Chronic histiocytic intervillositis: manifestation of placental alloantibody-mediated rejection

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Chronic histiocytic intervillositis (chronic intervillositis) is defined by a diffuse infiltration of monocytes into the intervillous space, which often leads to poor obstetrical outcomes, including recurrent intrauterine growth restriction, miscarriage, and fetal death. The pathogenesis of chronic intervillositis is still poorly defined, and there is an unmet medical need for improved management. This study aimed to demonstrate the role of anti-human leukocyte antigen alloantibodies in the pathogenesis of chronic intervillositis through the application of criteria used in solid-organ transplantation for the diagnosis of antibody-mediated rejection. A multidisciplinary research study based on thorough immunologic and pathologic investigations was carried out for 2 separate couples who experienced recurrent secondary fetal losses following a first normal pregnancy associated with histologic evidence of chronic intervillositis. Very high levels of complement-fixing, fetus-specific antibodies targeting mismatched human leukocyte antigen alleles, harbored by the 2 paternal haplotypes, were identified in both cases. Polymorphic human leukocyte antigens were expressed on the surface of trophoblastic villi of the inflamed placenta but not in healthy placental tissue. The binding of alloantibodies to paternal human leukocyte antigens induced dramatic activation of the complement classical pathway in trophoblastic villi, leading to C4d deposition and formation of the terminal complex C5b-9. All requirements for the diagnosis of antibody-mediated placental rejection were fulfilled according to the criteria used in the Banff classification of allograft pathology. In silico analysis was performed using a human leukocyte antigen epitope viewer to reconstitute the human leukocyte antigen sensitization history. Reactivity against a single mismatched epitope present in the first-born healthy child accounted for a broad sensitization to human leukocyte antigens, including those harbored by the 2 paternal haplotypes. This finding explained the high rates of chronic intervillositis recurrence during subsequent pregnancies. This study provides novel mechanistic insights into the pathogenesis of chronic intervillositis and provides new avenues for individualized counseling and therapeutic options.