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

Department of Medicine, UCSD, La Jolla, California 92093, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 05/2009; 119(5):1335-49. DOI: 10.1172/JCI36800
Source: PubMed


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.

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    • "T15 has also been shown to play an important role in first-line protection against lethal systemic pneumococcal infection in mice [9]. Furthermore, although mice reared in a germ-free environment produce IgM anti-PC antibodies at some stage during the postnatal period, their IgM anti-PC levels are lower compared with control mice [20]. We are not, however, aware of any data on anti-PC IgM levels of newborn mice. "
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    • "These include the alteration of the physical and chemical structure of target proteins causing oxidation of side-chain groups, protein scission, cross-linking, unfolding, and the formation of new reactive groups and thus followed by loss of protein function, resulting in cytotoxic by-products and/or protein aggregates, and may trigger the generation of cryptic and/or neoepitopes [9] [10] [11] [12]. The later has great implication on the role of OS and autoimmunity leading to B-and T-cell dysregulation and the generation of autoantibodies [13] [14] [15] [16]. This highlights the pleiotropic impact of OS on autoimmunity. "
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