AS337 - Lymphocyte subpopulations and clonal expansions in older women: epidemiologic factors and relationship to health and aging during the WHI 2010-2015 extension

Investigator Names and Contact Information

Kerstin Edlefsen (edlefsen@u.washington.edu)

Introduction/Intent

Advanced age is accompanied by a profound remodeling of circulating lymphocyte subsets, including decreased numbers of naïve T cells, memory T cells, memory B cells, and plasma cells. The diversity of the immune system repertoire also decreases, accompanied by clonal expansions of normal and abnormal lymphocyte subpopulations. Certain features of these lymphocyte subsets, including expansions of CD4-positive, CD28-negative T cells and inversions of the CD4:CD8 ratio, have been associated with increased risk of CVD and overall mortality. Extremely small monoclonal B-cell lymphocyte expansions (MBL) are another very common aging phenomenon, and existing evidence suggests that they are likely markers of immune senescence. However, these MBL populations have not yet been extensively correlated with better-established markers of immune senescence or with disease outcomes. The setting of the existing WHI 2010-2015 extension Long Life in-person visit and blood collection provides a unique opportunity to characterize epidemiologically significant lymphocyte subsets and clonal lymphocyte expansions in a racially diverse population of elderly women, and to associate these markers with specific CVD outcomes and total mortality. Using highly sensitive multi-color flow cytometry and residual samples from blood obtained from a selected subsample of 600 WHI participants 72 years and older during the 2010-2015 extension, we will perform lymphocyte subset phenotyping to characterize the distribution of circulating lymphocyte subsets in elderly women, to describe epidemiologic factors associated with their detection, and to determine whether these factors predict the occurrence of major disease outcomes, including incident cardiovascular disease and overall mortality.

Specific Aims

Using highly sensitive multi-color flow cytometry and residual samples from blood obtained from a selected subsample of 600 WHI participants 72 years and older who will be followed in the 2010-2015 extension, we will perform lymphocyte subset phenotyping to address the following aims:

1. Characterize the distribution of circulating lymphocyte subsets (including naïve T cells, memory T cells, late T cells (CD27-CD28-), NK cells, immature B cells, naïve B cells, memory B cells, plasmablasts/plasma cells, and MBL) in a well-characterized population of elderly women.

   1. Determine the cross-sectional associations between presence of and characteristics of MBL and the size of other lymphocyte compartments in the peripheral blood of older women, including markers of immune senescence (size of the CD4+CD28- late T cell compartment and the presence of an inverted CD4:CD8 T cell ratio).

2. Describe epidemiologic factors associated with detection of MBL and CD28- T cell subsets, including age, race, socio-economic status, medical history, white cell telomere length, smoking status, BMI, hypertension, and other aging-related pro-inflammatory cardiovascular risk factors such as C-reactive protein.

3. Examine whether characteristics of the lymphocyte subsets, specifically detection of MBL and size of the CD28-negative T cell subsets, predict the occurrence of major disease outcomes in WHI, including incident cardiovascular disease (myocardial infarction and stroke), congestive heart failure, hospitalization, and mortality during follow-up. Secondarily, we will assess whether the identification of an MBL population predicts the occurrence of clinically diagnosed leukemia/lymphoma (in particular CLL/SLL) during follow-up, and what characteristics of the MBL or other factors of the immune milieu predict progression.