anti-PC Levels Research Articles

Antibodies against phosphorylcholine in prediction of cardiovascular disease among women: a population-based prospective cohort study

Abstract Background and aims Antibodies against phosphorylcholine (anti-PC) have been reported as associated with protection against atherosclerosis, cardiovascular disease (CVD) and other chronic inflammatory diseases. Underlying potential mechanisms have been demonstrated and include anti-inflammatory, clearance of dead cells and inhibition of oxidized low-density lipoprotein-effects. The aim is to study the role of IgM anti-PC and incident CVD among women, where less is known than among men in the general population. Methods In a total of 932 women, 66 ± 6 years old at baseline, from the population-based Swedish Mammography Cohort IgM anti-PC levels of sera were measured using ELISA. Prospective associations with any first CVD, ischemic heart disease (IHD), myocardial infarction (MI) and ischemic stroke were assessed using Cox proportional hazard regression, generating hazard ratios (HR) and 95% confidence intervals (CI). The model was adjusted for potential confounding factors. Results Over the course of 16 years (14,900 person-years), we identified 113 cases of composite CVD, - 69 cases of ischemic heart disease (IHD), 44 cases of myocardial infarction (MI) and 50 cases of ischemic stroke. IgM antiPC was statistically significantly inversely associated with risk of CVD, IHD and MI, but not with ischemic stroke. Comparing the highest tertile with lowest, we observed multivariable-adjusted HR of 0.26 (95% CI: 0.10–0.66; p-trend <0.01) for MI. Conclusions IgM anti-PC may play an active role in inhibition of CVD development in women, especially MI. Elevating anti-PC concentration through immunization, may be a future development in CVD prevention.

Antibodies against Phosphorylcholine-Implications for Chronic Inflammatory Diseases.

Atherosclerosis and its main consequence, cardiovascular disease (CVD) are nowadays regarded as chronic inflammatory disease conditions, and CVD is the main cause of death in the world. Other examples of chronic inflammation are rheumatic and other autoimmune conditions, but also diabetes, obesity, and even osteoarthritis among others. In addition, infectious diseases can have traits in common with these conditions. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, where atherosclerosis is increased and the risk of CVD is very high. This is a clinical problem but could also shed light on the role of the immune system in atherosclerosis and CVD. Underlying mechanisms are of major interest and these are only partially known. Phosphorylcholine (PC) is a small lipid-related antigen, which is both a danger associated molecular pattern (DAMP), and a pathogen associated molecular pattern (PAMP). Antibodies against PC are ubiquitous and 5-10% of circulating IgM is IgM anti-PC. Anti-PC, especially IgM and IgG1 anti-PC, has been associated with protection in the chronic inflammatory conditions mentioned above, and develops during the first years of life, while being present at very low levels at birth. Animal experiments with immunization to raise anti-PC ameliorate atherosclerosis and other chronic inflammatory conditions. Potential mechanisms include anti-inflammatory, immune modulatory, clearance of dead cells and protection against infectious agents. An intriguing possibility is to raise anti-PC levels through immunization, to prevent and/or ameliorate chronic inflammation.

Antibodies against phosphorylcholine in hospitalized versus non-hospitalized obese subjects

Obesity associates with reduced life expectancy, type 2 diabetes, hypertension and cardiovascular disease, and is characterized by chronic inflammation. Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein, dead cells and some microorganisms. Antibodies against PC (anti-PC) have anti-inflammatory properties. Here, we explored the role of anti-PC in hospitalized versus non-hospitalized obese. One-hundred-and-twenty-eight obese (BMI ≥ 30 kg/m2) individuals (59.8 (± 5.5) years, 53.9% women) from the Malmö Diet and Cancer Cardiovascular Cohort were examined and IgM, IgG1 and IgG2 anti-PC were analyzed by ELISA. Individuals with at least one recorded history of hospitalization prior to study baseline were considered hospitalized obese (HO). Associations between IgM, IgG1 and IgG2 anti-PC and HO (n = 32)/non-hospitalized obese (NHO) (n = 96), but also with metabolic syndrome and diabetes were analysed using logistic regressions. Both IgM and IgG1 anti-PC were inversely associated with HO, also after controlling for age and sex. When further adjusted for waist circumference, systolic blood pressure, glucose levels and smoking status, only IgG1 anti-PC remained significantly associated with HO. In multivariate models, each 1 standard deviation of increment in anti-PC IgG1 levels was inversely associated with prevalence of HO (odds ratio 0.57; CI 95% 0.33–0.98; p = 0.044). IgG2 anti-PC did not show any associations with HO. Low levels of IgM and IgG1 anti-PC are associated with higher risk of being a HO individual independent of sex and age, IgG1 anti-PC also independently of diabetes and metabolic syndrome. The anti-inflammatory properties of these antibodies may be related to inflammation in obesity and its complications.

IgG1 antibodies against phosphorylcholine are associated with protection in SLE and atherosclerosis: potential underlying mechanisms

Abstract Background The risk of cardiovascular disease (CVD) and atherosclerosis is very high in SLE. This is a clinical problem, and could also shed light on immunity and atherosclerosis in general. IgM antibodies against phosphorylcholine (anti-PC) may be protective in atherosclerosis, cardiovascular disease (CVD) and systemic lupus erythematosus (SLE). We here study IgG1 and IgG2 anti-PC, with focus on atherosclerosis and SLE. Methods We determined anti-PC by ELISA in 116 SLE-patients and 110 age- and sex-matched controls. For functional studies, we used three in-house generated, fully human monoclonal IgG1 anti-PC (A01, D05, E01). Apoptosis was induced in Jurkat T-cells and pre-incubated with A01, D05, E01 or isotype control IgG1 and effects on efferocytosis by human macrophages studied. Anti-PC peptide/protein characterization was determined using a proteomics de novo sequencing approach. Results IgG1 but not IgG2 anti-PC levels were higher among SLE patients (p=0.02). IgG1 anti-PC was negatively associated with SLICC and SLEDAI (OR: 2,978 CI: 0.876–10.098, OR: 5.108 CI 1.3 20.067 respectively) and negatively associated with CVD, atherosclerotic plaques and echolucent (potentially vulnerable plaques) but the association for the two former was not significant after controlling for confounders. D05 had maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC associated neo-epitopes. Peptide analysis showed difference in the CDR3 region of the three anti-PC IgG1 clones which are crucial for recognition of PC on apoptotic cell surface and other neo-epitopes. Conclusion Anti-PC IgG1 is negatively associated with disease activity, and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swedish Heart and Lung Foundation, Reumatikerfonden

Anti-protein C antibodies and acquired protein C resistance in SLE: novel markers for thromboembolic events and disease activity?

Risk factors for thromboembolism in SLE are poorly understood. We hypothesized a possible role for protein C, based on its dual activity in inflammation and haemostasis and on the evidence of an association between acquired activated protein C (APC) resistance (APCR) and high-avidity anti-protein C antibodies (anti-PC) with a severe thrombotic phenotype in venous thrombosis APS patients. In a cross-sectional study of 156 SLE patients, the presence and avidity of IgG anti-PC was established by in house-ELISA, and APCR to exogenous recombinant human APC (rhAPC) and Protac (which activates endogenous protein C) was assessed by thrombin generation-based assays. Associations with aPL profile, thrombotic history and disease activity (BILAG and SLEDAI-2K) were also established. Anti-PC were detected in 54.5% of patients and APCR in 59%. Anti-PC positivity was associated with APCR to both rhAPC (P<0.0001) and Protac (P=0.0001). High-avidity anti-PC, detected in 26.3% of SLE patients, were associated with APCR in patients with thrombosis only (P<0.05), and with the development of thrombosis over time (range: 0-52 years; P=0.014). High-avidity anti-PC levels correlated with SLEDAI-2K (P=0.033) and total BILAG (P=0.019); SLEDAI-2K correlated inversely with APCR to Protac (P=0.004). Anti-PC occur in patients with SLE, independently of aPL profile, and are associated with APCR. High-avidity anti-PC are associated with thrombosis and with active disease and might prove a novel marker to monitor the risk of thrombosis and disease progression in SLE.

Immunoglobulin G1 Antibodies Against Phosphorylcholine Are Associated With Protection in Systemic Lupus Erythematosus and Atherosclerosis: Potential Underlying Mechanisms.

ObjectiveImmunoglobulin M antibodies against phosphorylcholine (anti‐PCs) may be protective in atherosclerosis, cardiovascular disease (CVD), and systemic lupus erythematosus (SLE). We study immunoglobulin G1 (IgG1) and immunoglobulin G2 (IgG2) anti‐PCs, with a focus on atherosclerosis and SLE.MethodsWe determined anti‐PCs by using the enzyme‐linked immunosorbent assay in 116 patients with SLE and 110 age‐ and sex‐matched controls. For functional studies, we used three in‐house–generated, fully human monoclonal IgG1 anti‐PCs (A01, D05, and E01). Apoptosis was induced in Jurkat T cells and preincubated with A01, D05, E01, or IgG1 isotype control, and effects on efferocytosis by human macrophages were studied. Anti‐PC peptide/protein characterization was determined using a proteomics de novo sequencing approach.ResultsIgG1, but not IgG2, anti‐PC levels were higher among patients with SLE (P = 0.02). IgG1 anti‐PCs were negatively associated with Systemic Lupus International Collaborating Clinics (SLICC) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (odds ratio [OR]: 2.978 [confidence interval (CI): 0.876‐10.098] and OR: 5.108 [CI 1.3‐20.067], respectively) and negatively associated with CVD, atherosclerotic plaques, and echolucent plaques (potentially vulnerable plaques), but the association for the two former was not significant after controlling for confounders. D05 had a maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC‐associated neoepitopes. A peptide analysis showed a difference in the complementarity‐determining region 3 of the three IgG1 anti‐PC clones that are crucial for recognition of PC on apoptotic cell surfaces and other neoepitopes.ConclusionIgG1 anti‐PCs are negatively associated with disease activity and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.

IgM anti-phosphorylcholine antibodies associate with senescent and IL-17+ T cells in SLE patients with a pro-inflammatory lipid profile.

The aim was to evaluate whether T cell subsets and the lipid profile could be linked to the cardioprotective effect of IgM anti-phosphorylcholine (PC) antibodies in SLE. Anti-PC antibodies were quantified by ELISA in 197 patients and 99 controls and analysed in relationship to clinical features, treatments and serum lipids. Carotid atheromatosis was evaluated by ultrasonography; Th1, Th17, Treg and CD4+CD28null cells by flow cytometry; and cytokine serum levels by immunoassays, in a subgroup of 120 SLE patients and 33 controls. IgM anti-PC serum levels were reduced in SLE patients compared with controls (P < 0.001) and were associated with age (β= -0.252; P = 0.002), high-density lipoprotein (HDL; β = 0.271; P = 0.001), low-density lipoprotein (LDL; β= -0.192; P = 0.017) and glucocorticoid treatment (β= -0.201; P = 0.012), whereas the IgG-to-IgM anti-PC ratio was increased (P = 0.007) and associated with age (β = 0.194; P = 0.028) and SLEDAI (β = 0.250; P = 0.005). Also, patients with clinical or subclinical cardiovascular disease exhibited reduced IgM anti-PC levels compared with their cardiovascular disease-free counterparts, regardless of glucocorticoid usage (P = 0.001). CD4+CD28null and Th17 cells were increased in SLE patients compared with controls (P < 0.01) and correlated inversely with IgM anti-PC levels. These associations were observed in patients displaying high triglyceride or low HDL levels, even after adjusting for clinical parameters and treatments (CD4+CD28null: β = -0.455, P = 0.001; Th17: β= -0.280, P = 0.035), but not in those with a normal lipid profile. High triglyceride and low HDL profiles were related to low IgM anti-PC and Treg levels, respectively, whereas both lipid profiles were associated with inflammatory markers and cytokines. The present study provides evidence for an association of IgM anti-PC antibodies with pro-atherogenic T cell subsets in SLE, with a high triglyceride/low HDL lipid profile playing a facilitating major role.

IgM antibodies against phosphorylcholine measured early after acute ST-elevation myocardial infarction in relation to atherosclerotic disease burden and long-term clinical outcome.

PurposeStudies have reported an association between low levels of natural immunoglobulin M antibodies against phosphorylcholine(IgM anti-PC) and worse prognosis in patients with coronary artery disease (CAD). The aims of the present study were, in patients with ST-elevation myocardial infarction (STEMI); 1) to compare serum levels of IgM anti-PC measured acutely and after 3 months; 2) to study an association between levels of IgM anti-PC and the severity ofCAD, and; 3) to investigate whether IgM anti-PC levels are associated with long-term clinical outcome.MethodsA total of 213 patients without known diabetes (median age 59 years) with a PCI treated STEMI were enrolled. IgM anti-PC was measured in-hospital and after 3 months. Median follow-up time was 6.5 years (all-cause mortality, non-fatal myocardial re-infarction, recurrent ischemia causing hospital admission, heart failure and stroke). The severity of CAD was evaluated by coronary angiograms and patients were classified as having single- or multi-vessel disease and by SYNTAX score (SXscore).ResultsIgM anti-PC levels were stable over time when measured acutely and after 3 months. Patients with multi-vessel disease and high SXscore had significantly lower levels of IgM anti-PC in the acute phase of STEMI. Low levels of IgM anti-PC (the 25 percentile) measured acutely were associated with a 2-fold increase in the odds of having multi-vessel disease (adjusted OR 2.28 (95% CI 1.17, 4.44), p = 0.016), but not with high SXscore (Crude OR 2.20 (95% CI 0.96, 5.07), p = 0.06). Fifty-three patients experienced a new clinical event during long-term follow-up. Low levels of IgM anti PC were not associated with worse prognosis, (crude HR 1.54 (0.87–2.76), p = 0.14).ConclusionSTEMI patients with multi-vessel disease or high SXscore had significantly lower levels of IgM anti-PC in the acute phase and low levels were associated with multi-vessel disease, but not with worse clinical outcome during long-term follow-up.

Antibodies against Phosphorylcholine among New Guineans Compared to Swedes: An Aspect of the Hygiene/Missing Old Friends Hypothesis

ABSTRACTBackground: We here study antibodies against phosphorylcholine (anti-PC) which we reported to be inversely associated with atherosclerosis, cardiovascular disease (CVD), and autoimmune conditions. In previous studies, we determined that this inverse association is more pronounced at low levels with high risk and at high levels, with decreased risk. We compare individuals from Kitava, New Guinea (with low risk of these conditions), with Swedish controls.Methods: We studied a group of 178 individuals from Kitava (age 20–86), and compared those above age 40 (n = 108) with a group of age- and sex-matched individuals from a population based cohort in Sweden (n = 108). Traditional risk factors for CVD and fatty acids were determined. IgM, IgG, and IgA anti-PC were tested by enzyme-linked immunosorbent assay (ELISA).Results: All anti-PC measures were significantly lower among Swedish controls as compared to Kitavans (p < 0.001), independent of traditional risk factors. Having low levels of anti-PC, defined as below 25th percentile of values among Swedish controls, was associated with this cohort after adjustment for other risk factors (OR 5.7, 95% CI 2.2–14.7 for IgM; OR 31.7, 95% CI 3.9–252 for IgA; and OR 11.1, 95% CI 2.4–51 for IgG).Conclusions: PC is highly exposed on microorganisms and helminths (common on Kitava) exposing much PC which humans and hominids may have been exposed to for millions of years. We propose that low anti-PC levels in the developed world could be a new aspect of the hygiene hypothesis, generating a pro-inflammatory and pro-atherosclerotic state.

Antibodies against phosphorylcholine are not altered in plasma of patients with Alzheimer’s disease

BackgroundPhosphorylcholine is one of the major epitopes of oxidised low density lipoprotein. Low levels of IgM antibodies against phosphorylcholine (anti-PC) are associated with development of myocardial infarction and stroke. It has been shown that patients with Alzheimer’s disease and other dementias have significantly lower serum anti-PC levels compared to controls, suggesting that low levels of atheroprotective anti-PC may play a role in AD and dementia.MethodsWe quantified levels of anti-PC levels using an ELISA in plasma from 176 controls, 125 patients with Alzheimer’s disease, 19 patients with vascular dementia and 63 patients with other dementias.ResultsWe observed similar plasma anti-PC levels in controls, patients with Alzheimer’s disease, and other dementias.ConclusionsOur data suggests that anti-PC is not useful as a biomarker for Alzheimer’s disease.

IgM-antibodies against phosphorylcholine in mothers and normal or low birth weight term newborn infants.

ObjectiveTo determine levels of athero-protective IgM antibodies against phosphorylcholine in mothers and term-born normal or low birth weight infants.ApproachTwenty 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.ResultsNeonatal 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).ConclusionsIgM 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.

Low levels of IgM antibodies against phosphorylcholine are associated with fast carotid intima media thickness progression and cardiovascular risk in men

ObjectiveLow levels of IgM anti-phosphorylcholine (anti-PC) increase the risk of cardiovascular events (CVE). Here we investigate the association of low anti-PC with the progression of carotid intima media thickness (C-IMT) and incidence of CVE in a large cohort of individuals at high risk of CVE, the IMPROVE, a prospective multicenter European study. Methods3711 subjects (54–79 years) with at least three established cardiovascular risk factors were enrolled. Baseline serum levels of IgM anti-PC were measured by ELISA. Carotid ultrasound investigations were performed at baseline and after 15 and 30 months of follow-up. The risk of C-IMT progression and ischemic CVE associated with low anti-PC levels was tested by logistic regression and Cox regression analysis, respectively. Risk estimates were adjusted by center and conventional cardiovascular risk factors. Results3670 study participants were included in the present analysis and 213 CVE were recorded during a 3 year follow up. Anti-PC levels (U/ml) were classified into quartiles [Q1≤ 40, Q2 >40-≤64, Q3 >64-≤102, Q4 >102]. In men, low levels of anti-PC (Q1) were associated with the highest (>90th) percentile of the fastest C-IMT progression, i.e. the segment showing the fastest progression over 30 months in the whole carotid tree, with an OR of 1.41 (95%CI, 1.02–1.9) and with an increased risk of CVE with a multivariable adjusted HR of 1.85 (95%CI, 1.1–3.1). No significant associations were found in women. ConclusionsLow anti-PC levels increase the risk of CVE in men. This effect may be partly mediated by a fast C-IMT progression.

SAT0016 Correlation of Carotid Intimal Plaque in SLE with Non-Traditional Serum Biomarkers

BackgroundLupus patients have a strikingly increased risk of premature atherosclerosis and fatal cardiovascular events. This predisposition is neither fully accounted for by traditional cardiovascular (CV) risk factors nor SLE disease...

Relation of carotid plaque with natural IgM antibodies in patients with systemic lupus erythematosus

Noninvasive carotid measurements have proven value in the estimation of future cardiovascular (CV) outcomes in systemic lupus erythematosus (SLE). Natural IgM-antibodies to phosphorylcholine (PC) epitopes can enhance apoptotic-cell clearance and induce anti-inflammatory pathways. Herein, we show that subclinical CV disease, as detected by carotid ultrasound, in a cross-sectional SLE cohort was associated with lower levels of IgM anti-PC, as well as lower levels of the ratio of IgM anti-PC/total IgM, compared to patients without plaque (p=0.004 and p=0.02, respectively). The IgM anti-PC/total IgM association remained significant after adjusting for age, cholesterol and hypertension. Adiponectin and sE-selectin were significantly elevated in patients with plaque, and statistical models showed that combining adiponectin, sE-selectin and IgM anti-PC/total IgM was better for predicting plaque than either test alone. These results support the hypothesis that IgM-natural autoantibodies may inhibit atherogenesis, and confirm the utility of IgM anti-PC levels as a biomarker for subclinical CV disease.

Autoantibodies to phosphorylcholine and cardiovascular outcomes in patients with acute coronary syndromes in the ATLAS ACS-TIMI 46 trial

Atherogenesis is a complex inflammatory process stemming from the accumulation and oxidation of low density lipoproteins (LDL). IgM autoantibodies against phosphorylcholine (anti-PC) bind to the PC epitope on oxidized LDL (OxLDL), inhibiting the uptake of oxLDL by macrophages in atherosclerotic lesions. Anti-PC autoantibodies have been reported to be protective against atherothrombosis. We investigated the relationship of anti-PC concentrations with cardiovascular outcomes in patients with acute coronary syndromes (ACS). We measured anti-PC levels within 7days of an ACS in 3,356 patients enrolled in the ATLAS ACS-TIMI 46 trial, a randomized dose ranging study of rivaroxaban versus placebo. The primary endpoint was death, myocardial infarction (MI), stroke, or severe recurrent ischemia (SRI) requiring revascularization during 6months. The median baseline anti-PC concentration was 40.9U/mL (25th, 75th percentiles: 25.4, 67.4). There was no significant association between anti-PC levels and the primary endpoint (Q1: 6.8%, Q2: 4.2%, Q3: 7.8%, Q4: 5.4%, p-trend=0.87), all-cause mortality (Q1: 1.4%, Q2: 0.7%, Q3: 2.4%, Q4: 0.9%, p-trend=0. 96), or any of the other individual endpoint components (MI: p-trend=0.87, Stroke: p-trend=0.43, SRI: p-trend=0.66). Using the previously reported anti-PC cutpoint of 17U/mL did not reveal a significant relationship between anti-PC concentrations and cardiovascular outcomes (<17U/mL: 8.1% vs. ≥17U/mL: 5.8%; p=0.11). Similarly, evaluation of anti-PC as a continuous variable did not reveal a significant association (p=0.30). In this study of patients early after ACS undergoing intensive secondary preventive therapy, IgM anti-PC titers did not exhibit a significant relationship with cardiovascular outcomes.

Carotid Atherosclerosis, Disease Measures, Oxidized Low-density Lipoproteins, and Atheroprotective Natural Antibodies for Cardiovascular Disease in Early Rheumatoid Arthritis — An Inception Cohort Study

Although an enhanced risk of cardiovascular disease (CVD) in persons with rheumatoid arthritis (RA) is well established, the mechanisms behind it remain unclear. We studied whether carotid atherosclerosis, RA disease measures, or potential cardiovascular biomarkers influenced the incidence of CVD in an RA inception cohort. RA disease measures and CVD biomarkers were assessed at 0, 3, 12, 24, and 60 months after disease onset, and carotid ultrasonography after 5 years. The study outcome was incident CVD events - acute myocardial infarction, angina pectoris, congestive heart failure, or ischemic cerebrovascular event. Survival analysis and Cox and longitudinal regressions were used for statistical analyses. A total of 105 patients, without CVD events prior to RA onset, experienced 17 CVD events, an incidence rate of 1.35 events per 100 person-years (95% CI 0.71-2.0). The rate of CVD events did not differ with regard to measures of carotid intima-media thickness, but it was higher for patients with bilateral carotid plaques than for those without (p = 0.012). Improvement in Disease Activity Score for 28 joints, visual analog scale for pain, and Stanford Health Assessment Questionnaire score over the first year, as well as usage of methotrexate (MTX), was associated, independent of age, with reduction of risk of CVD event [hazard ratios 0.68 (95% CI 0.5-0.97), 0.97 (95% CI 0.95-0.99), 0.35 (95% CI 0.15-0.82), and 0.34 (95% CI 0.12-0.91), respectively]. In longitudinal analyses, increasing oxidized low-density lipoprotein (oxLDL) and probability for low antiphosphorylcholine antibodies (anti-PC) were observed in those who experienced a subsequent CVD event. Bilateral carotid plaques were associated with poor CVD-free survival. Early reductions of inflammation, pain, and disability as well as MTX usage were associated with better CVD outcome. Elevated oxLDL and low IgM anti-PC levels may link chronic inflammation in RA to enhanced risk of CVD events.

Genetic and environmental regulation of inflammatory CVD biomarkers Lp-PLA2 and IgM anti-PC

ObjectiveWe set out to investigate the relative contribution of genetic and environmental effect on two inflammatory CVD biomarkers; lipoprotein-associated phospholipase A2 (Lp-PLA2) and anti-phosphorylcholine IgM (anti-PC). Their relationships and possible co-regulation with other established CVD biomarkers are also examined. MethodsLp-PLA2 activity (N=1600) and anti-PC (N=2036) levels were measured in elderly Swedish twins. Correlation analyses and heritability estimation were conducted by structural equation modeling. ResultsWe attribute 0.37 of the variance of Lp-PLA2 and 0.40 of anti-PC variance to genetic variance. In addition, a bivariate heritability of 0.33, 0.35 and 0.36 could be detected for levels of Lp-PLA2 together with ApoB, total cholesterol and LDL, respectively. Anti-PC was only weakly related to other biomarkers of CVD, which may suggest a more independent role of anti-PC as a biomarker. ConclusionsIn this large sample, Lp-PLA2 activity has lower heritability and higher environmental regulation than previously reported. Anti-PC levels are partly influenced by dominance genetics and appear to be regulated independently of more established CVD biomarkers.

Low Levels of Antibodies Against Phosphorylcholine in Alzheimer's Disease

Phosphorylcholine (PC) may play an important role in the atherogenic and pro-inflammatory effects of oxidized low density lipoproteins. We recently demonstrated that low levels of IgM antibodies against PC (anti-PC) are associated with development of myocardial infarction and stroke. We here evaluate the association between anti-PC and dementia and Alzheimer's disease (AD). We conducted a nested case-control study of 182 incident dementia cases (serum collected before onset of dementia) matched to 366 controls and a case-control study of 97 prevalent dementia cases (serum collected after dementia onset) matched to 205 controls. Controls were matched on gender and age at blood draw (+/- 1 year). Participants were from the Swedish Twin Registry. Anti-PC levels were measured by ELISA. The odds ratio (OR) of dementia was modeled using conditional logistic regression. Patients with dementia had significantly lower mean anti-PC levels than controls (39.1 versus 49.5 U/ml). The likelihood of having dementia or AD was doubled for individuals with the lowest 25% anti-PC levels (OR=2.04 and 2.70, respectively). The results were similar after adjustments for potential confounders. There was no association between anti-PC levels and incident dementia. Low levels of atheroprotective anti-PC could play a role in AD and dementia. Potential mechanisms include decreased anti-inflammatory potential and effects on the vasculature. Further attention is merited to elucidate the role of anti-PC in AD development and the usefulness of anti-PC as a part of risk prediction, prognosis, diagnosis, or treatment.

Patients with polycystic ovary syndrome have lower levels of IgM anti-phosphorylcholine antibodies than healthy women

Introduction. IgM antibodies against phosphorylcholine (IgM anti-PC) are natural autoantibodies, possibly exerting one of the atheroprotective functions of the immune system. Increased levels of these antibodies reduce the development of atherosclerosis in mice, and low levels of IgM anti-PC have been associated with increased risk for cardiovascular disease (CVD). This study compared levels of IgM anti-PC in women with polycystic ovary syndrome (PCOS, n = 111) and healthy controls (n = 79).Method. Levels of IgM anti-PC were measured with ELISA.Results. The median level of IgM anti-PC in patients with PCOS was not significantly different compared to control subjects. However, the proportion of patients with PCOS with low levels of IgM anti-PC, defined as number of individuals below the median level, was significantly higher than among healthy controls, p < 0.05. Patients with PCOS in the oldest age quintile had significantly lower level of IgM anti-PC than control subjects of similar age (p < 0.05) and younger women with PCOS (p < 0.01).Conclusion. Our results indicate that women with PCOS more frequently display below-median levels of IgM anti-PC than controls and older women with PCOS have lower median anti-PC levels. Further studies of how this finding translates into actual CVD risk in women with PCOS are needed.

Anti-phosphorylcholine-opsonized low-density lipoprotein promotes rapid production of proinflammatory cytokines by dendritic cells and natural killer cells

Epidemiological and animal studies suggest that periodontal infections increase atherosclerosis risk. Periodontitis patients have elevated levels of anti-phosphorylcholine (anti-PC) reactive not only with numerous periodontal organisms but also with minimally modified low-density lipoprotein (mmLDL). Dendritic cells (DCs) reside in arterial walls and accumulate in atherosclerotic lesions. The ability of anti-PC to bind mmLDL prompted the hypothesis that opsonized mmLDL would stimulate DCs and enhance the production of proinflammatory cytokines that promote atherogenic plaque development. Monocyte-derived DCs (mDCs) were generated using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, then stimulated with mmLDL or with anti-PC-opsonized mmLDL. The anti-PC effect was determined using flow cytometry, cofocal microscopy and cytokine assays. The production of CD83, IL-12p35 mRNA, IL-12p40 mRNA, IL-12p70 and IL-10 by DCs was monitored. Dendritic cells stimulated with mmLDL expressed little CD83 and produced little IL-12p70. However, anti-PC-opsonized mmLDL enhanced DC maturation, as indicated by upregulated CD83 and rapid (≤ 48 h) production of IL-12p70 if a source of interferon-γ (IFN-γ) was available. In leukocyte cultures, natural killer (NK) cells rapidly produced IFN-γ (≤ 48 h) when interacting with IL-12-producing DCs activated by anti-PC-opsonized mmLDL. Moreover, IFN-γ promoted DC IL-12 responses that were further augmented when mmLDL was opsonized with anti-PC. Minimally modified LDL-stimulated DCs and NK cells were mutually stimulatory, with DC IL-12p70 needed by NK cells and with NK cell IFN-γ needed by DCs. Moreover, production of these proinflammatory cytokines was markedly enhanced when LDL was opsonized by anti-PC. In short, the data suggest that the elevated anti-PC levels in periodontitis patients could promote a mechanism that facilitates atherosclerosis.