Author Identifier

John Taylor: http://orcid.org/0000-0002-7056-9660

Date of Award

2025

Document Type

Thesis - ECU Access Only

Publisher

Edith Cowan University

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Supervisor

Claus Christophersen

Second Supervisor

Deborah Strickland

Third Supervisor

Archita Mishra

Fourth Supervisor

Shailender Mehta

Fifth Supervisor

James Read

Abstract

Gestational diabetes mellitus (GDM) account for about 14% of all metabolic diseases in pregnant women and has been associated with dysregulated metabolic, hyperglycemia and maternal immune activation. However, the impact of the in-utero exposure to this metabolic environment on the developing immune system of the infant is not known. This is important for the future health of the child as an altered immune development places the infant at an increased risk of infections and other complicated diseases. The thesis presents a number of studies to understand the role of GDM on the maternal and infant immune profile in the first 3 months of life. Chapter 1 of the thesis is an introduction and review of the literature, which reviews the occurrence of GDM and demonstrates how GDM could influence the infant immune development, and the mechanisms involved, while Chapter 2 describes the methods and approaches employed in the thesis. The study was designed to address three aims, which will be covered in this thesis. Firstly, the maternal immune environment was assessed using a 48-plex cytokine Luminex assay, flow cytometry to identify several immune subsets and phenotypes and RNA sequencing to explore the transcriptome (Chapter 3). Secondly, the effect of the maternal environment on the immune profile of infants in the first 3-7 days of life was assessed (chapter 4) and finally, the last aim was to model the status of the infant immune profile at 3 months of life on in-utero exposure to GDM accounting for maternal obesity (chapter 5). Lastly, Chapter 6 provides a general discussion of findings, limitations, recommendations, and opportunities for improving infant immune development.

In the third trimester of pregnancy, we found an anti-inflammatory bias, characterised by increased IL-1ra in GDM positive women (p = 0.021), with no changes in immune cells and subsets but an increased CD25 expression on CD4+ regulatory T cells (p = 0.047). After accounting for maternal obesity, the most upregulated gene was the Humanin-like protein 1 which is thought to protect cells from stress induced damage and apoptosis, regulate insulin sensitivity and protect against diseases such as type 2 diabetes. The most downregulated gene was cytochrome P450 family 26 subfamily B member 1 (CYP26B1) which codes for enzymes involved in retinoic acid (RA) conversion into inactive forms, reducing RA availability in pregnant mothers. In infants in the first 3-7 days of life, no changes in immune cells were observed (p > 0.05 for all immune subsets). Similar as found in mothers, we found an anti-inflammatory cytokine profile characterised by decreased pro-inflammatory TNF-β in infants in the first week of life (p = 0.039), which remained significant after accounting for obesity (p = 0.0378). TNF-α also increased in the first week of life (p = 0.0451), however, this was non-significant after accounting for obesity (p = 0.0939). Higher CD11c and CD25 MFI were found on classical monocytes and CD4 Tregs respectively, however this was non-significant after accounting for maternal obesity in infants in the first 3-7 days of life. At 3 months of life, we found an enhanced pro-inflammatory environment characterised by higher MCP-1/MCAF (p = 0.0302) and PDGF-bb (p = 0.0260), which both remained significant after accounting for obesity. Overall, less effect of GDM on the transcriptome of infants at 3 months of life was observed and immune cell changes remained comparable at this time point. The findings of this thesis support the prevailing hypotheses that a tightly balanced maternal immune environment may be required for infant development and may not be strongly influenced by environmental factors such as GDM.

Access Note

Access to this thesis is embargoed until 6th November 2030

DOI

10.25958/3mt7-hp74

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Available for download on Wednesday, November 06, 2030

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