Exploration of antibody-mediated immunity in chronic histiocytic intervillositis reveals no evidence of maternal anti-fetal rejection

Abstract Chronic histiocytic intervillositis (CHI) is a recurrent placental lesion where maternal macrophages infiltrate the intervillous space. Currently, its cause is unknown, though due to similarities to rejected allografts one hypothesis is that CHI represents maternal-fetal rejection. Here, virtual crossmatching was applied to healthy pregnancies and those with a history of CHI. Plasma anti-HLA antibodies were measured via Luminex, and percentage calculated reaction frequency (%cRF) determined. Antibodies were compared to fetal HLA to identify fetal specific antibodies (FSAs). Immunohistochemistry was used to identify placental C4d in untreated (index) CHI, subsequent pregnancies and healthy controls. There were no significant differences in C4d deposition between controls, index pregnancies with CHI and subsequent pregnancies, (control 0.75 [IQR 0-1.1] vs index 1.06 [0.3–1.6] vs subsequent pregnancies 1.13 [0.6–1.4]). Anti-HLA antibodies were present in slightly more controls than CHI (8/17 (47.1%) vs 6/15 (40.0%), respectively), but there was no significant difference in levels of sensitisation or %cRF. There was no difference in FSAs between controls and CHI cases (median 2 [IQR 0-3.8] vs 5 [1.0–6.0]). Though CHI shares some similarities with rejection, an antibody-mediated component could not be confirmed. These data suggest that CHI may not result from anti-HLA antibodies, but immunomodulatory treatment is an important confounding factor. Further investigation of antibodies independent of treatment is required to determine any possible role in the pathophysiology of CHI.