Soluble immune checkpoints are dysregulated in patients with sickle cell disease and correlate with inflammatory mediators, autoantibodies, immune cell profiles, and clinical outcomes 2765

Abstract Description Sickle cell disease (SCD) is a chronic condition characterized by inflammation, immune dysregulation, and debilitating pain. This study investigates soluble immune checkpoints (sICPs) and their associations with inflammatory mediators, immune cell profiles, autoantibodies, and clinical outcomes in SCD. Peripheral blood samples from 50 SCD patients and 40 demographic-matched healthy controls (HCs) were analyzed for 37 sICPs, 80 inflammatory mediators, and 18 autoantibodies using multiplex assays, alongside immune cell profiles via flow cytometry. Pain and quality of life (QoL) were assessed through patient-reported outcome measures (PROMs). Twenty sICPs, including both inhibitory and stimulatory ICPs, such as arginase-1, BTLA, CD28, CD47, CD80, CD134, CTLA-4, HVEM, LAG-3, PD-1, TIM-3, and VISTA, were significantly elevated in SCD patients compared to HCs. These sICPs correlated with multiple proinflammatory mediators (e.g., IL-18, PTX3), autoantibodies (e.g., SSA/Ro60), and immune cell activation markers (e.g., CD38and HLA-DR on CD8 T cells). Some of those elevated sICPs correlated with pain, physical function, and QoL, Notably, CD28 and VISTA were strongly associated with systemic inflammation and immune cell activation. This study highlights complex interactions between sICPs, immune activation, inflammation, and clinical outcomes in SCD, underscoring their potential as biomarkers or therapeutic targets to alleviate inflammation and improve QoL in this patient population. Funding Sources NIH K99/R00 4R00AT010012; Indiana University Health – Indiana University School of Medicine Strategic Research Initiative funding Topic Categories Immune Mechanisms of Human Disease (HUM)