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PMID: 20603314 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

B cell depletion reduces the development of atherosclerosis in mice.

The Journal of experimental medicine ·Vol. 207 ·No. 8 ·2010-08-02 ·Pages 1579-87

Ait-Oufella H, Herbin O, Bouaziz JD, Binder CJ, Uyttenhove C, Laurans L, Taleb S, Van Vré E, Esposito B, Vilar J, Sirvent J, Van Snick J, Tedgui A, Tedder TF, Mallat Z

Abstract

B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting that B cell-depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti-oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell-derived IFN-gamma secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody-mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation.

MeSH Terms
Animals Antibodies, Monoclonal/immunology,pharmacology Antigens, CD20/immunology Apolipoproteins E/genetics Atherosclerosis/immunology,pathology,prevention & control B-Lymphocytes/cytology,drug effects,immunology Cell Proliferation Cholesterol/blood Dendritic Cells/immunology Immunoglobulin G/blood,immunology Immunoglobulin M/blood,immunology Interferon-gamma/metabolism Interleukin-17/immunology,metabolism Lipoproteins, LDL/immunology Lymphocyte Activation/immunology Lymphocyte Depletion Male Mice Mice, Inbred C57BL Mice, Knockout Receptors, LDL/genetics Sinus of Valsalva/pathology T-Lymphocytes/immunology,metabolism,pathology
Chemicals
Antibodies, Monoclonal Antigens, CD20 Apolipoproteins E Immunoglobulin G Immunoglobulin M Interleukin-17 Lipoproteins, LDL Receptors, LDL oxidized low density lipoprotein Interferon-gamma Cholesterol
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Ait-Oufella Hafid
Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, 75015 Paris, France.
Herbin Olivier
Bouaziz Jean-David
Binder Christoph J
Uyttenhove Catherine
Laurans Ludivine
Taleb Soraya
Van Vré Emily
Esposito Bruno
Vilar José
Sirvent Jérôme
Van Snick Jacques
Tedgui Alain
Tedder Thomas F
Mallat Ziad
References (44)
44 references, click to expand
  1. The immune response in atherosclerosis: a double-edged sword.
    Nat Rev Immunol. 2006 Jul;6(7):508-19 PMID: 16778830
  2. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events.
    J Lipid Res. 2007 Feb;48(2):425-33 PMID: 17093289
  3. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.
    Nat Immunol. 2007 Dec;8(12):1390-7 PMID: 17994024
  4. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis.
    J Clin Invest. 2004 Aug;114(3):427-37 PMID: 15286809
  5. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state.
    J Exp Med. 2003 Sep 1;198(5):737-46 PMID: 12939344
  6. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy.
    J Exp Med. 2004 Jun 21;199(12):1659-69 PMID: 15210744
  7. The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice.
    J Immunol. 2005 Apr 1;174(7):4389-99 PMID: 15778404
  8. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice.
    Circulation. 2009 Aug 4;120(5):417-26 PMID: 19620499
  9. Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis.
    Circulation. 2003 Oct 28;108(17):2107-12 PMID: 14530200
  10. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.
    Immunity. 2008 May;28(5):639-50 PMID: 18482568
  11. A protective function for interleukin 17A in T cell-mediated intestinal inflammation.
    Nat Immunol. 2009 Jun;10(6):603-9 PMID: 19448631
  12. Splenic T zone development is B cell dependent.
    J Exp Med. 2001 Dec 3;194(11):1649-60 PMID: 11733579
  13. The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E-/- mice.
    J Clin Invest. 1997 Sep 15;100(6):1575-80 PMID: 9294126
  14. Cytokines in atherosclerosis: pathogenic and regulatory pathways.
    Physiol Rev. 2006 Apr;86(2):515-81 PMID: 16601268
  15. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.
    J Clin Invest. 1996 Aug 1;98(3):800-14 PMID: 8698873
  16. Fitness of cell-mediated immunity independent of repertoire diversity.
    J Immunol. 2007 Mar 1;178(5):2950-60 PMID: 17312140
  17. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4642-6 PMID: 9114044
  18. IL-33 reduces the development of atherosclerosis.
    J Exp Med. 2008 Feb 18;205(2):339-46 PMID: 18268038
  19. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum.
    Arterioscler Thromb. 1994 Apr;14(4):605-16 PMID: 7511933
  20. Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice.
    Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20878-83 PMID: 18093919
  21. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice.
    J Clin Invest. 1997 Jun 1;99(11):2752-61 PMID: 9169506
  22. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E.
    Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8264-8 PMID: 7667279
  23. B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation.
    J Exp Med. 2000 Aug 21;192(4):475-82 PMID: 10952717
  24. Anti-IL-17A autovaccination prevents clinical and histological manifestations of experimental autoimmune encephalomyelitis.
    Ann N Y Acad Sci. 2007 Sep;1110:330-6 PMID: 17911448
  25. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans.
    J Clin Invest. 2009 May;119(5):1335-49 PMID: 19363291
  26. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice.
    Arterioscler Thromb Vasc Biol. 2002 Nov 1;22(11):1892-8 PMID: 12426221
  27. Natural regulatory T cells control the development of atherosclerosis in mice.
    Nat Med. 2006 Feb;12(2):178-80 PMID: 16462800
  28. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice.
    J Clin Invest. 2002 Mar;109(6):745-53 PMID: 11901183
  29. Innate and acquired immunity in atherogenesis.
    Nat Med. 2002 Nov;8(11):1218-26 PMID: 12411948
  30. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses.
    Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1596-601 PMID: 15665085
  31. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice.
    J Immunol. 2008 Jan 1;180(1):361-71 PMID: 18097037
  32. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis.
    J Exp Med. 2009 Sep 28;206(10):2067-77 PMID: 19737863
  33. Prevalence and relation to risk factors of carotid atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome.
    Am J Cardiol. 2001 Mar 1;87(5):663-6, A11 PMID: 11230862
  34. Development of an anti-IL-17A auto-vaccine that prevents experimental auto-immune encephalomyelitis.
    Eur J Immunol. 2006 Nov;36(11):2868-74 PMID: 17048276
  35. B-Lymphocytes in plaque and adventitia of coronary arteries in two patients with rheumatoid arthritis and coronary atherosclerosis: preliminary observations.
    Cardiovasc Pathol. 2004 Jul-Aug;13(4):233-6 PMID: 15210141
  36. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice.
    Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2386-91 PMID: 16179593
  37. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.
    Nat Med. 2003 Jun;9(6):736-43 PMID: 12740573
  38. Fcgamma receptor deficiency confers protection against atherosclerosis in apolipoprotein E knockout mice.
    Circ Res. 2006 Nov 24;99(11):1188-96 PMID: 17053192
  39. Measurements of the true affinity constant in solution of antigen-antibody complexes by enzyme-linked immunosorbent assay.
    J Immunol Methods. 1985 Mar 18;77(2):305-19 PMID: 3981007
  40. B cell-dependent TCR diversification.
    J Immunol. 2004 Apr 15;172(8):4709-16 PMID: 15067046
  41. Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis.
    Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2691-8 PMID: 17690315
  42. Mouse CD20 expression and function.
    Int Immunol. 2004 Jan;16(1):119-29 PMID: 14688067
  43. Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice.
    Circulation. 2000 Dec 12;102(24):2919-22 PMID: 11113040
  44. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity.
    J Clin Invest. 2000 Jun;105(12):1731-40 PMID: 10862788
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20100155
Published
2010-08-02
Epub
2010-00-05
Pages
1579-87
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2916123
Subset
IM
Grants
NIAID NIH HHS · AI56363 · United States
NIAID NIH HHS · U19 AI056363 · United States
NCI NIH HHS · R01 CA105001 · United States
NIAID NIH HHS · U54 AI057157 · United States
NCI NIH HHS · CA105001 · United States
NIAID NIH HHS · AI057157 · United States
British Heart Foundation · RG/10/001/27643 · United Kingdom
External Links
PubMed source DOI: 10.1084/jem.20100155 PMC Full Text View journal details
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