Immune Response Mechanisms in Haemophilia A

Haemophilia A (HA) is an X-linked bleeding disorder caused by the deficiency or dysfunction of coagulation factor VIII (FVIII). Substitution therapy with recombinant or plasma-derived FVIII effectively restores haemostasis but carries the risk of eliciting FVIII-specific neutralizing antibodies known as inhibitors. Inhibitor formation reflects the absence of central immune tolerance, driven by complex interactions among antigen-presenting cells, B cells and CD4 T cell subsets. Recent studies highlight the essential roles of T cell polarization, costimulatory signalling and cytokine networks in shaping the immunogenic or tolerogenic outcome of FVIII exposure. This review summarizes mechanistic insights into how distinct CD4 T cell subpopulations, including Th1, Th2, Th17, follicular helper (Tfh), follicular regulatory (Tfr) and regulatory T cells (Tregs), influence inhibitor development in HA. Furthermore, it discusses emerging immunological concepts and cellular pathways that could be targeted to achieve durable tolerance towards FVIII, with emphasis on translational strategies that align mechanistic understanding with clinical need.