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IgA antibodies to phosphocholine associate with long-term cardiovascular disease risk

  • Jari Kankaanpää
    Affiliations
    Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, POB 5000, FI-90014, Finland

    Medical Research Center and Nordlab Oulu, University Hospital, University of Oulu, POB 5000, Oulu FI-90014, Finland
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  • Maritta Sämpi
    Affiliations
    Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, POB 5000, FI-90014, Finland
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  • Risto Bloigu
    Affiliations
    Medical Informatics and Statistics Research Group, University of Oulu, POB 5000, Oulu FI-90014, Finland
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  • Chunguang Wang
    Affiliations
    Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, POB 5000, FI-90014, Finland

    Medical Research Center and Nordlab Oulu, University Hospital, University of Oulu, POB 5000, Oulu FI-90014, Finland
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  • Ramin Akhi
    Affiliations
    Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, POB 5000, FI-90014, Finland

    Medical Research Center and Nordlab Oulu, University Hospital, University of Oulu, POB 5000, Oulu FI-90014, Finland
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  • Y. Antero Kesäniemi
    Affiliations
    Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, POB 5000, Oulu FI-90014, Finland
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  • Anne M. Remes
    Affiliations
    Medical Research Center and Nordlab Oulu, University Hospital, University of Oulu, POB 5000, Oulu FI-90014, Finland

    Institute of Clinical Medicine- Neurology, University of Eastern Finland, POB 1627, Kuopio FI-70211, Finland

    Department of Neurology, Kuopio University Hospital, POB 100, Kuopio FI-70029, Finland

    Research Unit of Clinical Neuroscience, University of Oulu, POB 5000, FI-90014, Finland
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  • Olavi Ukkola
    Affiliations
    Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, POB 5000, Oulu FI-90014, Finland
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  • Sohvi Hörkkö
    Correspondence
    Corresponding author. University of Oulu, POB 5000, 90014, Finland.
    Affiliations
    Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, POB 5000, FI-90014, Finland

    Medical Research Center and Nordlab Oulu, University Hospital, University of Oulu, POB 5000, Oulu FI-90014, Finland
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      Highlights

      • Antibodies to OxLDL modify the progression of atherosclerosis.
      • IgA class antibodies to OxLDL have received less interest.
      • IgA to phosphocholine increased the long-term risk of CVD.
      • This association was maintained regardless of known CVD risk factors.

      Abstract

      Background and aims

      Antibodies to phosphocholine and oxidized LDL (oxLDL) are proposed to modify progression of atherosclerosis. We investigated the prognostic value of antibodies to phosphocholine (PCho), Streptococcus pneumoniae cell wall polysaccharide (CWPS) and oxLDL in defining long-term CVD survival.

      Methods

      CVD incidence was followed for 18 years and analyzed with baseline plasma IgM, IgG and IgA antibody levels to PCho, CWPS and oxLDL in 1044 subjects of Oulu Project Elucidating Risk of Atherosclerosis study (OPERA).

      Results

      During the follow-up period, 195 subjects (18.7%) had a CVD event. Cox model with ACC/AHA CVD adjustments (ASCVD) showed that IgA levels to PCho and IgA to CWPS were statistically significant factors predicting CVD risk. IgM and IgG antibodies to PCho, CWPS and oxLDL had no effect on CVD risk after adjusting for other risk factors. Net reclassification improvement (categories: 17-year risk <15%, 15–30%, >30%), was 0.06 (−0.001–0.12, p < 0.054), and IDI was 0.0124 (0.0036–0.0211, p < 0.006) with IgA-PCho added to the ASCVD risk model. Seventeen (9.4%) study subjects with CVD events were correctly reclassified into higher risk category while 9 (5.0%) subjects were classified into lower risk category. Among the non-cases, 58 (8.7%) subjects were correctly reclassified into lower risk, and 46 (5.9%) were reclassified into higher risk category.

      Conclusions

      Plasma IgA antibodies to PCho and Streptococcus pneumoniae CWPS are significant predictors of long-term CVD risk. Additional studies on the role of IgA antibodies in atherogenesis and CVD are warranted.

      Keywords

      ABBREVIATIONS:

      CVD (cardiovascular disease), LDL (low-density lipoprotein), OxLDL (oxidized LDL), PCho (phosphocholine), CWPS (Streptococcus Pneumoniae cell wall polysaccharide), OPERA (Oulu Project Elucidating Risk of Atherosclerosis), ICD (International Classification of Diseases), CHD (coronary heart disease), MDA-LDL (malondialdehyde modified LDL), CuOx-LDL (copper oxidized LDL), IMT (intima media thickness), ASCVD (ACC/AHA atherosclerotic cardiovascular disease risk model), HDL (high density lipoprotein), hsCRP (high sensitivity CRP), IDI (integrated discrimination index), NRI (net reclassification improvement), MAA (malondialdehyde-acetaldehyde), PAF (platelet-activating factor)
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      References

        • Cooney M.T.
        • Dudina A.L.
        • Graham I.M.
        Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians.
        J. Am. Coll. Cardiol. 2009; 54: 1209-1227
        • Kolberg J.
        • Høiby E.A.
        • Jantzen E.
        Detection of the phosphorylcholine epitope in streptococci, Haemophilus and pathogenic Neisseriae by immunoblotting.
        Microb. Pathog. 1997; 22: 321-329
        • Potter M.
        Antigen-binding myeloma proteins in mice.
        Ann. N. Y. Acad. Sci. 1971; 190: 306-321
        • Grabitzki J.
        • Lochnit G.
        Immunomodulation by phosphocholine—biosynthesis, structures and immunological implications of parasitic PC-epitopes.
        Mol. Immunol. 2009; 47: 149-163
        • MacLeod C.M.
        • Hodges R.G.
        • Heidelberger M.
        • Bernhard W.G.
        Prevention of pneumococcal pneumonia by immunization with spesific capsular polysaccharides.
        J. Exp. Med. 1945; 82: 445-465
        • Friedman P.
        • Hörkkö S.
        • Steinberg D.
        • Witztum J.L.
        • Dennis E.A.
        Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids: importance of schiff base formation and aldol condensation.
        J. Biol. Chem. 2002; 277: 7010-7020
        • Frostegård J.
        Low level natural antibodies against phosphorylcholine: a novel risk marker and potential mechanism in atherosclerosis and cardiovascular disease.
        Clin. Immunol. 2010; 134: 47-54
        • Palinski W.
        • Hörkkö S.
        • Miller E.
        • et al.
        Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.
        J. Clin. Invest. 1996; 98: 800-814
        • Karvonen J.
        • Päivänsalo M.
        • Kesäniemi Y.A.
        • Hörkkö S.
        Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis.
        Circulation. 2003; 108: 2107-2112
        • Tsimikas S.
        • Willeit P.
        • Willeit J.
        • et al.
        Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.
        J. Am. Coll. Cardiol. 2012; 60: 2218-2229
        • Tsiantoulas D.
        • Diehl C.J.
        • Witztum J.L.
        • Binder C.J.
        B cells and humoral immunity in atherosclerosis.
        Circ. Res. 2014; 114: 1743-1756
        • Rantala A.O.
        • Kauma H.
        • Lilja M.
        • Savolainen M.J.
        • Reunanen A.
        • Kesäniemi Y.A.
        Prevalence of the metabolic syndrome in drug-treated hypertensive patients and control subjects.
        J. Intern Med. 1999; 245: 163-174
        • Pajunen P.
        • Jousilahti P.
        • Borodulin K.
        • Harald K.
        • Tuomilehto J.
        • Salomaa V.
        Body fat measured by a near-infrared interactance device as a predictor of cardiovascular events: the FINRISK'92 cohort.
        Obesity. 2011; 19: 848-852
        • Sämpi M.
        • Veneskoski M.
        • Ukkola O.
        • Kesäniemi Y.A.
        • Hörkkö S.
        High plasma immunoglobulin (Ig) A and low IgG antibody titers to oxidized low-density lipoprotein are associated with markers of glucose metabolism.
        J. Clin. Endocrinol. Metab. 2010; 95: 2467-2475
        • Goff D.C.
        • Lloyd-Jones D.
        • Bennett G.
        • et al.
        2013 ACC/AHA guideline on the assessment of cardiovascular risk.
        Circulation. 2014; 129: S49-S73
        • D'Agostino R.B.
        • Vasan R.S.
        • Pencina M.J.
        • et al.
        General cardiovascular risk profile for use in primary care: the Framingham heart study.
        Circulation. 2008; 117: 743-753
        • DeLong E.R.
        • DeLong D.M.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Pencina M.J.
        • D'Agostino R.B.
        • Steyerberg E.W.
        Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers.
        Stat. Med. 2011; 30: 11-21
        • Muscari A.
        • Bozzoli C.
        • Gerratana C.
        • et al.
        Association of serum IgA and C4 with severe atherosclerosis.
        Atherosclerosis. 1988; 74: 179-186
        • Kervinen H.
        • Huittinen T.
        • Vaarala O.
        • et al.
        Antibodies to human heat shock protein 60, hypertension and dyslipidemia. A study of joint effects on coronary risk.
        Atherosclerosis. 2003; 169: 339-344
        • Kovanen P.T.
        • Manttari M.
        • Palosuo T.
        • Manninen V.
        • Aho K.
        Prediction of myocardial infarction in dyslipidemic men by elevated levels of immunoglobulin classes A, E, and G, but not M.
        Arch. Intern Med. 1998; 158: 1434-1439
        • Anderson D.R.
        • Duryee M.J.
        • Shurmur S.W.
        • et al.
        Unique antibody responses to malondialdehyde-acetaldehyde (MAA)-Protein adducts predict coronary artery disease.
        PLoS One. 2014; 9: e107440
        • Fiskesund R.
        • Su J.
        • Bulatovic I.
        • Vikström M.
        • de Faire U.
        • Frostegård J.
        IgM phosphorylcholine antibodies inhibit cell death and constitute a strong protection marker for atherosclerosis development, particularly in combination with other auto-antibodies against modified LDL.
        Results Immunol. 2012; 2: 13-18
      1. Macpherson AJ, McCoy KD, Johansen F, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol. 0000;1:11–22.

        • Rodriguez-Segade S.
        • Camiña M.F.
        • Carnero A.
        • et al.
        High serum IgA concentrations in patients with diabetes mellitus: agewise distribution and relation to chronic complications.
        Clin. Chem. 1996; 42: 1064-1067
        • Gonzalez-Quintela A.
        • Alende R.
        • Gude F.
        • et al.
        Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities.
        Clin. Exp. Immunol. 2008; 151: 42-50
        • Miller A.M.
        • Xu D.
        • Asquith D.L.
        • et al.
        IL-33 reduces the development of atherosclerosis.
        J. Exp. Med. 2008; 205: 339-346
        • van Egmond M.
        • van Garderen E.
        • van Spriel A.B.
        • et al.
        FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity.
        Nat. Med. 2000; 6: 680-685
        • Wang Z.
        • Klipfell E.
        • Bennett B.J.
        • et al.
        Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
        Nature. 2011; 472: 57-63
        • Schenkein H.A.
        • Barbour S.E.
        • Berry C.R.
        • Kipps B.
        • Tew J.G.
        Invasion of human vascular endothelial cells by Actinobacillus actinomycetemcomitans via the receptor for platelet-activating factor.
        Infect. Immun. 2000; 68: 5416-5419
        • Chang M.
        • Bergmark C.
        • Laurila A.
        • et al.
        Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition.
        Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6353-6358
        • Fiskesund R.
        • Steen J.
        • Amara K.
        • et al.
        Naturally occurring human phosphorylcholine antibodies are predominantly products of affinity-matured B cells in the adult.
        J. Immunol. 2014; 192: 4551-4559
        • Schütz K.
        • Hughes R.G.
        • Parker A.
        • et al.
        Kinetics of IgM and IgA antibody response to 23-valent pneumococcal polysaccharide vaccination in healthy subjects.
        J. Clin. Immunol. 2012; 33: 288-296
        • Binder C.J.
        • Hörkkö S.
        • Dewan A.
        • et al.
        Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.
        Nat. Med. 2003; 9: 736-743
        • Ren S.
        • Newby D.
        • Li S.C.
        • et al.
        Effect of the adult pneumococcal polysaccharide vaccine on cardiovascular disease: a systematic review and meta-analysis.
        Open Heart. 2015; 2
        • Fedson D.S.
        Pneumococcal vaccination in the United States and 20 other developed countries, 1981–1996.
        Clin. Infect. Dis. 1998; 26: 1117-1123
        • Kerr K.F.
        • Wang Z.
        • Janes H.
        • McClelland R.L.
        • Psaty B.M.
        • Pepe M.S.
        Net reclassification indices for evaluating risk prediction instruments: a critical review.
        Epidemiology. 2014; 25