Title: Adaptive immune-mediated endometrial tissue dysfunction in recurrent pregnancy loss
Funder: The Academy of Medical Sciences

Abstract: This project will investigate the immune landscape in the peri-implantation endometrium, using single cell transcriptomics and high-throughput flow cytometry protein expression profiling. I will specifically focus on T and B cell subpopulations, with detailed antigen receptor analysis to study clonal diversity and identify potential cellular pathogenicity. I will define immune populations in healthy women and compare to those with recurrent pregnancy loss (RPL). For 50-70% of couples seeking medical advice for RPL, no cause can be found and there are few evidence-based treatments. The most commonly identified known risk factor for RPL (15-20% of women) is the presence of antiphospholipid antibodies that define the autoimmune disorder anti-phospholipid syndrome (APS), however the localized mechanism that causes pregnancy loss is unknown. Upon embryo implantation the endometrium undergoes decidualization, dynamic cellular changes producing factors not only required for embryonic growth but also triggering immune cell dependent cascades that orchestrate repair to the breached epithelial barrier, remodelling of spiral artery endothelium enabling placentation, and tolerance mechanisms to the semi-allogeneic fetus. My previous research has identified phenotypic changes in the endometrium of women with RPL, to both Treg and CD8T cells, and increased numbers of B cells. The study will focus on both patients with APS and RPL, and RPL with no known cause, comparing to controls. This fellowship will allow me to dissect endometrial adaptive immunity with the aim of identifying patients that would benefit from immune modulators.

Lay abstract: Up to 1 in 25 women have 2 consecutive miscarriages that occur before 24 weeks' pregnancy, clinically termed Recurrent Pregnancy Loss (RPL). For the majority of patients, no reason is found for the miscarriages, although a significant proportion of RPL is linked with an autoimmune disorder called antiphospholipid syndrome (APS), in which women have abnormal antibodies, called phospholipid autoantibodies. The ways in which these autoantibodies cause miscarriage and other pregnancy complications are unknown and pregnancy outcomes remain poor even with recommended treatments. Importantly RPL also predisposes women to an increased lifetime risk of developing cardiovascular disease and, if women do have a continuing pregnancy, other complications such as pre-term birth and low birthweight babies are more frequent. Pregnancy begins when an embryo implants into the endometrium (the lining of the womb) and animal models indicate that local immune cells are critically important, if a specific type of immune cells known as 'T regulatory' cells are not present in the endometrium, the mice miscarry. My prior research has shown that T regulatory cells are altered in women with RPL, which may partly explain the miscarriages. In addition, B cells, that produce antibodies such as those in antiphospholipid syndrome, are increased in RPL endometrium, but they have not been investigated in patients with APS and RPL. This project aims to fully characterise T and B cells in the endometrium to help us reveal the underlying immune causes in RPL, providing a rationale for novel treatment strategies (that target immune cells).

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH