Immune Tolerance Breakdown in Pregnancy: Transplantation Parallels in Chronic Intervillositis and Villitis of Unknown Etiology

Abstract

Pregnancy represents a unique immunological paradox, requiring a delicate balance between immune tolerance and protective immune responses. While historically conceptualized as a semi-allogeneic graft, emerging evidence suggests that the maternal-fetal interface is a highly specialized immune environment with distinct regulatory mechanisms. Disruptions in these mechanisms have been implicated in severe obstetric complications, including chronic histiocytic intervillositis and villitis of unknown etiology, which exhibit striking immunopathological similarities to solid organ transplant rejection. This expert review examines the fundamental principles of maternal-fetal immune tolerance, focusing on complement regulation, decidual natural killer cells, regulatory T cells, and trophoblastic immune evasion strategies, including HLA-G expression and extracellular vesicle-mediated immunomodulation. We further explore how failures in these tolerance mechanisms can lead to T-cell-mediated rejection and antibody-mediated rejection, highlighting their mechanistic parallels with transplantation immunobiology. Chronic intervillositis and villitis share key histopathological features with T-cell-mediated rejection and antibody-mediated rejection, including the infiltration of maternal cytotoxic T cells, the presence of donor-specific anti-HLA antibodies, and the deposition of complement component C4d in the placental microvasculature. The loss of immune privilege at the maternal-fetal interface, marked by aberrant HLA class I and II expression on chorionic villi, recapitulates classical mechanisms of allograft rejection. These findings strongly suggest that intervillositis and villitis represent manifestations of maternal immune rejection, emphasizing the need for targeted immunomodulatory approaches. These insights have profound implications for developing novel therapeutic strategies. Building on approaches used in transplantation medicine, emerging evidence supports the potential role of intravenous immunoglobulins, hydroxychloroquine, and targeted inflammasome inhibition in managing these obstetric syndromes. Despite these advancements, further research is required to refine diagnostic biomarkers and optimize immunomodulatory treatments. Recognizing chronic intervillositis and villitis of unknown etiology as immune rejection syndromes not only enhances our understanding of immune tolerance but also offers new avenues for integrating transplant-derived immunomodulatory strategies into obstetric care. A multidisciplinary approach involving obstetricians, immunologists, and transplant specialists will be essential in translating these insights into clinical practice.

Keywords: C4d; FSA; HLA; T cells; T-cell-mediated rejection; allograft; alloimmunity; antibody-mediated rejection; chonic intervillositis; complement; growth restriction; immunomodulatory treatments; maternal-fetal tolerance; pregnancy complications; transplantation; villitis of unknown etiology.