Interplay between per- and polyfluoroalkyl substances and T cell epigenetics in autoimmunity and lupus

/ABSTRACT Autoimmune diseases collectively rank among the top causes of death for adult females. Systemic lupus erythematosus (SLE, or lupus) is a prototypic and serious autoimmune disease of largely unknown etiology that disproportionately affects females and people from certain racial and ethnic groups. There is a critical need to identify environmental exposures in the general population that contribute to the development and progression of autoreactivity and autoimmune diseases such as lupus, in order to inform prevention and control efforts. Per- and polyfluoroalkyl substances (PFAS), also referred to as “forever” chemicals, are toxicants with extensive distribution and persistent effects in the environment, for which chronic, low-dose exposures are common. Data are accumulating on immunotoxicities associated with PFAS. This project will interrogate the contributions of environmental and epigenetic factors to autoimmunity and lupus, utilizing data and biospecimens from two complementary, population-based and extensively phenotyped cohorts: (1) the Michigan Lupus Epidemiology & Surveillance (MILES) Program of persons with lupus and general population controls from southeastern Michigan, through which our group has pioneered the public health surveillance and monitoring of lupus; and (2) the Study of Women's Health Across the Nation (SWAN), a multi-site cohort of women followed for over two decades from midlife. A leading paradigm for lupus etiology and potential mechanism by which exposures exert immunotoxic effects involves epigenetic alterations to lymphocyte DNA that increase the propensity for lupus development and flares. This project will examine relationships between PFAS exposures, immune dysregulation, phenotypic autoimmune expression including lupus, and T cell epigenetics (DNA methylation). Our overarching hypothesis is that PFAS exposures are associated in dose- dependent fashion with markers of immune dysregulation in both adults from the general population (SWAN and MILES) and persons with lupus (MILES). We also hypothesize that PFAS are associated with alterations in lymphocyte DNA methylation patterns of key genes/pathways involved in immune regulation among persons with lupus. We will address these hypotheses via these specific aims: 1) characterize the relationship between PFAS exposure biomarkers and immune dysregulation in adult females from the general population (without autoimmune disease), assessed separately in SWAN and MILES cohorts; 2) delineate associations between PFAS exposures and autoimmune disease development over 20 years of follow-up in SWAN and with lupus activity in MILES; and 3) identify whether DNA methylation differences in CD4+ T lymphocytes in autoimmune- and lupus- relevant genes are associated with PFAS exposures in MILES. Overall, this research will provide novel data related to the role of these toxicants in immune dysregulation and autoimmune disease and inform future intervention and prevention strategies. Project Number: 1R01ES037308-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Emily Somers (+1 co-PI) | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $771,168 | Activity Code: R01 | Study Section: Aging, Injury, Musculoskeletal, and Rheumatologic Disorders Study Section[AIMR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11295122