Oxidation‐specific epitopes are important targets of innate immunity

Abstract. During the oxidation of LDL, a central pathophysiological component of atherogenesis, a wide variety of chemical and physical changes occur leading to the generation of oxidation‐specific neoepitopes. These epitopes are not only immunogenic, leading to adaptive humoral responses, but are also a prominent target of multiple arcs of innate immunity. The pattern recognition receptors (PRRs) of innate immunity are germ line encoded, conserved by natural selection, and bind to pathogen‐associated molecular patterns (PAMPs) common on multiple structures. However, it is not intuitive as to why they should recognize oxidation‐specific neoepitopes. Yet it is clear that multiple macrophage scavenger receptors, which are classic PRRs, recognize oxidation‐specific epitopes, such as those found on oxidized LDL (OxLDL). Other innate proteins, such as C‐reactive protein, also bind to OxLDL. Natural antibodies (NAbs), the humoral arc of innate immunity, provide a nonredundant role in the first line of defence against pathogens, but are also believed to provide important homeostatic house‐keeping functions against self‐antigens. Our work demonstrates that oxidation‐specific epitopes, as found on OxLDL, are a major target of NAbs. In this review, we will discuss the specific example of the prototypic NAb T15/E06, which is increased in atherosclerotic mice and mediates atheroprotection, and discuss the potential role of NAbs in atherogenesis, and in inflammation in general. We also review data that oxidation‐specific epitopes are generated whenever cells undergo programmed cell death, forming a common set of PAMPs recognized by oxidation‐specific PRRs on macrophages, NAbs and innate proteins. We present the hypothesis that oxidation‐specific epitopes on apoptotic cells exerted evolutionary pressure for the conservation of these PRRs and also serve to maintain the expansion of a substantial proportion of NAbs directed to these stress‐induced self‐antigens.