Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans
Meng-Yun Chou, … , Joseph L. Witztum, Christoph J. Binder
Meng-Yun Chou, … , Joseph L. Witztum, Christoph J. Binder
Published April 13, 2009
Citation Information: J Clin Invest. 2009;119(5):1335-1349. https://doi.org/10.1172/JCI36800.
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Research Article Cardiology

Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of oxidized lipoproteins and apoptotic cells. Adaptive immune responses to various oxidation-specific epitopes play an important role in atherogenesis. However, accumulating evidence suggests that these epitopes are also recognized by innate receptors, such as scavenger receptors on macrophages, and plasma proteins, such as C-reactive protein (CRP). Here, we provide multiple lines of evidence that oxidation-specific epitopes constitute a dominant, previously unrecognized target of natural Abs (NAbs) in both mice and humans. Using reconstituted mice expressing solely IgM NAbs, we have shown that approximately 30% of all NAbs bound to model oxidation-specific epitopes, as well as to atherosclerotic lesions and apoptotic cells. Because oxidative processes are ubiquitous, we hypothesized that these epitopes exert selective pressure to expand NAbs, which in turn play an important role in mediating homeostatic functions consequent to inflammation and cell death, as demonstrated by their ability to facilitate apoptotic cell clearance. These findings provide novel insights into the functions of NAbs in mediating host homeostasis and into their roles in health and diseases, such as chronic inflammatory diseases and atherosclerosis.

Authors

Meng-Yun Chou, Linda Fogelstrand, Karsten Hartvigsen, Lotte F. Hansen, Douglas Woelkers, Peter X. Shaw, Jeomil Choi, Thomas Perkmann, Fredrik Bäckhed, Yury I. Miller, Sohvi Hörkkö, Maripat Corr, Joseph L. Witztum, Christoph J. Binder

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Figure 3

Characterization of Rag1–/– recipients adoptively transferred with B-1 cells.

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Characterization of Rag1–/– recipients adoptively transferred with B-1 c...
(A) Adoptive transfer of B-1 cells into Rag1–/– mice replenishes B-1 cell population. Rag1–/– mice were injected with PBS (Rag1–/– + PBS) or with B-1 cells (Rag1–/– + B-1). Rag1–/– + PBS: Lymphocyte populations were absent in the peritoneal cavity (PEC, left). B-1 cells (IgM+CD43+) were also absent from the spleen (Spleen, left). C57BL/6: Peritoneal macrophages (CD11bhiCD5–) and T cells (CD11b–CD5hi) were intact (PEC, upper middle). B cells could be divided into B-1a (CD19+CD11bintCD5int), B-1b (CD19+CD11bintCD5–), and B-2 cells (CD19+CD11b–CD5–) (PEC, lower middle). In the spleen, B-1 cells were about 2.4% of total splenocytes (Spleen, middle). Rag1–/– + B-1: B-1 cell populations were reconstituted in the peritoneal cavity (PEC, lower right) and spleen (Spleen, right), without B-2 cell or T cell contamination (PEC, right). (B) IgM Abs to oxidation-specific epitopes are present in the plasma of B-1 reconstituted Rag1–/– mice. Plasma collected after 15 weeks from Rag1–/– + B-1 (n = 8) or Rag1–/– + PBS (n = 6) and age-matched C57BL/6 mice (n = 7) were tested. Data shown are from 1 transfer experiment representative of 6. Values are mean and SEM. Numbers in the upper-right corner represent the IgM titer to each antigen. (C) Natural IgM Abs produced in vivo show specificity to MDA-LDL and CuOx-LDL. Data are the mean of triplicate determinations, expressed as the ratio of IgM binding to MDA-LDL or CuOx-LDL in the presence or absence of competitor (B/B0). Data are from 1 experiment representative of 3.