Immune cell phenotypes and mortality in the Framingham Heart Study

Ahmed A Y Ragab; Margaret F Doyle; Jiachen Chen; Yuan Fang; Kathryn L Lunetta; Joanne M Murabito

doi:10.1186/s12979-024-00431-6

Immune cell phenotypes and mortality in the Framingham Heart Study

Immun Ageing. 2024 Jun 12;21(1):37. doi: 10.1186/s12979-024-00431-6.

Authors

Ahmed A Y Ragab¹, Margaret F Doyle², Jiachen Chen³, Yuan Fang⁴, Kathryn L Lunetta³, Joanne M Murabito^{5

6}

Affiliations

¹ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA. aragab@bu.edu.
² Department of Pathology and Laboratory Medicine, University of Vermont, Larner College of Medicine, Burlington, VT, USA.
³ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
⁴ Binghamton University, State University of New York, School of Pharmacy and Pharmaceutical Sciences, Binghamton, NY, USA.
⁵ Framingham Heart Study, National Heart, Lung, and Blood Institute and Boston University Chobanian & Avedisian School of Medicine, Framingham, MA, USA. murabito@bu.edu.
⁶ Department of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA, USA. murabito@bu.edu.

Abstract

Background: Global life expectancy is rising, with the 60 + age group projected to hit 2 billion by 2050. Aging impacts the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their importance, links between immune cell phenotypes including ARIPs and mortality are underexplored. We prospectively investigated 16 different immune cell phenotypes using flow cytometry and IL-6 in relation to survival outcome among dementia-free Framingham Heart Study (FHS) offspring cohort participants who attended the seventh exam (1998-2001).

Results: Among 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the 19-year survival rate was 65%. Adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR: 0.86 [0.76-0.96], 0.84 [0.74-0.94], respectively), while higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3 +) were associated with increased all-cause mortality risk (HR = 1.17, [1.03-1.32]). Elevated IL-6 levels correlated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26-1.62], 1.70 [1.31-2.21], and 1.36 [1.18-1.57], respectively). However, after adjusting for cardiovascular risk factors and prevalent cancer alongside age, sex, and CMV, immune cell phenotypes were no longer associated with mortality in our cohort. Nonetheless, IL-6 remained significantly associated with all-cause and cardiovascular mortality (HRs: 1.3 [1.13-1.49], 1.5 [1.12-1.99], respectively).

Conclusions: In 19-year follow-up, higher Tc17/CD8 + Treg and CD4/CD8 ratios were associated with lower all-cause mortality, while the CD8 + CD25 + FoxP3 + (CD8 + Treg) phenotype showed increased risk. Elevated IL-6 levels consistently correlated with amplified mortality risks. These findings highlight the links between immune phenotypes and mortality, suggesting implications for future research and clinical considerations.

Keywords: Aging; All-cause mortality; Cardiovascular mortality; Immune cell phenotype; Immune system; Immunosenescence; Inflammaging; Non-cardiovascular mortality; T cells.

Abstract

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