T‐Helper Type 1 Bias in Healthy People Is Associated With Cytomegalovirus Serology and Atherosclerosis: The Multi‐Ethnic Study of Atherosclerosis

Abstract

BackgroundAlthough T‐helper type 1 (Th1) cells are considered important in atherosclerosis, the relationships between Th1 and Th2 cells and atherosclerosis have not been examined in population‐based studies.Methods and ResultsWe measured Th cells as a percentage of lymphocytes by flow cytometry using CD4 staining (%CD4) in 917 participants of the Multi‐Ethnic Study of Atherosclerosis. We also measured interferon gamma–positive and interleukin‐4‐positive CD4+ cells, representing Th1 and Th2 subpopulations (%Th1 and %Th2), respectively. We found that %CD4 was 1.5% lower per 10 years of age (P<0.0001). Whites had higher %CD4 and lower %Th1 and %Th2 values than other race/ethnic groups. Body mass index (BMI) and blood pressure were associated with %CD4, but no traditional cardiovascular disease (CVD) risk factors were associated with %Th1 or %Th2. In multivariable models, the major independent variable associated with %Th1 was cytomegalovirus (CMV) antibody titer, with minor contributions from age, sex, seasonality, and interleukin‐6. In models with coronary artery calcification level as the outcome, significant independent variables included age, sex, smoking status, and %Th1 (β=0.25; P≤0.01). Both %Th1 and %Th2 were associated with common carotid intimal media thickness (β=0.02 and −0.02, respectively; both P<0.05), as were age, sex, race/ethnicity, blood pressure, and BMI.ConclusionsTh1 bias is associated with subclinical atherosclerosis in a multiethnic population. The main Th1 correlate was CMV infectious burden. These findings are consistent with a role of Th1 cells in atherosclerosis and suggest the importance of prospective studies of T‐helper cell biasing in CVD.

Biomarkers of Key Biological Pathways in CVD

“…These results were consistent with a pro-atherogenic role for Th1 cells and an anti-atherogenic role for Th2 cells, and is the first demonstration of these relationships in a multi-ethnic population[21]. In addition, the degree of chronic adaptive immune activation, as estimated by higher memory and lower naïve CD4 + cell phenotypes, was associated with subclinical atherosclerosis and type 2 diabetes.…”

“…Results from variability studies demonstrated that these cellular phenotypes were reproducible and generally stable, indicating, for the first time, their suitability for evaluation in epidemiological research[21]. …”

Interferons as Essential Modulators of Atherosclerosis

“…29,30 Furthermore, Th1 cytokines are prevalent in both human and murine atherosclerotic lesions. 15,31 Studies in mice with a deficiency of IFN-γ, IFNGR1, or the Th1 differentiating factor T-bet resulted in diminished atherosclerosis, indicating the importance of this Th1 response.…”

Recent findings of long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFAs) on atherosclerosis and coronary heart disease (CHD) contrasting studies in Western countries to Japan

“…32 Recently we have shown that circulating levels of Th1 had significant positive associations with both CAC and cIMT in 917 men and women from the US general population. 38 The significant associations were independent of traditional and novel risk factors including CRP and sICAM-1. Though the study was cross sectional, currently a large epidemiological study is ongoing to examine a longitudinal association of T cell phenotypes including Th1 with cardiovascular outcomes.…”