B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis

Sam M. Rosenfeld, Heather M. Perry, Ayelet Gonen, Thomas A. Prohaska, Prasad Srikakulapu, Sukhdeep Grewal, Deepanjana Das, Chantel McSkimming, Angela M. Taylor, Sotirios Tsimikas, Timothy P. Bender, Joseph L. Witztum, Coleen A. McNamara

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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 BKO Apoe -/- ) 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 WT Apoe -/- 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.

Original languageEnglish (US)
Pages (from-to)e28-e39
JournalCirculation research
Volume117
Issue number3
DOIs
StatePublished - Jul 17 2015

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Immunoglobulin M
Atherosclerosis
Apolipoproteins E
Antibodies
Epitopes
LDL Lipoproteins
B-Lymphocytes
T Independent Antigens
Diet
B-Lymphocyte Subsets
T-Lymphocytes
Adoptive Transfer
Malondialdehyde
Knockout Mice
Single Nucleotide Polymorphism
Antigens

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Rosenfeld, S. M., Perry, H. M., Gonen, A., Prohaska, T. A., Srikakulapu, P., Grewal, S., ... McNamara, C. A. (2015). B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis. Circulation research, 117(3), e28-e39. https://doi.org/10.1161/CIRCRESAHA.117.306044

B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis. / Rosenfeld, Sam M.; Perry, Heather M.; Gonen, Ayelet; Prohaska, Thomas A.; Srikakulapu, Prasad; Grewal, Sukhdeep; Das, Deepanjana; McSkimming, Chantel; Taylor, Angela M.; Tsimikas, Sotirios; Bender, Timothy P.; Witztum, Joseph L.; McNamara, Coleen A.

In: Circulation research, Vol. 117, No. 3, 17.07.2015, p. e28-e39.

Research output: Contribution to journalArticle

Rosenfeld, SM, Perry, HM, Gonen, A, Prohaska, TA, Srikakulapu, P, Grewal, S, Das, D, McSkimming, C, Taylor, AM, Tsimikas, S, Bender, TP, Witztum, JL & McNamara, CA 2015, 'B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis', Circulation research, vol. 117, no. 3, pp. e28-e39. https://doi.org/10.1161/CIRCRESAHA.117.306044
Rosenfeld, Sam M. ; Perry, Heather M. ; Gonen, Ayelet ; Prohaska, Thomas A. ; Srikakulapu, Prasad ; Grewal, Sukhdeep ; Das, Deepanjana ; McSkimming, Chantel ; Taylor, Angela M. ; Tsimikas, Sotirios ; Bender, Timothy P. ; Witztum, Joseph L. ; McNamara, Coleen A. / B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis. In: Circulation research. 2015 ; Vol. 117, No. 3. pp. e28-e39.
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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 BKO Apoe -/- ) 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 WT Apoe -/- 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.",
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AU - Rosenfeld, Sam M.

AU - Perry, Heather M.

AU - Gonen, Ayelet

AU - Prohaska, Thomas A.

AU - Srikakulapu, Prasad

AU - Grewal, Sukhdeep

AU - Das, Deepanjana

AU - McSkimming, Chantel

AU - Taylor, Angela M.

AU - Tsimikas, Sotirios

AU - Bender, Timothy P.

AU - Witztum, Joseph L.

AU - McNamara, Coleen A.

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N2 - 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 BKO Apoe -/- ) 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 WT Apoe -/- 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.

AB - 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 BKO Apoe -/- ) 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 WT Apoe -/- 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.

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