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    • Atherosclerosis the main pathological entity that leads to c

    2018-11-14

    Atherosclerosis, the main pathological entity that leads to cardiovascular events, is a chronic inflammatory disease in which the innate and adaptive immune systems can play pathological or protective roles, depending on context (Hansson and Libby, 2006). Although total serum immunoglobulins (Igs) are not normally considered as relevant to clinical CV disease, there is abundant evidence in the preclinical literature to suggest links with atherosclerosis. Our group established that mice deficient in IgM develop marked acceleration of atherosclerosis (Lewis et al., 2009). Moreover, passive immunization of mice with polyclonal IgM or IgG, or adoptive transfer of IgM-secreting B-1 cells, retards atherosclerosis progression (Nicoletti et al., 1998; Yuan et al., 2003; Kyaw et al., 2011; Cesena et al., 2012; Rosenfeld et al., 2015). On the other hand, depletion of IgG-secreting B cells reduces atherosclerosis and their adoptive transfer accelerates it (Ait-Oufella et al., 2010; Kyaw et al., 2010). Whilst the weight of evidence favors IgM being protective, there is still uncertainty as to how IgG purchase Flavopiridol hydrochloride influence atherosclerosis, in view of the pathogenic potential of IgG Fc-mediated pro-inflammatory effector functions. A previous study found that serum IgG but not IgM was associated with a higher risk of myocardial infarction in dyslipidemic patients (Kovanen et al., 1998), whilst another failed to show any association between IgG or IgM and risk of myocardial infarction in a general population (Muscari et al., 1995). However, the roles of specific antibodies as biomarkers in atherosclerosis have been more extensively studied. These include antibodies directed against epitopes induced by oxidative modifications of low-density lipoprotein (LDL), in particular antibodies reacting with phosphorylcholine or adducted malondialdehyde (MDA), as well as many less well-defined epitopes (Leibundgut et al., 2013; Tsiantoulas et al., 2014). In the Bruneck study, IgG antibodies against copper-oxidized LDL (heavily-oxidized LDL that includes MDA-LDL epitopes) were associated with higher risk of CV events, whilst IgM antibodies were associated with lower risk (Rosenfeld et al., 1990; Tsimikas et al., 2012). In contrast, the EPIC Norfolk study implicated IgG and IgM anti-MDA-LDL antibodies as possible modifiers of the risk associated with oxidative biomarkers, rather than independent predictors of coronary artery disease events (Ravandi et al., 2011). Recently, a study from Sweden has reported that individuals with low levels of antibodies against MDA-adducted LDL peptides are associated with significantly higher coronary acute event rate (Bjorkbacka et al., 2016). The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was an independent, investigator-led, multicenter, randomized trial designed to compare two anti-hypertensive treatment strategies for the prevention of CV events in more than 19,000 hypertensive patients without a clinical history of CHD. Using a nested case-control substudy of ASCOT, we set out to test the hypothesis that total serum IgM and IgG levels, as well as antibodies to MDA-LDL, are negative risk factors for cardiovascular events in a hypertensive population. Our analyses incorporated adjustments for levels of C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NtProBNP), which have previously been studied in the ASCOT population (Sever et al., 2012; Welsh et al., 2014).
    Material and Methods
    Results
    Discussion We postulate that the greater predictive power of total Ig levels reflects a broad role of the polyreactive antibody repertoire in cardiovascular protection. On the one hand, the composite antibody repertoire can be expected to contribute to the safe disposal of a variety of other endogenous atherogenic autoantigens besides modified LDL, including apoptotic cells and microparticles (Chang et al., 1999; Chou et al., 2009; Tsiantoulas et al., 2015). On the other hand, the conventional role of antibodies in preventing bacterial infection may also be important for reducing the rate of atherosclerosis progression and reducing infection-triggered acute cardiac events (Smeeth et al., 2004). In this light, the greater predictive capacity of the total IgG level compared to IgM argues for the importance of a robust adaptive immune response. Certainly the relative roles of genetic and environmental influences in setting Ig levels merits further study (Chen et al., 2011; Paavola et al., 2012), and in this light it is interesting that serum IgG and IgM levels in our study were significantly higher in women, consistent with previous observations (Gonzalez-Quintela et al., 2008).