B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis

A very simple question for your doctor. How do you create B-1b cells?
http://circres.ahajournals.org/content/117/3/e28.abstract?etoc

1. Sam M. Rosenfeld,
2. Heather M. Perry,
3. Ayelet Gonen,
4. Thomas A. Prohaska,
5. Prasad Srikakulapu,
6. Sukhdeep Grewal,
7. Deepanjana Das,
8. Chantel McSkimming,
9. Angela M. Taylor,
10. Sotirios Tsimikas,
11. Timothy P. Bender,
12. Joseph L. Witztum,
13. Coleen A. McNamara

+ Author Affiliations

1. From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.

1. Correspondence to Coleen A. McNamara, University of Virginia, PO Box 801394, 415 Lane Rd, Charlottesville, VA 22908. E-mail cam8c@virginia.edu

Abstract

Rationale: B cells contribute to atherosclerosis through subset-specific mechanisms. Whereas some controversy exists about the role of B-2 cells, B-1a cells are atheroprotective because of secretion of atheroprotective IgM antibodies independent of antigen. B-1b cells, a unique subset of B-1 cells that respond specifically to T-cell–independent antigens, have not been studied within the context of atherosclerosis.

Objective: To determine whether B-1b cells produce atheroprotective IgM antibodies and function to protect against diet-induced atherosclerosis.

Methods and Results: We demonstrate that B-1b cells are sufficient to produce IgM antibodies against oxidation-specific epitopes on low-density lipoprotein both in vitro and in vivo. In addition, we demonstrate that B-1b cells provide atheroprotection after adoptive transfer into B- and T-cell deficient (Rag1^−/−Apoe^−/−) hosts. We implicate inhibitor of differentiation 3 (Id3) in the regulation of B-1b cells as B-cell–specific Id3 knockout mice (Id3^BKOApoe^−/−) have increased numbers of B-1b cells systemically, increased titers of oxidation-specific epitope–reactive IgM antibodies, and significantly reduced diet-induced atherosclerosis when compared with Id3^WTApoe^−/− controls. Finally, we report that the presence of a homozygous single nucleotide polymorphism in ID3 in humans that attenuates Id3 function is associated with an increased percentage of circulating B-1 cells and anti–malondialdehyde-low-density lipoprotein IgM suggesting clinical relevance.

Conclusions: These results provide novel evidence that B-1b cells produce atheroprotective oxidation-specific epitope–reactive IgM antibodies and protect against atherosclerosis in mice and suggest that similar mechanisms may occur in humans.