Publications

Naive B cells co-express two BCR isotypes, IgM and IgD, with identical antigen-binding domains but distinct constant regions. IgM but not IgD is downregulated on autoreactive B cells. Because these isotypes are presumed to be redundant, it is unknown how this could impose tolerance. We introduced the Nur77-eGFP reporter of BCR signaling into mice that express each BCR isotype alone. Despite signaling strongly in vitro, IgD is less sensitive than IgM to endogenous antigen in vivo and developmental fate decisions are skewed accordingly. IgD-only B cells cannot generate autoantibodies and short-lived plasma cells (SLPCs) in vivo, a fate thought to be driven by intense BCR signaling induced by endogenous antigens. Similarly, IgD-only B cells generate normal germinal center, but impaired IgG1 SLPC responses to T-dependent immunization. We propose a role for IgD in maintaining the quiescence of autoreactive B cells and restricting their differentiation into autoantibody secreting cells.

BACKGROUND

The meaning of high-sensitivity troponin I (hsTnI) concentrations in patients without acute myocardial infarction (MI) requires clarity. We hypothesized that among patients referred for diagnostic coronary angiography without acute MI, hsTnI concentrations would correlate with prevalent coronary artery disease (CAD) and predict incident cardiovascular events and mortality.

METHODS AND RESULTS

We measured hsTnI using a single-molecule counting assay (99th percentile, 6 ng/L) in samples from 991 patients obtained at the time of angiography. Concentrations of hsTnI were assessed relative to the severity of CAD and prognosis during mean follow-up of 3.7 years. Median hsTnI concentration was 4.19 ng/L; 38% of patients had hsTnI concentrations ≥99th percentile. Across increasing hsTnI quartiles, patients had higher prevalence of angiographic CAD; in multivariate models, hsTnI ≥99th percentile independently predicted obstructive CAD (odds ratio: 2.57; <0.001) and incident MI (hazard ratio [HR]: 2.68; <0.001), cardiovascular death (HR: 2.29; =0.001), and all-cause death (HR: 1.84; =0.004). In those with >70% coronary stenosis, hsTnI ≥99th percentile independently predicted incident MI (HR: 1.87; =0.01), cardiovascular mortality (HR: 2.74; =0.001), and the composite end point of MI and all-cause death (HR: 2.06; <0.001). In participants with coronary stenosis <70%, hsTnI ≥99th percentile even more strongly predicted incident MI (HR: 8.41; <0.001), cardiovascular mortality (HR: 3.60; =0.03), and the composite end point of MI and all-cause death (HR: 3.62; <0.001).

CONCLUSIONS

In a large prospective cohort of patients who were free of prevalent MI and undergoing diagnostic coronary angiography, hsTnI concentrations were associated with higher prevalence of CAD and predicted incident MI, cardiovascular death, and all-cause death.

CLINICAL TRIAL REGISTRATION

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868.

BACKGROUND/AIMS

Asian Indians have a high prevalence of vitamin D deficiency and metabolic syndrome. Vitamin D deficiency is associated with an increased risk of cardiovascular disease and diabetes.

METHODS

We performed a cross-sectional study of 150 Asian Indians (50% male) from the San Francisco Bay Area. We assessed the association between 25-OH vitamin D (25-OHD) levels and vitamin D deficiency with body composition (anthropometric and radiographic measures) and metabolic outcomes.

RESULTS

In both men and women, the presence of vitamin D deficiency was associated with higher systolic (p = 0.004) and diastolic (p = 0.01) blood pressure, and fasting glucose (p = 0.01). Only in women, vitamin D deficiency status was associated with higher body mass index (BMI), waist-to-hip ratio, visceral fat area, and hepatic fat content after adjusting for age, income, and physical activity level. In women, 25-OHD was also associated with fasting glucose after adjusting for age, income, and physical activity and further adjusting for BMI and waist circumference (β -2.1, 95% CI -0.86 to -0.01, p = 0.04). This association between vitamin D deficiency and metabolic parameters was not significant in men.

CONCLUSIONS

A lower level of 25-OHD and vitamin D deficiency were associated with higher levels of metabolic factors among Asian Indians. Our findings suggest that 25-OHD metabolism may differ by the distribution of adipose tissue and involve previously unexplored pathways accounting for the variability in the role of vitamin D in cardiovascular disease.