IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors

Atherosclerosis. 2018 Jan:268:36-48. doi: 10.1016/j.atherosclerosis.2017.11.010. Epub 2017 Nov 16.

Abstract

Background and aims: IgM antibodies against phosphorylcholine (anti-PC) are negatively associated with atherosclerosis, cardiovascular disease (CVD) and systemic lupus erythematosus (SLE), where the risk of CVD and atherosclerosis is high. We here study the effects of IgM anti-PC immune regulation.

Methods: Mononuclear leukocytes were isolated from peripheral blood (PBMC) obtained from healthy blood donors, six SLE patients with age- and sex-matched controls, and symptom-giving human atherosclerotic plaques. The proportion of Th17 (CD4+CCR6+) and Treg (CD4+CD25+CD127dim/-) cells was determined by flow cytometry in CD4+T cells after 6 days of culture with Th17 or Treg-polarizing cytokines, with PMA and Ionomycin stimulation. IgM anti-PC were extracted from total IgM, with flow-through IgM as controls. Dendritic cells (DC) were differentiated from PBMC. Antibody peptide/protein characterization was done by a proteomics de novo sequencing approach.

Results: IgM anti-PC increased significantly the proportion of Tregs from healthy donors, SLE patients and atherosclerotic plaque cells while control antibodies did not. T cells from SLE patients had a significantly lower proportion of Tregs and a higher proportion of Th17 cells as compared to matched controls. IgM anti-PC, but not control antibodies, significantly reduced the production of IL-17 and TNF-α in cell cultures from SLE patients and atherosclerotic plaque cells. IgM anti-PC interacted with CD40 and kept DCs in an immature stage, potentially being tolerogenic. We observed differences in the IgM peptide expression levels in anti-PC compared to control antibodies.

Conclusions: IgM anti-PC promote polarization of Tregs, which could represent a novel protective mechanism in atherosclerosis and autoimmune conditions as SLE.

Keywords: Antibodies; Atherosclerosis; Autoimmunity; Phosphorylcholine; T regulatory cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis / immunology*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • Autoimmunity
  • Case-Control Studies
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Immune Tolerance
  • Immunoglobulin M / immunology*
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Lupus Erythematosus, Systemic / diagnosis
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / prevention & control
  • Lymphocyte Activation*
  • Male
  • Middle Aged
  • Phenotype
  • Phosphorylcholine / immunology*
  • Plaque, Atherosclerotic*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Immunoglobulin M
  • Interleukin-17
  • Tumor Necrosis Factor-alpha
  • Phosphorylcholine