Effect of vitamin D supplementation on N-glycan branching and cellular immunophenotypes in MS

Priscilla Bäcker-Koduah, Carmen Infante-Duarte, Federico Ivaldi, Antonio Uccelli, Judith Bellmann-Strobl, Klaus-Dieter Wernecke, Michael Sy, Michael Demetriou, Jan Dörr, Friedemann Paul, Alexander Ulrich Brandt, Priscilla Bäcker-Koduah, Carmen Infante-Duarte, Federico Ivaldi, Antonio Uccelli, Judith Bellmann-Strobl, Klaus-Dieter Wernecke, Michael Sy, Michael Demetriou, Jan Dörr, Friedemann Paul, Alexander Ulrich Brandt

Abstract

Objective: To investigate the effect of cholecalciferol (vitamin D3) supplementation on peripheral immune cell frequency and N-glycan branching in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: Exploratory analysis of high-dose (20 400 IU) and low-dose (400 IU) vitamin D3 supplementation taken every other day of an 18-month randomized controlled clinical trial including 38 RRMS patients on stable immunomodulatory therapy (NCT01440062). We investigated cholecalciferol treatment effects on N-glycan branching using L-PHA stain (phaseolus vulgaris leukoagglutinin) at 6 months and frequencies of T-, B-, and NK-cell subpopulations at 12 months with flow cytometry.

Results: High-dose supplementation did not change CD3+ T cell subsets, CD19+ B cells subsets, and NK cells frequencies, except for CD8+ T regulatory cells, which were reduced in the low-dose arm compared to the high-dose arm at 12 months. High-dose supplementation decreased N-glycan branching on T and NK cells, measured as L-PHA mean fluorescence intensity (MFI). A reduction of N-glycan branching in B cells was not significant. In contrast, low-dose supplementation did not affect N-glycan branching. Changes in N-glycan branching did not correlate with cell frequencies.

Interpretation: Immunomodulatory effect of vitamin D may involve regulation of N-glycan branching in vivo. Vitamin D3 supplementation did at large not affect the frequencies of peripheral immune cells.

Conflict of interest statement

Priscilla Bäcker‐Koduah is a Junior scholar of the Einstein Foundation Berlin. Carmen Duarte‐Infante receives research support from Novartis and Sanofi‐Genzyme and travels support from Novartis. Federico Ivaldi reports no disclosures. Antonio Uccelli has received personal compensation from Novartis, TEVA, Biogen, Merck, Roche, and Genzyme for public speaking and advisory boards. Judith Bellmann‐Strobl received speaking fees and travel grants from Bayer Healthcare, Sanofi Aventis/Genzyme, Biogen and Teva Pharmaceuticals, unrelated to the present scientific work. Klaus‐Dieter Wernecke reports no disclosures. Michael Sy reports no disclosures. Michael Demetriou reports no disclosures. Jan Dörr received research support by Bayer and Novartis, Honoraria for Lectures and Advisory by Bayer, Biogen, Merck Serono, Sanofi‐Genzyme, Novartis, Roche; Travel support by Bayer, Novartis, Merck‐Serono, Biogen. Friedemann Paul served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi‐Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi‐Aventis/Genzyme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Pro‐gram, Arthur Arnstein Foundation Berlin, Guthy‐Jackson Charitable Foundation, and NMSS. Alexander Ulrich Brandt is co‐founder and shareholder of Motognosis GmbH and Nocturne GmbH. He is named as an inventor on several patent applications regarding MS serum biomarkers, OCT image analysis and perceptive visual computing.

© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Experimental design flowchart.
Figure 2
Figure 2
Immune cell frequencies expressed as percentage fold change at 12 months in B and NK cells (B/NK). The figure shows the gating strategy (A) and boxplot of the frequencies of immune cells ( percentage fold change) between high‐dose (blue) and low‐dose (gray) arms in; (B) CD19+ B cells+ (C) CD19+ CD24lowCD38low (B‐mature), (D) CD19+CD24highCD38low (B‐memory), (E) CD19+CD24highCD38high (B‐regulatory), (F) CD19+CD24highCD38‐(B‐memory atypical), (G) CD19+CD24‐CD38high (B‐plasma), (H) CD16+CD56low (CD56dim), and (I) CD16+CD56high (CD56bright). Nonparametric analysis of covariate (ANCOVA) with baseline as covariate (n = 29). Abbreviations: BL, baseline; V12, 12 months.
Figure 3
Figure 3
Immune cell frequencies expressed as percentage fold change at 12 months in T regulatory cells (Tregs). The figure shows the gating strategy (A) and boxplot of the frequencies of immune cells (percentage fold change) between high‐dose (blue) and low‐dose (gray) arms in; (B) CD3+ T cells (C) CD3+CD4+ T cells (T helper), (D) CD3+CD8+ T cells (T cytotoxic), (E) CD45RA+CD25low (naïve T regulatory), (F) CD3+CD8+CD28‐CD127‐ (CD8+ T regulatory), and (G) CD3+CD4+CD25+CD127‐ (CD4+ T regulatory). Nonparametric analysis of covariate (ANCOVA) with baseline as covariate (n = 29).
Figure 4
Figure 4
Immune cell frequencies expressed as percentage fold change at 12 months in T effector cells (Teff). Gating strategy (A) and boxplot of immune cell frequencies (percentage fold change) between high‐dose (blue) and low‐dose (gray) arms in; (B) CD3+CD4+CCR6+CD161+CXCR3‐CCR4+ (Th17), (C) CD3+CD4+CCR6‐CD161‐CXCR3+ (Th1), and (D) CD3+CD4+CCR6‐CD161+CXCR3+ (Th1 nonclassic). Nonparametric analysis of covariate (ANCOVA) with baseline as covariate (n = 29).
Figure 5
Figure 5
Immune cells L‐PHA MFI over different time points. Boxplots of L‐PHA MFI on immune cells expressed as percentage fold change in T, B, and NK cells. The change in MFI of L‐PHA was compared between baseline and 6 months in the high‐dose arm (blue) and the low‐dose arm (gray) in (A) CD3+ (P = 0.007), (B) CD4+ (P = 0.005), (C) CD8+ (P = 0.026) T cells, (D) CD19+ B cells (P = 0.178), (E) CD56bright (P = 0.020), and (F) CD56dim, (p = 0.028) NK cells. Nonparametric analysis of covariate (ANCOVA) with baseline as covariate (n = 38). Abbreviations: BL, baseline, V6, 6 months, V12, 12 months, V18, 18 months.
Figure 6
Figure 6
Correlational analyses at 6 months between L‐PHA MFI and serum 25(OH)D levels. Association of serum 25(OH)D levels in both arms with the L‐PHA MFI of (A) CD3+, (B) CD4+, (C) CD8+ T cells, (D) CD19+ B cells, (E) CD56dim, and (F) CD56bright NK cells. Spearman’s Rho (n = 38).
Figure 7
Figure 7
Correlational analyses at 6 months between L‐PHA MFI and the corresponding cell frequencies. The plot of L‐PHA MFI with the corresponding cell frequencies at 6 months in both arms, (A) CD3+, (B) CD4+, (C) CD8+ T cells, (D) CD19+ B cells, (E) CD56dim, and (F) CD56bright NK cells. Spearman’s Rho (n = 38).

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