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postgraduate thesis: Sublethal iron overload can alter the morphology and function of dendritic cells which may predispose to gram-negative infection in beta-thalassemia

TitleSublethal iron overload can alter the morphology and function of dendritic cells which may predispose to gram-negative infection in beta-thalassemia
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Dee, C. M. A. [李明芳]. (2014). Sublethal iron overload can alter the morphology and function of dendritic cells which may predispose to gram-negative infection in beta-thalassemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5387950
AbstractIron overload is the most common complication in transfusion-dependent thalassemias. Iron overloaded patients are frequently susceptible to gram-negative organisms such as Klebsiella pneumonaie. Literature has shown that iron overload can alter immune response but hitherto little work has been done on the effect of iron-overload on dendritic cells or T helper cells. We aimed to investigate if iron overload in beta thalassemia patients can predispose to gram-negative infection. First, we investigated the effect of iron overload on Th-related cytokine expression in β-thalassemia patients. All iron overload patients on various chelators had suppressed Th1-; Th2- or Th17-related cytokine expression. Only IL23 was elevated but it was not associated with an elevated Th17 response. Next we evaluated iron overload using two recently developed assays and examined the strength of association between iron overload and Th cytokine expression. Short term iron overload were inversely associated with Th1-, Th2- and Th17- cytokine expression levels with the exception of IL23. However, confounding variables such as the effect of blood transfusion could not be completely ruled out. Therefore, we used monocyte derived dendritic cells (DCs) as our model, since DCs direct the class and magnitude of the T helper cell response. Iron overload suppressed IL12 and IL23, cytokines critical for Th1 and Th17 expansion, and increased IL4, crucial for Th2 generation. There was a concurrent increase in Th2 cells and suppression of Th1 and Th17 cell populations. The expansion of Th2 cell population was not only induced by an increase in DC-mediated IL4 expression, but also from PDL2 suppression. The increase in CD4+ cell proliferation could also be explained by suppressed PDL2. We confirmed that these results were not due to iron-induced cellular apoptosis. Since Th1 and Th17 are critical for protective immunity against pathogenic gram-negative bacteria, our results provided a possible explanation as to why iron overloaded beta-thalassemia patients are prone to K. pneumoniae infections. The defective Th17 response correlated well with our clinical data obtained from thalassaemia patients. Aside from the functional effect, we also observed that iron overload affects the morphology of mature DCs. We used various gram-negative analogues to show that iron overload could increase dendrite formations and decrease cellular aggregations in mature but not immature DCs. This phenomenon was abrogated by deferasirox. We also showed that iron overload induced dynamic remodeling of dendrite formations and cell aggregates ex vivo. We investigated the mechanisms involved by using inhibitors specific for MAPK pathway proteins. Iron augments LPS-induced phosphorylation of p38 leading to increased dendritic formations. Iron also enhances LPS-induced phosphorylation of JNK to suppress cell aggregation. Finally, we investigated an adverse effect associated with deferasirox use. Deferasirox is a commercially available iron chelator indicated for iron overload β-thalassemia. Compared to those on other chelation regimens, patients on deferasirox were more likely to develop renal tubular dysfunction, and/or serum electrolyte imbalances. These effects were reversible with suspension or dose reduction of deferasirox. Vigilant monitoring of renal tubular dysfunction and serum electrolyte is recommended in patients who receive deferasirox.
DegreeDoctor of Philosophy
SubjectIron - Pathophysiology
Dendritic cells
Thalassemia
Dept/ProgramPaediatrics and Adolescent Medicine
Persistent Identifierhttp://hdl.handle.net/10722/221235

 

DC FieldValueLanguage
dc.contributor.authorDee, Cathleen Michelle Ang-
dc.contributor.author李明芳-
dc.date.accessioned2015-11-06T23:11:50Z-
dc.date.available2015-11-06T23:11:50Z-
dc.date.issued2014-
dc.identifier.citationDee, C. M. A. [李明芳]. (2014). Sublethal iron overload can alter the morphology and function of dendritic cells which may predispose to gram-negative infection in beta-thalassemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5387950-
dc.identifier.urihttp://hdl.handle.net/10722/221235-
dc.description.abstractIron overload is the most common complication in transfusion-dependent thalassemias. Iron overloaded patients are frequently susceptible to gram-negative organisms such as Klebsiella pneumonaie. Literature has shown that iron overload can alter immune response but hitherto little work has been done on the effect of iron-overload on dendritic cells or T helper cells. We aimed to investigate if iron overload in beta thalassemia patients can predispose to gram-negative infection. First, we investigated the effect of iron overload on Th-related cytokine expression in β-thalassemia patients. All iron overload patients on various chelators had suppressed Th1-; Th2- or Th17-related cytokine expression. Only IL23 was elevated but it was not associated with an elevated Th17 response. Next we evaluated iron overload using two recently developed assays and examined the strength of association between iron overload and Th cytokine expression. Short term iron overload were inversely associated with Th1-, Th2- and Th17- cytokine expression levels with the exception of IL23. However, confounding variables such as the effect of blood transfusion could not be completely ruled out. Therefore, we used monocyte derived dendritic cells (DCs) as our model, since DCs direct the class and magnitude of the T helper cell response. Iron overload suppressed IL12 and IL23, cytokines critical for Th1 and Th17 expansion, and increased IL4, crucial for Th2 generation. There was a concurrent increase in Th2 cells and suppression of Th1 and Th17 cell populations. The expansion of Th2 cell population was not only induced by an increase in DC-mediated IL4 expression, but also from PDL2 suppression. The increase in CD4+ cell proliferation could also be explained by suppressed PDL2. We confirmed that these results were not due to iron-induced cellular apoptosis. Since Th1 and Th17 are critical for protective immunity against pathogenic gram-negative bacteria, our results provided a possible explanation as to why iron overloaded beta-thalassemia patients are prone to K. pneumoniae infections. The defective Th17 response correlated well with our clinical data obtained from thalassaemia patients. Aside from the functional effect, we also observed that iron overload affects the morphology of mature DCs. We used various gram-negative analogues to show that iron overload could increase dendrite formations and decrease cellular aggregations in mature but not immature DCs. This phenomenon was abrogated by deferasirox. We also showed that iron overload induced dynamic remodeling of dendrite formations and cell aggregates ex vivo. We investigated the mechanisms involved by using inhibitors specific for MAPK pathway proteins. Iron augments LPS-induced phosphorylation of p38 leading to increased dendritic formations. Iron also enhances LPS-induced phosphorylation of JNK to suppress cell aggregation. Finally, we investigated an adverse effect associated with deferasirox use. Deferasirox is a commercially available iron chelator indicated for iron overload β-thalassemia. Compared to those on other chelation regimens, patients on deferasirox were more likely to develop renal tubular dysfunction, and/or serum electrolyte imbalances. These effects were reversible with suspension or dose reduction of deferasirox. Vigilant monitoring of renal tubular dysfunction and serum electrolyte is recommended in patients who receive deferasirox.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshIron - Pathophysiology-
dc.subject.lcshDendritic cells-
dc.subject.lcshThalassemia-
dc.titleSublethal iron overload can alter the morphology and function of dendritic cells which may predispose to gram-negative infection in beta-thalassemia-
dc.typePG_Thesis-
dc.identifier.hkulb5387950-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePaediatrics and Adolescent Medicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5387950-

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