Plasma autoantibodies against apolipoprotein B-100 peptide 210 in subclinical atherosclerosis

Objective

Experimental studies have suggested that autoimmunity is involved in atherosclerosis and provided evidence that both protective and pro-atherogenic immune responses exist. This concept has received support from small clinical studies implicating autoantibodies directed against apolipoprotein B-100 (apoB-100) in human atherosclerosis. We examined circulating autoantibodies directed against native and malondialdehyde (MDA)-modified epitope p210 of apoB-100 (IgG-p210_nat and IgM-p210_MDA) in relation to early atherosclerosis in a large, European longitudinal cohort study of healthy high-risk individuals.

Approach and results

IgG-p210_nat and IgM-p210_MDA were quantified in baseline plasma samples of 3430 participants in the IMPROVE study and related to composite and segment-specific measures of severity and rate of progression of carotid intima-media thickness (cIMT) determined at baseline and after 30 months. IgM-p210_MDA autoantibody levels were independently related to several cIMT measures both in the common carotid artery and in the carotid bulb, including measures of cIMT progression, higher levels being associated with lower cIMT or slower cIMT progression. Consistent inverse relationships were also found between plasma levels of IgG-p210_nat and baseline composite measures of cIMT. These associations disappeared when adjusting for established and emerging risk factors, and there were no associations with rate of cIMT progression besides in certain secondary stratified analyses.

Conclusions

The present study provides further evidence of involvement of autoantibodies against native and MDA-modified apoB-100 peptide 210 in cardiovascular disease in humans and demonstrates that these associations are present already at a subclinical stage of the disease.     

Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine

Abstract. Wigren M, Kolbus D, Dunér P, Ljungcrantz I, Söderberg I, Björkbacka H, Fredrikson GN, Nilsson J. (Malmö University Hospital, Lund University; Malmö University, Malmo; Sweden) Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 2011; 269 : 546–556. Objectives. Autoimmune responses against oxidized low‐density lipoprotein are considered to play an important pro‐inflammatory role in atherosclerosis and to promote disease progression. T‐regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self‐tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. Design. Six‐week‐old Apoe^?/? mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. Results. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)‐induced interferon‐γ, interleukin (IL)‐4, and IL‐10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A‐induced splenic T‐cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210‐induced Treg activation as well as the reduction of atherosclerosis. Conclusions. The present findings demonstrate that immunization of Apoe^?/? mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis‐related autoimmunity by antigen‐specific activation of Tregs represents a novel approach for treatment of atherosclerosis.     

Islet antibodies associated with pancreatic B-cell dysfunction at and 3 years after diagnosis of diabetes in subjects aged 35-64 years old: degree of impairment less severe than in those aged 0-34 years old.

AIMS: To determine differences in pancreatic B-cell function in relation to islet antibodies at diagnosis of diabetes and 3 years later in subjects aged 35-64 years old compared with those aged 0-34 years. METHODS: From a population-based diabetes register, 46 (0-34 years old) and 323 (35-64 years old) incident diabetic patients were investigated at diagnosis and 3 years later. Islet cell antibodies (ICA, GADA and IA-2A) and fasting plasma C-peptide were measured. RESULTS: Islet antibodies were found in 80% of the subjects aged 0-34 years and in 11% of those aged 35-64 years at diagnosis. ICA and GADA was the only combination of two islet antibodies detected in those aged 35-64 years and was, with or without IA-2A, associated with significantly lower median fasting C-peptide values than in those without or with only one antibody [0.35 nmol/l, interquartile range (IQR) 0.63 vs. 0.85 nmol/l, IQR 0.49; P = 0.0004]. However, fasting C-peptide in subjects aged 35-64 years old with multiple islet antibodies was higher than in those aged 0-34 years with islet antibodies (median 0 nmol/l, IQR 0.16, P = 0.0019). After 3 years' follow-up, fasting C-peptide was even lower in subjects aged 35-64 years old with three islet antibodies (median 0.14 nmol/l, IQR 0.27; P = 0.05). CONCLUSIONS: Islet antibodies were common in adults at diagnosis of diabetes. The combination of ICA and GADA indicates impaired B-cell function at diagnosis of diabetes in those aged 35-64 years old.     

Prevalence of anti cyclic citrullinated peptide antibodies in Malaysian rheumatoid arthritis patients and its correlation with disease activity

Aim: The objectives of this study are to provide data regarding the prevalence of anti‐cyclic citrullinated peptide (CCP) antibodies in Malaysian rheumatoid arthritis (RA) patients and to correlate the levels of anti‐CCP antibody with the Disease Activity Score (DAS). Method: We studied the prevalence of anti‐CCP antibodies in 51 RA patients attending our clinic and 29 controls. We also looked for correlation between anti‐CCP antibody levels with the DAS and parameters such as duration of disease, rheumatoid factor (RF) and disease‐modifying anti rheumatic drug (DMARD) usage. Results: None of the controls demonstrated anti‐CCP antibodies. Forty‐one out of 51 patients (80.4%) were positive for anti‐CCP antibodies. Sensitivity and specificity were 80.4% and 100% respectively in this study. Anti‐CCP levels correlated significantly with rheumatoid factor, but no correlation was observed with the other parameters. Conclusions: Anti‐CCP antibody is prevalent in Malaysian RA patients at 80.4% and more sensitive than RF in our cohort of established RA patients. Even though the anti‐CCP levels correlated with RF, it did not show correlation with DAS.     

Protective efficacy and hepatitis B virus clearance in mice enhanced by cell‐mediated immunity with novel prime‐boost regimens

In this study, anti‐hepatitis B virus (HBV) immunity was evaluated in mice using several regimens of the HBV recombinant protein vaccine HBSS1 that expressed in CHO cells containing S (1‐223 aa) and preS1 (21‐47 aa) and recombinant adenovirus rAdSS1 vaccine. Further, the protective efficacy of these vaccine regimens was studied in a mouse model. High titres of antigen‐specific antibodies and neutralizing activity were elicited in mice after vaccination. However, robust multi‐antigen (preS1 and S)‐specific cell‐mediated immunity (CMI) was only detected in mice primed with HBSS1 and boosted with rAdSS1. Moreover, functional T‐cell responses with high levels of cytokines and antigen‐specific cytotoxic T‐cell responses (CD107a⁺CD8⁺) were also detected in the mice. Rapid clearance of hepatitis B surface antigen and HBV DNA in blood and significantly decreased hepatitis B envelope antigen levels were observed in mice immunized with the heterogeneous prime‐boost vaccine after hepatitis B virus challenge by hydrodynamic injection (HI) of pCS‐HBV1.3. The clearance of HBV correlated well with antigen‐specific CMI (Th1 and CTL responses) and cytokine profiles (IFN‐γ, TNF‐α, IL‐2) elicited by vaccination. Taken together, our results might contribute to the development of new human HBV vaccines and a better understanding of the mechanisms underlying immune protection and clearance of hepatitis B virus infection.     

Relationship of B-type natriuretic peptide and anemia in patients with and without heart failure: a substudy from the Breathing Not Properly (BNP) Multinational Study

While anemia is a significant risk factor for poor outcomes in patients with heart failure (HF), it is not in defined guidelines for HF assessment. B-type natriuretic peptide (BNP) is a marker for diagnosis and management of patients with HF. We determined the incidence of anemia in patients with HF and the relationship between BNP and hemoglobin (Hgb) levels in patients with and without HF. Results from the Breathing Not Properly Multinational Trial consisted of 1,586 patients presenting to the emergency department (ED) with dyspnea. Because renal insufficiency is a confounding variable for BNP, patients with a creatinine of >or=2.0 mg/dL were excluded. The remaining data were evaluated from 620 non-HF patients (337 M, 283 F) and 547 HF patients (299 M, 248 F). The New York Heart Association (NYHA) HF classification and ejection fraction by echocardiography were assessed for HF patients. Blood was tested for Hgb, BNP, and creatinine. Using World Health Organization criteria for anemia, we observed that HF patients in NYHA class III or IV had lower mean Hgb levels (12.5 g/dL, P < 0.05) and a higher incidence of anemia (48.2%, P < 0.05) than did HF patients in class I or II (13.4 g/dL and 33.9%, respectively). There was no correlation between Hgb and log BNP for females without HF or the aggregate of all HF patients. In contrast, a significant inverse correlation was observed for males without HF (P < 0.001). Although there were differences in the BMI, age, and estimated glomerular filtration rate (eGFR) versus Hgb observed in this group, the log BNP correlation remained significant after multivariate analysis. A significant inverse correlation for log BNP and Hgb were also observed for diastolic (EF >or= 50) HF (P < 0.05) that was also not accounted for by the BMI, age, or eGFR. The presence of anemia is associated with worsening HF at ED presentation. For males without HF and diastolic HF patients of both genders, a low Hgb may be a confounding variable toward increasing BNP. Among systolic HF patients, the presence of a low hemoglobin concentration is not a factor in the interpretation of BNP results.     

Increased left atrial volume index is an independent predictor of raised serum natriuretic peptide in patients with suspected heart failure but normal left ventricular ejection fraction: Implication for diagnosis of diastolic heart failure

BACKGROUND: Left atrial volume index (LAVI) is increasingly recognised as a relatively load-independent marker of left ventricular (LV) filling pressures. We assessed the capacity of LAVI to predict LV diastolic dysfunction in comparison with N-terminal pro B-type natriuretic peptide (NTproBNP) in patients with suspected heart failure and a normal ejection fraction (EF). METHODS: 137 patients with suspected heart failure (HF), referred from the community for echocardiography, prospectively underwent Doppler echocardiography, LAVI and NTproBNP estimation. Raised LAVI and reduced LV systolic function were defined as >26 ml/m2 and LV EF <50% respectively. RESULTS: Of 137 patients, 21 were excluded (2 with significant mitral valve disease and 19 with atrial fibrillation). Of the remaining 116 subjects, 92 showed normal LV systolic function. The univariate predictors of serum log NTproBNP were age (p < 0.001), LA dimension (p = 0.001), LAVI (p < 0.001), A wave (p = 0.001), E:A (p = 0.07) and septal wall thickness (p = 0.004). However on multivariate analysis, LAVI was found to be the most consistent and significant predictor of NTproBNP. The area under the curve of the receiver operating characteristic (ROC) curve for NTproBNP in detecting patients with LVEF > or = 50% and LAVI >26 ml/m2 was 0.81 (p < 0.0001) and for patients with LAVI > 26 ml/m2 with and without LVEF > or = 50% was 0.82 (p < 0.0001). CONCLUSION: This data confirms that LAVI on resting echocardiography, specifically in patients with suspected HF and normal LV systolic function is a powerful independent predictor of LV diastolic dysfunction as predicted by serum NTproBNP. In a population with a high suspicion of diastolic heart failure, LAVI may significantly contribute to diagnostic precision.