INVESTIGATING THE ROLE OF SOLUBLE IMMUNE CHECKPOINT MARKERS IN INFLAMMATORY DISEASES

Abstract

Introduction: Membrane-bound immune checkpoint markers (mICMs) are inhibitory and activatory receptors and ligands expressed on immune cells and are associated with immune regulation. Studies have reported the association of activatory mICMs with inflammatory diseases. Recently, the soluble isoforms of these mICMs have been described; however, their association with inflammatory diseases is yet to be understood. Therefore, this study investigated the association of soluble (s)ICMs with inflammatory diseases. Method: A systematic literature review was performed using PubMed and Google Scholar databases to search for articles. Keywords from the research topic were used to develop Medical Subject Heading terms (MeSH). Free text terms were used to search for extra articles. Texts without abstracts and those on membrane-bound markers were excluded. Joanna Briggs's critical appraisal tools were used to evaluate the credibility of the articles. The search strategy included studies published up to the end of August 2022. Secondary analysis of shared data from Luminex assay measuring sICMs in microscopic colitis (MC) patients was used to investigate the role of sICM. The data was divided into active MC (n=33), MC in remission (n=18), and healthy controls (n=19). For the malaria study, the population comprised 156 children who are part of an ongoing cohort under weekly surveillance of malaria in Kenya since 2005. Sera from 78 children from Junju (High malaria transmission) age-matched with 78 children from Ngerenya (Low malaria transmission) was used to measure anti-malaria IgG antibody levels using Enzyme-Linked Immunosorbent Assay (ELISA) and then screened for 14 sICMs the using the Luminex assay. Results: From the systemic review, 47 articles from the systematic review are included in this study. 44 of the articles showed that increased levels of sICMs are biomarkers of inflammation and disease severity. Three articles showed that reduced levels are associated with reduced pathogenesis. From the secondary analysis of MC data, regression analysis showed sIL-2Rα (Interleukin 2 receptor alpha) is associated with active MC. However, sTIM-3 (T cell immunoglobulin and mucin domain 3), sCD27, sE-cadherin, and sCD80 were negatively associated with MC. Random Forest analysis showed that sIL-2Rα, sTIM-3, sCD27, sCD80, and sEcadherin could predict patients with inflammation. Distinct clustering patterns from Principal component analysis (PCA) separated patients with active MC from the control group. The experimental procedure failed to measure sICMs in the malaria samples. Conclusion: Increased levels of sICMs symbolize an ongoing inflammation. Soluble IL2Rα was associated with MC and may be used to predict patients with inflammation. These results shed some light that sIL-2Rα can potentially play a role in the pathogenesis of inflammatory diseases. This study however failed to measure the levels of sICMs in malaria; therefore, a gap exists to explore and compare the levels of sICMs in plasma from children in high and low malaria transmission areas.