Cornish, Emily; (2025) Chronic histiocytic intervillositis: a manifestation of maternal rejection of the placenta? Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chronic histiocytic intervillositis (CHI) is an inflammatory placental disorder that affects 1 in 2,000 pregnancies. It can only be diagnosed through placental histology and is defined by accumulation of CD68+ maternal macrophages in the intervillous space. CHI is strongly associated with miscarriage, stillbirth and severe fetal growth restriction. It recurs in over 50% of affected women and there are no biomarkers or treatments proven to predict or prevent recurrence. The aetiology of CHI is poorly understood, but it is thought to be driven by an abnormal maternal immune response to the developing placenta. The aim of this work was to investigate the pathogenesis of CHI, focusing specifically on: 1) the role of maternal antibody-mediated rejection of the feto-placental allograft; and 2) the contribution of dysregulated endometrial immune cell activity. To achieve this, I recruited a cohort of 54 affected women and 23 healthy controls. I found that CHI was strongly associated with coexistent maternal autoimmune disease (33%), asymptomatic autoantibody positivity (25%) and high levels of complement-fixing antibodies against paternally-inherited placental HLA antigens. Consistent with these findings, maternal immunosuppression with an anti-rejection regimen of prednisolone, azathioprine and tacrolimus significantly improved live birth rate (75%, vs. 17% in untreated pregnancies, p<0.0001). Together, these data provide compelling support for an antibody-mediated rejection mechanism in CHI. I also showed that the co-inhibitory immune checkpoint molecules TIGIT and PD-1 are significantly downregulated in endometrial T cells in women with CHI, compared to healthy controls, using high-dimensional flow cytometry to study immune cells isolated from menstrual blood. This indicates dysregulation of the endometrial immune environment prior to pregnancy in affected women, providing a rationale for preconception immunosuppression. This is the first study to analyse the endometrial immune phenotype in CHI and to demonstrate the clinical benefit of anti-rejection therapy in prevention of recurrent pregnancy loss.

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