Impact of the B Cell Growth Factor APRIL on the Qualitative and Immunological Characteristics of Atherosclerotic Plaques

PLoS One. 2016 Nov 7;11(11):e0164690. doi: 10.1371/journal.pone.0164690. eCollection 2016.


Studies on the role of B lymphocytes in atherosclerosis development, have yielded contradictory results. Whereas B lymphocyte-deficiency aggravates atherosclerosis in mice; depletion of mature B lymphocytes reduces atherosclerosis. These observations led to the notion that distinct B lymphocyte subsets have different roles. B1a lymphocytes exert an atheroprotective effect, which has been attributed to secretion of IgM, which can be deposited in atherosclerotic lesions thereby reducing necrotic core formation. Tumor necrosis factor (TNF)-family member 'A Proliferation-Inducing Ligand' (APRIL, also known as TNFSF13) was previously shown to increase serum IgM levels in a murine model. In this study, we investigated the effect of APRIL overexpression on advanced lesion formation and composition, IgM production and B cell phenotype. We crossed APRIL transgenic (APRIL-Tg) mice with ApoE knockout (ApoE-/-) mice. After a 12-week Western Type Diet, ApoE-/-APRIL-Tg mice and ApoE-/- littermates showed similar increases in body weight and lipid levels. Histologic evaluation showed no differences in lesion size, stage or necrotic area. However, smooth muscle cell (α-actin stain) content was increased in ApoE-/-APRIL-Tg mice, implying more stable lesions. In addition, increases in both plaque IgM deposition and plasma IgM levels were found in ApoE-/-APRIL-Tg mice compared with ApoE-/- mice. Flow cytometry revealed a concomitant increase in peritoneal B1a lymphocytes in ApoE-/-APRIL-Tg mice. This study shows that ApoE-/-APRIL-Tg mice have increased oxLDL-specific serum IgM levels, potentially mediated via an increase in B1a lymphocytes. Although no differences in lesion size were found, transgenic ApoE-/-APRIL-Tg mice do show potential plaque stabilizing features in advanced atherosclerotic lesions.

MeSH terms

  • Animals
  • Cell Count
  • Ectopic Gene Expression
  • Humans
  • Immunoglobulin M / blood
  • Mice
  • Myocytes, Smooth Muscle / pathology
  • Peritoneum / immunology
  • Plaque, Atherosclerotic / blood
  • Plaque, Atherosclerotic / immunology*
  • Plaque, Atherosclerotic / metabolism*
  • Plaque, Atherosclerotic / pathology
  • T-Lymphocytes / cytology
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism*


  • Immunoglobulin M
  • Tumor Necrosis Factor Ligand Superfamily Member 13

Grant support

This research is supported by The Netherlands Heart Foundation (CVON 2011/ B019: Generating the best evidence-based pharmaceutical targets for atherosclerosis (GENIUS).