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 (OSE) 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. The chemokine receptor CXCR4 has been implicated in human CVD and B cell homeostasis, yet the role of B-1 cell CXCR4 in regulating atheroprotective IgM levels and human CVD 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 N-additions and a greater frequency of unique CDR-H3 sequences compared to peritoneal (PerC) B-1a cells. Some CDR-H3 sequences were common to both compartments suggesting B-1a migration between compartments. Indeed, mature PerC B-1a cells migrated to BM in a CXCR4-dependent manner. Furthermore, BM production of anti-OSE IgM 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 bone marrow localization and plasma anti-OSE IgM, including IgM against malondialdehyde(MDA)-modified LDL. Finally, in a 50-subject human cohort, we find that CXCR4 expression on circulating human B-1 cells positively associates with plasma levels of anti-MDA-LDL IgM antibodies 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 anti-OSE IgM production. 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.