Narrative review discusses CD40/CD40L signaling regulation in rheumatoid arthritis and other autoimmune conditionsSafer CD40/CD40L targeting needs selectivity for autoimmune diseases

The CD40–CD40L axis is a central costimulatory pathway that links innate and adaptive immunity and contributes to autoimmune inflammation. However, CD40 signaling does not operate in the same way across cell types, and these differences are relevant to both therapeutic efficacy and safety. In this review, we discuss the molecular features of CD40 and CD40L, the TRAF-dependent signaling pathways activated downstream of CD40, and the distinct cellular responses observed in B cells, dendritic cells, and macrophages. We also examine how dysregulated CD40/CD40L signaling contributes to key pathological features of Rheumatoid arthritis, Systemic lupus erythematosus, and Sjögren’s syndrome, including ectopic germinal center reactions, pathogenic autoantibody production, and chronic tissue inflammation. Platelet-derived CD40L and CD40 expression on vascular cells may also help explain the thromboembolic complications observed with early CD40/CD40L-targeted biologics. Current evidence suggests that safer therapeutic targeting of this pathway will require greater selectivity, particularly with respect to cell-specific signaling and Fc-mediated adverse effects.