Abstract
Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory lesion increasingly viewed through maternal-foetal immune rejection. In this invited commentary, we discuss how a recent study bolsters the paradigm that CHI represents maternal immune rejection of the semi-allogeneic foetus, analogous to antibody-mediated rejection in organ transplantation. We highlight the shared histological and molecular features between CHI and kidney allograft rejection, including macrophage-dominated inflammation, complement activation, and interferon-gamma-driven gene expression signatures and explore the implications of this common pathogenesis for clinical practice. Recognising CHI as an alloimmune process opens new avenues for early prediction, diagnosis, and intervention. We particularly emphasise the need for early identification of CHI, even in a first pregnancy, where no prior obstetric history exists to raise suspicion. Finally, we outline how transplant immunotherapy principles (e.g. immunosuppression and immune modulation) could transform the management of CHI, and we call for forward-looking research that bridges immune pathology, maternal-foetal medicine, and translational therapeutics to improve pregnancy outcomes. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.