CD40-CD40L interactions in systemic autoimmune diseases.

Authors

Motomu Hashimoto, Masao Katsushima, Fabienne Mackay, Chaim Putterman

Published in

Rheumatology (Oxford, England). Oct 16, 2026. Epub Oct 16, 2026.

Abstract

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.

PMID:
42885554
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.

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