1. Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis
- Author
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Upadhye, Aditi, Srikakulapu, Prasad, Gonen, Ayelet, Hendrikx, Sabrina, Perry, Heather M, Nguyen, Anh, McSkimming, Chantel, Marshall, Melissa A, Garmey, James C, Taylor, Angela M, Bender, Timothy P, Tsimikas, Sotirios, Holodick, Nichol E, Rothstein, Thomas L, Witztum, Joseph L, and McNamara, Coleen A
- Subjects
Prevention ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Atherosclerosis ,Immunization ,Vaccine Related (AIDS) ,Vaccine Related ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,B-Lymphocyte Subsets ,Bone Marrow Cells ,Coronary Artery Disease ,Humans ,Immunoglobulin M ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Receptors ,CXCR4 ,atherosclerosis ,bone marrow ,cardiovascular disease ,immunoglobulin M ,inflammation ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology - 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.
- Published
- 2019