Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis.

Abstract

RATIONALE:

B-1 cell-derived natural IgM antibodies against oxidation-specific epitopes on low-density lipoprotein are anti-inflammatory and atheroprotective. Bone marrow (BM) B-1a cells contribute abundantly to IgM production, yet the unique repertoire of IgM antibodies generated by BM B-1a and the factors maintaining the BM B-1a population remain unexplored. CXCR4 (C-X-C motif chemokine receptor 4) has been implicated in human cardiovascular disease and B-cell homeostasis, yet the role of B-1 cell CXCR4 in regulating atheroprotective IgM levels and human cardiovascular disease is unknown.

OBJECTIVE:

To characterize the BM B-1a IgM repertoire and to determine whether CXCR4 regulates B-1 production of atheroprotective IgM in mice and humans.

METHODS AND RESULTS:

Single-cell sequencing demonstrated that BM B-1a cells from aged ApoE-/- mice with established atherosclerosis express a unique repertoire of IgM antibodies containing increased nontemplate-encoded nucleotide additions and a greater frequency of unique heavy chain complementarity determining region 3 sequences compared with peritoneal cavity B-1a cells. Some complementarity determining region 3 sequences were common to both compartments suggesting B-1a migration between compartments. Indeed, mature peritoneal cavity B-1a cells migrated to BM in a CXCR4-dependent manner. Furthermore, BM IgM production and plasma IgM levels were reduced in ApoE-/- mice with B-cell-specific knockout of CXCR4, and overexpression of CXCR4 on B-1a cells increased BM localization and plasma IgM against oxidation specific epitopes, including IgM specific for malondialdehyde-modified LDL (low-density lipoprotein). Finally, in a 50-subject human cohort, we find that CXCR4 expression on circulating human B-1 cells positively associates with plasma levels of IgM antibodies specific for malondialdehyde-modified LDL and inversely associates with human coronary artery plaque burden and necrosis.

CONCLUSIONS:

These data provide the first report of a unique BM B-1a cell IgM repertoire and identifies CXCR4 expression as a critical factor selectively governing BM B-1a localization and production of IgM against oxidation specific epitopes. That CXCR4 expression on human B-1 cells was greater in humans with low coronary artery plaque burden suggests a potential targeted approach for immune modulation to limit atherosclerosis.

• Authors: Aditi Upadhye, Prasad Srikakulapu, Ayelet Gonen, Sabrina Hendrikx, Heather M Perry, Anh Nguyen, Chantel McSkimming, Melissa A Marshall, James C Garmey, Angela M Taylor, Timothy P Bender, Sotirios Tsimikas, Nichol E Holodick, Thomas L Rothstein, Joseph L Witztum, Coleen A McNamara
• Journal: Circulation research (Circ Res) Vol. 125 Issue 10 Pg. e55-e70 (10 25 2019) ISSN: 1524-4571 [Electronic] United States
• PMID: 31549940 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR4 protein, human
• Immunoglobulin M
• Receptors, CXCR4

Topics

• Animals
• B-Lymphocyte Subsets (metabolism)
• Bone Marrow Cells (metabolism)
• Coronary Artery Disease (blood, pathology)
• Humans
• Immunoglobulin M (blood)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Receptors, CXCR4 (biosynthesis, blood)