Evaluation of the immune phenotype of women with recurrent pregnancy loss

Bagkou Dimakou, Danai ORCID: 0000-0002-7085-0188 (2022). Evaluation of the immune phenotype of women with recurrent pregnancy loss. University of Birmingham. Ph.D.

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Abstract

The current working hypothesis in recurrent pregnancy loss (RPL) suggests an immune dysregulation in women with this condition, with most studies highlighting an increase in natural killer (NK) cell numbers and cytotoxicity and a shift towards T helper (TH) cell pro-inflammatory cytokine secretion, termed “Type-1/Type-2 hypothesis”. Experimental findings however remain contentious, hindering the introduction of immunological testing into clinical practice, despite the increasing pressure from clinicians and couples affected.
Through a nationwide survey, a strong variation in clinical practice was observed, with different definitions of RPL used and multiple tests employed for the identification of potential risk factors. Immunological testing was offered in 3 (9.38%) clinics included, while several therapies, including immunomodulatory agents, were utilised for the management of idiopathic RPL, underlining the need for further research into the role of the immune system in this condition.
Using peripheral blood samples from non-pregnant women with RPL and healthy controls, a broad immunophenotypic analysis was performed, confirming the NK cell increase and revealing a reduction in T cell prevalence in women with RPL. Further examination by mass cytometry displayed a decrease in regulatory-like T and B cell subsets and an increase in a plasma cell-like subpopulation, although validation of these findings utilising additional markers is required.
The elevated NK cell cytotoxicity, often referenced in RPL, was undetectable in the present study, although an increased degranulation capacity of these cells was seen. Cytolytic molecule release by peripheral blood mononuclear cells (PBMCs) appeared reduced in women with RPL, possibly counterbalancing the enhanced degranulation. A unique mass cytometry panel was employed for the detailed investigation of activating and inhibitory receptor expression on NK cells. Increased prevalence of mature cytotoxic CD57+ NK cells was detected in the RPL population, accompanied by an increase in subsets lacking the expression of multiple inhibitory receptors, indicating an enhanced responsiveness of the NK cell population to activating signalling.
Furthermore, elevated pro-/anti-inflammatory cytokine-producing TH cell ratios were detected in women with RPL, accompanied however by decreased pro-/anti-inflammatory cytokine expression intensity on these cells. NK cell cytokine production appeared deficient in women with this condition. Interestingly, the shift towards pro-inflammatory molecules was evident when the levels of cytokine secretion by PBMCs were assessed, in agreement to the Type-1/Type-2 hypothesis. Pro- and anti-inflammatory cytokine secretion by PBMCs also appeared elevated in women with RPL and a following miscarriage, compared to those that were either in the 3rd trimester of their subsequent pregnancy or had a live birth, highlighting a potential prognostic capacity of these markers.
The findings of the present study highlight a dysregulation in peripheral immunity of women with RPL, which cannot however be appropriately described using a pro-/anti-inflammatory dichotomy. Although certain immune parameters, such as elevated NK cell levels, could provide potential diagnostic biomarkers, with plausible prognostic markers also proposed, further research on both peripheral and uterine samples is required to fully elucidate the role of the immune system in RPL, allowing the introduction of immunological testing into clinical practice.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):