T helper cells in development of chronic inflammation and multimorbidity - Multimorbidity, the coexistence of two or more chronic and often aging-related diseases, affects the majority of older adults. Chronic inflammation has been implicated in multimorbidity and individual aging-related diseases including cardiovascular disease, diabetes, cancer, Alzheimer’s disease, and osteoporosis. Anti-inflammatory therapy targeting IL1β reduces risk for cardiovascular disease, but clinical benefits of modulating inflammation remain controversial. Animal studies suggest that the infiltration of immune cells including T helper cells into the arterial wall, adipose, and other tissues may be the central mechanism underlying chronic inflammation and subsequent diseases. Most human studies, however, rely on inflammatory biomarkers such as IL6 and CRP, which lack mechanistic specificity. The paucity of human studies directly characterizing the immune cells’ role in the inflammatory process is a major gap retarding the translation of animal-based mechanistic work. We propose that T helper cells are an important contributor to both chronic inflammation and subsequent diseases because of their regulating immune response of both adaptive and innate immune cells including activation of monocytes/macrophages. This view is supported by our preliminary data from the Multi-Ethnic Study of Atherosclerosis (MESA) which shows the associations of pro-inflammatory signatures of T helper cells with multimorbidity, chronic inflammation, and inflammatory response of monocytes. While these microarray data support the role of T helper cells in chronic inflammation and multimorbidity, large longitudinal studies are needed to establish whether cellular features precede disease development. The proposed study will leverage the unique resource of isolated human T helper cells in MESA (N=1,900). We hypothesize that cellular features that coordinate the inflammatory response in peripheral T helper cells contribute to subsequent chronic inflammation, inflammatory changes in peripheral monocytes, and multimorbidity. To test this hypothesis, we will examine the following specific aims: 1) to examine whether omics profiles of T helper cells predict 11-year changes in multimorbidity in 1,900 MESA participants, 2) to evaluate whether omics profiles of T helper cells predict 6-year changes in omics profiles of monocytes and circulating pro-inflammatory biomarkers in 1,900 individuals, and 3) To test effects of pharmacological modulation of T helper cells from MESA participants on inflammatory responses. The proposed study will for the first time investigate the longitudinal relationship between omics profiles of T helper cells and multimorbidity in humans. The results from the proposed study will improve our understanding of inflammatory processes in humans, particularly their cellular features, and accelerate the development of more precisely targeted anti-inflammatory interventions for preventing multimorbidity.
