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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    ABSTRACT: Objective To determine levels of athero-protective IgM antibodies against phosphorylcholine in mothers and term-born normal or low birth weight infants. Approach Twenty three mother-infant pairs were studied, of whom 16 infants were within the normal weight range for gestational age (NGA; 3652[504] g) and 7 were small for gestational age (SGA; birth weight: 2715[255] g), the latter <2SD below the Swedish reference data mean for normal fetal growth. All infants were born at term (mean±SD 40.5±1.1 weeks). Serum was available from 6 mothers with SGA and 14 with NGA infants. Participating mothers were aged 34.0±3.9 years (no difference between groups). Fourteen neonates were boys and seven were girls. Levels of anti-PC IgM were determined by ELISA. Results Neonatal IgM anti-PC levels were low (undetectable in 8 infants out of which 3 were SGA) with a median of 76[range 0–2.51] U/ml. Maternal IgM anti-PC levels were significantly higher (median 7198[range: 25.32–656.0]) U/ml) and the proportion of mothers in highest quartile (>75th percentile) was larger in mothers of NGA-infants (43%) vs. those of SGA-infants (0%, p = 0.032). Conclusions IgM anti-PC levels are low at birth, which suggests that these antibodies do not play a “housekeeping” role in immune function during fetal life/development, but arise predominately on exposure to external antigens after birth. Furthermore, low maternal IgM anti-PC levels may play a role in placental insufficiency, contributing to poor fetal growth and a small-for-date baby. This preliminary observation may have implications for the future risk of atherosclerosis/cardiovascular disease development in pregnant women and their offspring.
    PLoS ONE 09/2014; 9(9):e106584. DOI:10.1371/journal.pone.0106584 · 3.23 Impact Factor
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    • "Levels of specific IgG and IgM directed against copper OxLDL and malondialdehyde-modified LDL (MDA-LDL) were determined in thawed plasma/serum from all study subjects by chemiluminescent enzyme-linked immunosorbent assay (ELISA) as previously described [26]. Briefly, microtiter plates were coated with OxLDL (5 mg/L) or MDA-LDL (5 mg/L) and the samples were added for one hour in dilutions of 1:200 (for IgG) or 1:100 (for IgM). "
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    ABSTRACT: Chronic HIV infection is associated with increased risk of cardiovascular disease caused by atherosclerosis. Oxidized forms of low-density lipoprotein (LDL) are present in atherosclerotic lesions and constitute major epitopes for natural antibodies. IgM has been shown to be protective against atherosclerosis, whereas the role of corresponding IgG is less clear. The objective of this study was to determine if HIV + individuals have disturbed levels of IgM and IgG directed against oxidized forms of LDL as compared to HIV- individuals. Ninety-one HIV + patients and 92 HIV- controls were included in this retrospective study. Circulating levels of IgG and IgM directed against two forms of oxidized LDL; copper oxidized (OxLDL) and malondialdehyde modified (MDA-LDL), total IgM and IgG, C-reactive protein (CRP), soluble CD14, and apolipoproteins A1 and B were determined. HIV + individuals had slightly lower levels of IgM against MDA-LDL and higher levels of IgG against MDA-LDL, OxLDL, and total IgG, than HIV- controls. Anti-MDA-LDL and Anti-OxLDL IgG displayed a positive correlation with viral load and a negative correlation with the CD4+ T-cell count. HIV + individuals also displayed elevated CRP and soluble CD14 levels compared to HIV- individuals, but there were no correlations between CRP or soluble CD14 and specific antibodies. HIV infection is associated with higher levels of IgG including specific IgG against oxidized forms of LDL, and lower IgM against the same epitope. In addition to dyslipidemia, immune activation, HIV-replication and an accumulation of risk factors for atherosclerosis, this adverse antibody profile may be of major importance for the increased risk of cardiovascular disease in HIV + individuals.
    BMC Infectious Diseases 03/2014; 14(1):143. DOI:10.1186/1471-2334-14-143 · 2.61 Impact Factor
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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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    ABSTRACT: As the involvement of oxidative stress (OS) in autoimmune thrombocytopenia (AITP) has been reported, a fast and rapid test for the reliable measurement of OS and antioxidant capacities (AOCs) might be a useful tool in extending current diagnostic possibilities. The free oxygen radical test (FORT) and free oxygen radical defence (FORD) assay (Callegari, Italy) are easy to perform and reliable, with results available within 15 minutes. Thirty-seven AITP patients and 37 matched healthy individuals were included in this study. All participants responded to a standard questionnaire provided by these assays. Female patients with AITP were observed to demonstrate significantly higher OS in comparison to female controls (P = 0.0027) and male AITP patients (P = 0.0018). The AOCs were not reduced in patients with AITP (P = 0.7648). Correlation of OS with platelet count identified a weak positive correlation (P = 0.0327, Spearman R = 0.4672). The questionnaire revealed that ITP patients in comparison to healthy controls are more stressed, feel exhausted and fatigued, and eat a healthier diet. In conclusion, OS is predominant in female but not in male patients with AITP suggesting gender-specific differences in the pathomechanisms of AITP. Identification of patients with high levels of OS might be beneficial in the management of AITP.
    Oxidative Medicine and Cellular Longevity 01/2014; 2014:720347. DOI:10.1155/2014/720347 · 3.36 Impact Factor
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