Class II as well as (H) for secretion of cytokines. Data are shown as median; n = 4; *p < 0.05; Mann-Whitney U test. GA = glatiramer acetate.

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    Figure 4 GA prevents B-cell activation and ameliorates clinical severity of active EAE

    (A) GA therapy was performed by a daily SC injection of 150 μg, starting 7 days before MOG peptide35-55 immunization. Serum and splenic B cells were isolated on day 23 post-immunization. (B) Mean group EAE severity is given as mean ± SEM; disease incidence is indicated in brackets; n = 15; *p < 0.05; Mann-Whitney U test. (C) GA antibody titers were measured at 450 nm (data given as median; n = 3–4; ***p < 0.001; Student t test). (D) B-cell activation, expression of molecules involved in antigen presentation, and cytokine secretion were analyzed by FACS (data given as median; n = 5; *p < 0.05, **p < 0.01; Mann-Whitney U test). (E) B cells were cocultured with CFSE-labeled myelin-specific (2D2) naive T cells in the presence of 5, 25, or 100 μg/mL MOG peptide35-55. T-cell proliferation was evaluated by CFSE dilution and stratified by division frequency as follows: few divisions (1–2; black), intermediate divisions (3; medium gray), and many divisions (≥4; light gray). T-cell divisions are shown as mean ± SEM; n = 5; *p < 0.05; Mann-Whitney U test. Differentiation of myelin-specific naive T cells into (F) Treg cells (CD25+FoxP3+CD4+) or (G) Th1- (IFN-γ+CD4+) and Th17 cells (IL-17+CD4+) was analyzed by FACS (data given as median; n = 5). EAE = experimental autoimmune encephalomyelitis; GA = glatiramer acetate.

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    Figure 5 GA-treated B cells preferentially generate T regs, whereas development of proinflammatory T cells is diminished

    (A) Naive B cells purified from WT mice were incubated with 50 μg/mL GA or vehicle at 37°C for 3 hours. After washing, B cells were cocultured with CFSE-labeled myelin-specific (2D2) naive T cells in the presence of 5, 25, or 100 μg/mL MOG peptide35-55. (B) T-cell proliferation was evaluated by CFSE dilution and stratified by division frequency as follows: few divisions (1–2; black), intermediate divisions (3; medium gray), and many divisions (≥4; light gray). T-cell divisions are shown as mean ± SEM; n = 4; *p < 0.05; Mann-Whitney U test. Differentiation of myelin-specific naive T cells into (C) Treg cells (CD25+FoxP3+CD4+) or (D) Th1- (IFN-γ+CD4+) and (E) Th17 cells (IL-17+CD4+) was analyzed by FACS (data given as median; n = 4; *p < 0.05; Mann-Whitney U test). GA = glatiramer acetate.

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