CD40-CD40L interactions in systemic autoimmune diseases

Systemic autoimmune diseases arise from a heterogeneous interplay of genetic, epigenetic, and environmental factors that culminates in loss of tolerance, chronic inflammation, and tissue injury. Among the pathways linking susceptibility to effector disease, CD40-CD40L is a central regulator of antigen presentation, T-B cell collaboration, and germinal centre responses, while also contributing to extrafollicular autoantibody production. In this review, we first introduce the disease-specific rationale for targeting CD40-CD40L interactions, with a particular focus on systemic lupus erythematosus, Sjögren's disease, and rheumatoid arthritis. We then summarize the multifaceted roles of CD40-CD40L signalling across adaptive immunity, innate immune priming, tissue inflammation, and platelet-driven thrombo-inflammation. Finally, we review the therapeutic translation of this pathway, highlighting insights from early trials of anti-CD40/CD40L antibodies and recent advances in Fc-silent antibody engineering that preserve target binding while minimizing platelet activation. Together, these data support CD40-CD40L blockade as a renewed and promising mechanism-based strategy in systemic autoimmune rheumatic diseases.