Endometriosis (EMS) is a chronic inflammatory disease characterized by ectopic endometrial-like tissue growth and immune dysregulation. Aberrant T cell responses are implicated in EMS pathogenesis, however, functional reprogramming of T helper (Th) subsets across disease stages remain unclear. We profiled systemic and local immune mediators (cytokines/chemokines) and performed bulk RNA sequencing to comprehensively characterize Th1, Th1/17, and Th17 cell subsets from EMS patients and healthy controls. Across patient plasma, peritoneal fluid (PF), and matched eutopic and ectopic tissues, we observed systemic and local cytokine/chemokine alterations, including elevated IL-6 (plasma), FLT-3L and G-CSF (eutopic), and IL-1RA and IL-23 (p40; PF) in severe-stage EMS. Flow cytometry depicted elevated pathogenic Th17 cells in patient PF compared to matched non-pathogenic Th17 and Treg cell subsets. Additionally, circulating Th17 cells were increased in patients with mild (stages I-II) relative to severe (stages III-IV) EMS. RNA sequencing revealed extensive Th subset reprogramming in EMS, most predominately in Th17 cells (2,220 DEGs). Collectively, we reveal significant immune remodeling in EMS and highlight a distinct, aberrant Th17 cell phenotype. Results support repurposing of IL-23- and IL-17-targeted therapeutics, already effectively implemented in other chronic inflammatory diseases, to broaden therapeutic options for EMS and associated comorbidities.
Sisnett, D. J., Zutautas, K. B., Holmes, J. P., Pudwell, J., King, K., Bougie, O., Tayade, C.
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