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Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL

Nature Medicine volume 9, pages 736–743 (2003)Cite this article

Abstract

During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr−/− mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.

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Figure 1: Pneumococcal immunization induces oxLDL-specific IgM.
Figure 2: ELISpot assay of frequencies of immunoglobulin-secreting cells (ISCs) in the spleens of the three groups of immunized mice.
Figure 3: First pneumococcal intervention study (24 weeks of atherogenic diet).
Figure 4: Second pneumococcal intervention study (16 weeks of atherogenic diet).
Figure 5: Plasma from pneumococcal-immunized mice inhibits oxLDL binding by macrophages.

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Acknowledgements

We thank A. Kesäniemi and M. Leinonen(University of Oulu, Finland) for provision of human samples and F. Casanada, D. Dwyer, J. Juliano, E. Miller, J. Pattison and M. Silvestre for technical assistance. This work was supported by National Institutes of Health grants HL56989 (SCOR in Molecular Medicine and Atherosclerosis), HL6946, HL57505, AI40305 and the UCSD Rheumatic Disease Core Center (P30 AR47360). C.J.B. was supported by a Ph.D. scholarship from the Boehringer Ingelheim Fonds and a scholarship from the Austrian Academy of Science; E.K. was a recipient of a summer undergraduate research fellowship from the medical scientist training program at UCSD and a student investigator grant from the Stein Institute for Research in Aging. The laboratories of G.J.S., W.P. and J.L.W. contributed equally to this work.

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  1. Christoph J Binder, Sohvi Hörkkö and Asheesh Dewan: These authors contributed equally to this work.

Authors and Affiliations

  1. Divisions of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0682, California, USA

    Christoph J Binder, Sohvi Hörkkö, Asheesh Dewan, Mi-Kyung Chang, Emily P Kieu, Peter X Shaw, Wulf Palinski & Joseph L Witztum

  2. Department of Medicine, Rheumatology, Allergy & Immunology, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0682, California, USA

    Carl S Goodyear & Gregg J Silverman

  3. Department of Internal Medicine and Biocenter Oulu, Kajaanintie 50, University of Oulu, Oulu, 90220, Finland

    Sohvi Hörkkö

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Correspondence to Joseph L Witztum.

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Binder, C., Hörkkö, S., Dewan, A. et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 9, 736–743 (2003). https://doi.org/10.1038/nm876

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