ORIGINAL RESEARCH article
Front. Hematol.
Sec. Red Cells, Iron and Erythropoiesis
Volume 4 - 2025 | doi: 10.3389/frhem.2025.1580009
This article is part of the Research TopicInnovations and Challenges in Sickle Cell Disease: Bridging Gaps in Global HealthView all articles
Soluble immune checkpoint landscape in sickle cell disease links systemic inflammation, autoimmunity, and pain
Provisionally accepted
Wei Li1*
Andrew Pucka2Lina Houran2Xiaoqing Huang3
Candice DeBats2
Brandon Reyes2Andrew RW O'Brien4Qigui Yu1*
Ying Wang2,4*- 1Department of Microbiology and Immunology, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
- 2Department of Anesthesia, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
- 3Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, United States
- 4Division of Hematology and Oncology, Department of Medicine, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
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Background: Sickle cell disease (SCD) is a chronic condition characterized by inflammation, immune dysregulation, and debilitating pain.Aim: This study investigates soluble immune checkpoints (sICPs) and their associations with inflammatory mediators, immune cell profiles, autoantibodies, and clinical outcomes in SCD.Method: 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).Results: Twenty-three sICPs, including arginase-1, BTLA, CD27, CD28, CD47, CD80, CD96, CD134, CD137, CD152, GITR, HVEM, IDO, LAG-3, MICA, MICB, Nectin-2, PD-1, Siglec-7, Siglec-9, TIM-3, TIMD-4, and VISTA, were significantly elevated in SCD patients compared to HCs. These sICPs correlated with multiple proinflammatory mediators (e.g., IL-18), autoantibodies (e.g., MPO), and immune cell activation markers (e.g., CD38/HLA-DR on CD8 T cells). Notably, CD28, CD152, HVEM, and VISTA were strongly associated with systemic inflammation and immune cell activation, while BTLA, LAG-3, PD-1, and CD80 correlated with pain and anxiety scores and QoL.Conclusion: 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 challenging clinical population.
Keywords: Sickle Cell Disease, Soluble immune checkpoints, Inflammation, Steady-state condition, Vaso-occlusive crisis
Received: 26 Feb 2025; Accepted: 18 Jun 2025.
Copyright: © 2025 Li, Pucka, Houran, Huang, DeBats, Reyes, O'Brien, Yu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wei Li, Department of Microbiology and Immunology, School of Medicine, Indiana University Bloomington, Indianapolis, 46202, Indiana, United States
Qigui Yu, Department of Microbiology and Immunology, School of Medicine, Indiana University Bloomington, Indianapolis, 46202, Indiana, United States
Ying Wang, Department of Anesthesia, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.