Abstract | RATIONALE: 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)
|