- Title
- Characterising the immunopathology of functional dyspepsia
- Creator
- Burns, Grace
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Functional gastrointestinal disorders (FGIDs) describe a range of chronic gastrointestinal (GI) conditions traditionally characterised by a lack of obvious pathological or biochemical abnormality. Diagnosis of these disorders is reliant on self-reported symptom patterns according to the Rome Criteria. FGIDs represent a considerable burden on the healthcare system, with approximately half of all general practice consultations regarding GI symptoms resulting in a diagnosis of an FGID, such as irritable bowel syndrome (IBS) or functional dyspepsia (FD). FD is characterised by recurrent symptoms of post-prandial fullness and early satiety, epigastric pain and burning, bloating, belching and nausea. Duodenal eosinophilia and increased proportions of T cells homing to the gastrointestinal tract (GIT) have been identified as hallmarks of this condition, challenging the designation of this condition as ‘functional’. However, to date, no mechanism has conclusively demonstrated the role of the adaptive immune system in FD. Further, the stigma and debilitating symptoms associated with FGIDs, combined with a lack of effective therapies or management strategies, contribute to high social and economic costs of these conditions. The current symptom-based diagnostic method for FGIDs has major limitations and would be enhanced by the characterisation of the underlying mechanism. Given the emergence of microinflammation as a feature of FD, we hypothesised that a loss of mucosal homeostasis allows for the induction of a T cell mediated immune response, driving symptom onset in FD. The aim of this study was to therefore characterise the immunophenotype in the duodenal mucosa and periphery of FD patients and to determine immune pathways that may contribute to the development and pathophysiology of FD. The first study of this thesis is a systematic review answering the question: ‘Do IBS and FD have clinically definable immune profiles?’. The 51 included studies suggested that the immune activity in FGIDs is likely related to subtle alterations in the activation status of the cellular populations at both the systemic and local level, rather than an influx of newly recruited cells. However, consensus regarding the involvement of specific T cell subsets was lacking. Flow cytometric analysis of T cell subsets in the periphery of FD patients revealed increases in the T helper (Th) 1 and 17.1 subsets. The Th17.1 population was also increased in the mucosa of these patients, along with the Th2 effector memory population. We also demonstrated increased populations of memory T cells in FD patients compared to controls. The findings of this work suggest the immunophenotype of FD more closely resembles that of autoimmune or post-infectious immune responses, rather than an allergic-like phenotype that duodenal eosinophilia suggests. Given no antigens have been conclusively implicated in FD, and the duodenal microbial profile has been shown to be altered in these patients, we then designed a modified immunoblot methodology to test patient plasma for antibodies directed against species of the microbiota. We identified IgG antibodies directed against Streptococcus salivarius cell wall proteins were present in a significant proportion of FD patients compared to controls. This would suggest altered immune-microbiota relationships are a characteristic of FD, and with further characterisation, this finding may become a diagnostic indicator of FD subtypes, providing further insight to the mechanisms that initiate FD. There is an association between self-reported wheat sensitivity and symptom onset in FD, and so the final study of this thesis aimed to determine if gluten or gliadin provoked responses in duodenal T cells isolated from patients. Cells were stimulated with gluten and gliadin before supernatant cytokines were analysed using a cytometric bead array and cell subsets were identified by flow cytometry. Gluten, but not gliadin, provoked an increase in Th17 cells in FD patients but not controls. We also showed the Th17 response to gluten correlated with real-time polymerase chain reaction (PCR) gene expression of T cell receptor alpha variant 26-2 (TRAV26-2), a T cell receptor variant that has previously been associated with the immune response to wheat in coeliac patients. This study suggests that gluten does drive an immune response in a subset of FD patients, and this may be associated with genetic susceptibilities in genes involved in antigen-presentation. These investigations demonstrate antigen-driven, adaptive T cell responses as a feature of FD. Specifically, the increases in Th1 and Th17.1 cells in these patients suggest the immune response is similar to an autoimmune or post-infectious condition. We also identified a mucosal Th2 signature in the effector memory lymphocyte population that might be associated with eosinophilia as a feature of FD. Further, the demonstration of IgG antibodies in plasma from patients directed against a specific species of microbiota isolated from FD patients suggests post-infectious development of FD is more common than currently thought. Collectively, these studies suggest FD is not a functional condition as traditionally accepted, but rather represents immune responses to altered homeostasis. Further identification of these mechanisms will allow for implementation of objective diagnostic measures, allowing for better characterisation of disease subsets to subsequently improved therapeutic response and management for patients.
- Subject
- functional dyspepsia; functional gastrointestinal disorder; immunology; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1468530
- Identifier
- uon:48060
- Rights
- Copyright 2021 Grace Burns
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Thesis | 97 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 364 KB | Adobe Acrobat PDF | View Details Download |