Platelet-Derived Soluble CD40L and Its Impact on Immune Modulation and Treatment Outcome in Rheumatoid Arthritis

Background: Platelets (PLTs) from healthy donors (HD) modulate T lymphocyte respons-es but PLTs from rheumatoid arthritis (RA) patients contribute to persistent systemic in-flammation. This suggests that PLTs from RA patients and HD have different immuno-modulatory effects. Methods: Using cell culture, flow cytometry, proteomics, and ELISA, we compared PLTs from HD and RA patients and their effects on T lymphocyte activation and cytokine pro-duction. Results: HD PLTs suppressed T lymphocyte proliferation and IFNγ and TNF production, while RA PLTs exhibited reduced suppressive capacity. In the presence of RA PLTs, IFNγ levels correlated with T lymphocyte proliferation, greater disease activity and ACPA. Pro-teomic analysis revealed that RA PLTs show upregulation of proteins linked to acute-phase response and complement activation. RA PLTs secreted higher levels of solu-ble CD40L (sCD40L) and PDGF-BB that correlated with enhanced IFNγ production. Sero-positive RA patients had higher levels of sCD40L and these levels were predictive of dis-ease remission in RA patients treated with anti-IL6R. sCD40L was found to enhance T lymphocyte activation and to contribute to increased pro-inflammatory cytokine produc-tion. Conclusion: This study highlights the diminished ability of RA PLTs to suppress T lym-phocyte activation and that sCD40L can be a potential biomarker and therapeutic target in RA.