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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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 4

Oxidation-specific epitopes are dominant targets of NAbs.

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Oxidation-specific epitopes are dominant targets of NAbs. (A) Preabsorpt...
(A) Preabsorption of plasma from Rag1–/– + B-1 mice with oxidation-specific antigens shows that oxidation-specific epitopes (OxEpitopes) are dominant targets for NAbs. Plasmas from Rag1–/– + B-1 mice were preincubated in the absence or presence of the indicated antigens (250 μg/ml total antigen) overnight and antigen-immune complexes pelleted by centrifugation. Total IgM levels were then tested by ELISA. *P < 0.05, **P < 0.01, ***P < 0.002 compared with native LDL (ANOVA with Tukey-Kramer multiple comparisons test). Data are means (and SEM) from 5 separate experiments, each using 3–7 plasma samples obtained from 5 different transfer experiments, with each sample assayed in triplicate. (B) ELISpot assay of frequencies of MDA-LDL–specific ISCs in the spleens of wild-type C57BL/6, Rag1–/– + B-1, and Rag1–/– + PBS mice. Results are from individual mice, and data are from 3 separate B-1 cell transfer experiments. Horizontal bar represents the mean for the group. †P < 0.002 compared with Rag1–/– + PBS (unpaired t test). (C) B-1 cell–derived natural mAb NA-17. DNA sequences of VDJ splice sites of the VH and VL rearrangements expressed in NA-17 B-1 cell hybridoma and their relationship to the most homologous germline V, D, J gene segments. Sequence analysis of NA-17 VH rearrangement did not reveal nucleotide variation to germline genes. Sequence analysis of VL rearrangement revealed 1 nucleotide insertion between VL and JL germline gene segments.