The role of mast cells and Th9 cells under estrogen influence in endometriosis pathophysiology
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Authors
McCallion, Alison
Date
2024-10-29
Type
thesis
Language
eng
Keyword
Endometriosis , mast cell , T helper cell , pathophysiology , inflammation , cytokine , interleukin 9
Alternative Title
Abstract
Endometriosis is a chronic, estrogen-dependent, inflammatory gynaecologic disease wherein endometrium-like tissue grows at sites outside the uterus, primarily in the peritoneal cavity, and causes severe pain and infertility. Unfortunately, no curative therapeutic options exist for endometriosis, partially because of the incomplete understanding of its complex pathophysiology. Many facets, including genetics and hormonal imbalance, contribute to disease progression. Importantly, our group and others have identified that immune dysregulation plays central role in the pathophysiology of endometriosis. A lesser-studied aspect is the influence of estrogen dominance on the immune dysregulation that propels this disease. Within this context, the work presented in this thesis focuses upon mast cells and a subset of T helper cells, called T helper 9 (Th9) cells, in endometriosis. Mast cells (MCs) are known for their role in allergic reactions and are implicated in various inflammatory diseases. Th9 cells produce interleukin-9 (IL-9), a cytokine that is vital for mast cell development, but also independently involved in several inflammatory responses. Relationships between these immune cells have been identified in other inflammatory diseases; however, it is not known if Th9 cells contribute to endometriosis, either independently or in concert with MCs. We hypothesized that MCs contribute to endometriosis-associated inflammation, scaffolded by the impacts of high estrogen. Within our human patient samples, increased MC presence was discovered both histologically and through upregulation of MC-relevant genes in endometriotic lesion tissue. In the in vivo experiments, we found that estrogen altered MC populations and relevant transcripts in mice induced with endometriosis. Based on these observations, we hypothesized that Th9 cells and MCs collaborate to exacerbate the inflammatory and proliferative environment of endometriotic lesions, and
sought to validate whether this relationship is regulated by elevated estradiol levels. Dysregulated IL-9 signalling in endometriosis was evidenced by elevated IL-9 presence in human endometriotic lesions. We uncovered details of crosstalk between human Th9-driven lymphocytes and MCs under the influence of estrogen in vitro. In our mouse model, we provided evidence that adoptively transferred Th9 cells alter lesion proliferation and transcriptional profile of endometriotic lesions. These findings deepen our understanding of how immune-endocrine mechanisms affect MC involvement in endometriosis and lay groundwork for investigating participation of Th9 cells in endometriosis.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.