Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.784499
Title: The role of intracellular complement in the induction of ineffective CD4+ T-cell mediated immune responses in myelodysplastic syndrome (MDS)
Author: Al-Shouli, Samia Towfeek S.
ISNI:       0000 0004 7970 048X
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Abstract:
Myelodysplastic syndrome (MDS) is a relatively uncommon clonal haematological disease that is characterised by peripheral blood cytopenias despite a normal or hypercellular bone marrow. The disease transforms to acute myeloid leukaemia in up to 40% of cases. Several studies have established that the T-cell mediated immune dysregulation is an important feature of MDS. Low risk MDS is associated with a pro-inflammatory environment and an increase in IL-17 producing T-cells as well as an increase in the serum IL-17, IL-12, RANTES and IFN-γ. In contrast, IL-10 (inhibitory factor) and IL-2R (soluble receptor) are increased in high risk MDS. A high number of IL-17 producing CD4+ T-cells are found in low-risk MDS compared to the high-risk disease where expansion of T regulatory cells (Tregs) is the main feature. However, the mechanism for this switch in the immune signature is not fully understood. Immune cell derived complement activation fragments are recently identified as key players in driving and modulating adaptive immunity, C3a and C3b. C3 fragments C3a and C5a are particularly important in induction of IFN-γ secretion through autocrine engagement of the C3a receptor and CD46 (C3b receptor). The activation pathway following CD46 activation varies between Tconv and Tregs and the balance between these pathways is crucial for the Treg/Tconv equilibrium. The objective of this project was to elucidate the role of intracellular complement components (C3a and C5a), regulators (CD46) and their receptors (C3aR, C5aR1 and C5aR2) in the expansion of T regulatory cells, which is one of the main factors in the progression of high-risk MDS patients towards AML. In conclusion, this work shows for the first time the potential role of complement in CD4+ T-cells polarisation in MDS patients and provides data on three major pathways that may be implicated in the lack of complement in T-cells of MDS patients. Future work to explore these further may help to identify potential molecules involved which can serve as potential therapeutic targets in MDS in the future.
Supervisor: Mufti, Ghulam Jeelani ; Kordasti, Shahram Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.784499  DOI: Not available
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