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Postgraduate Thesis: The role of dectin-1 expressing dendritic cells in the pathogenesis ofsystemic lupus erythematosus
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TitleThe role of dectin-1 expressing dendritic cells in the pathogenesis ofsystemic lupus erythematosus
 
AuthorsLuk, Tung-wing.
陸東嶸.
 
Issue Date2011
 
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
 
AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease with diverse manifestations affecting multiple organs. Current understanding of its pathogenesis remains largely inadequate despite recent progress in SLE research on the characterization of immune system dysfunction and its link with heritable and environmental factors. Dendritic cells (DCs) are immune cells that express pattern recognition receptors (PRRs) for the recognition of pathogen associated molecular patterns (PAMPs). Aberrant functions of DCs have been reported in SLE including recognition of self-nucleic acids, presentation of self-antigens and strong induction of interferon response, depending on their expression of PRRs. Dectin-1 is a non-toll like receptor PRR that is highly expressed in DCs for the recognition of pathogenic carbohydrates found mostly in fungi. Recognition of fungal carbohydrates by dectin-1 promotes DC maturation and production of pro-inflammatory cytokines that preferentially skew towards a T helper-17 (Th17) response which has been found to be engaged in the pathogenesis of SLE and other autoimmune diseases. Therefore, the current investigation aimed to study the expression of dectin-1 and the effect of dectin-1 activation in DCs from SLE patients. Dectin-1 expression on CD14+ monocytes from peripheral blood of SLE patients and healthy controls was measured by flow cytometry. SLE patients (mean+/-SD = 92.05+/-3.471%) were found to have higher dectin-1 expression on CD14+ monocytes compared to controls (mean+/-SD = 83.7+/-14.64%) (p=0.02). Monocyte derived DCs (MoDCs) were then derived from CD14+ monocytes in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4. Pre-treated moDCs with curdlan, a dectin-1 specific ligand, showed increased expression of costimulatory molecules including CD83 and CD86 and enhanced production of IL-1β compared with healthy controls (all p<0.05). Curdlan treated moDCs were further co-cultured with CD4+ na?ve T cells and polarization into Th17 cells was subsequently evaluated by measuring the percentage of Th17 per moDCs-na?ve T cells and expression of intracellular IL-17. Curdlan treated moDCs from SLE patients were found to have enhanced Th17 polarization capacity (mean+/-SEM = 28.33+/-5.64%) compared with controls (mean+/-SEM = 12.77+/-2.56%) (p<0.05). To address the mechanism of Th17 polarization, expression of caspase-1 which promotes the production of IL-1β was measured. Curdlan treated moDCs in SLE patients expressed higher levels of caspase-1 detected in the cell lysate as measured using Western Blot compared with healthy controls (p<0.05). In conclusion, compared with healthy individuals, SLE moDCs were more matured and activated in response to β-glucan as shown by their higher expression of co-stimulatory molecules, enhanced production of IL-1β and stronger Th17 polarizing effect. These findings suggest functional dysregulation of dectin-1 expressing DCs in patients with SLE which may be involved in the pathogenesis of this condition.
 
AdvisorsLau, WCS
Mok, TMY
 
DegreeMaster of Philosophy
 
SubjectDendritic cells.
Systemic lupus erythematosus - Pathogenesis.
 
Dept/ProgramMedicine
 
DC FieldValue
dc.contributor.advisorLau, WCS
 
dc.contributor.advisorMok, TMY
 
dc.contributor.authorLuk, Tung-wing.
 
dc.contributor.author陸東嶸.
 
dc.date.hkucongregation2012
 
dc.date.issued2011
 
dc.description.abstractSystemic lupus erythematosus (SLE) is an autoimmune disease with diverse manifestations affecting multiple organs. Current understanding of its pathogenesis remains largely inadequate despite recent progress in SLE research on the characterization of immune system dysfunction and its link with heritable and environmental factors. Dendritic cells (DCs) are immune cells that express pattern recognition receptors (PRRs) for the recognition of pathogen associated molecular patterns (PAMPs). Aberrant functions of DCs have been reported in SLE including recognition of self-nucleic acids, presentation of self-antigens and strong induction of interferon response, depending on their expression of PRRs. Dectin-1 is a non-toll like receptor PRR that is highly expressed in DCs for the recognition of pathogenic carbohydrates found mostly in fungi. Recognition of fungal carbohydrates by dectin-1 promotes DC maturation and production of pro-inflammatory cytokines that preferentially skew towards a T helper-17 (Th17) response which has been found to be engaged in the pathogenesis of SLE and other autoimmune diseases. Therefore, the current investigation aimed to study the expression of dectin-1 and the effect of dectin-1 activation in DCs from SLE patients. Dectin-1 expression on CD14+ monocytes from peripheral blood of SLE patients and healthy controls was measured by flow cytometry. SLE patients (mean+/-SD = 92.05+/-3.471%) were found to have higher dectin-1 expression on CD14+ monocytes compared to controls (mean+/-SD = 83.7+/-14.64%) (p=0.02). Monocyte derived DCs (MoDCs) were then derived from CD14+ monocytes in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4. Pre-treated moDCs with curdlan, a dectin-1 specific ligand, showed increased expression of costimulatory molecules including CD83 and CD86 and enhanced production of IL-1β compared with healthy controls (all p<0.05). Curdlan treated moDCs were further co-cultured with CD4+ na?ve T cells and polarization into Th17 cells was subsequently evaluated by measuring the percentage of Th17 per moDCs-na?ve T cells and expression of intracellular IL-17. Curdlan treated moDCs from SLE patients were found to have enhanced Th17 polarization capacity (mean+/-SEM = 28.33+/-5.64%) compared with controls (mean+/-SEM = 12.77+/-2.56%) (p<0.05). To address the mechanism of Th17 polarization, expression of caspase-1 which promotes the production of IL-1β was measured. Curdlan treated moDCs in SLE patients expressed higher levels of caspase-1 detected in the cell lysate as measured using Western Blot compared with healthy controls (p<0.05). In conclusion, compared with healthy individuals, SLE moDCs were more matured and activated in response to β-glucan as shown by their higher expression of co-stimulatory molecules, enhanced production of IL-1β and stronger Th17 polarizing effect. These findings suggest functional dysregulation of dectin-1 expressing DCs in patients with SLE which may be involved in the pathogenesis of this condition.
 
dc.description.naturepublished_or_final_version
 
dc.description.thesisdisciplineMedicine
 
dc.description.thesislevelmaster's
 
dc.description.thesisnameMaster of Philosophy
 
dc.identifier.hkulb4786999
 
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.source.urihttp://hub.hku.hk/bib/B47869999
 
dc.subject.lcshDendritic cells.
 
dc.subject.lcshSystemic lupus erythematosus - Pathogenesis.
 
dc.titleThe role of dectin-1 expressing dendritic cells in the pathogenesis ofsystemic lupus erythematosus
 
dc.typePG_Thesis
 
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<contributor.advisor>Mok, TMY</contributor.advisor>
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<date.issued>2011</date.issued>
<description.abstract>&#65279;Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse manifestations affecting multiple organs. Current understanding of its pathogenesis remains largely inadequate despite recent progress in SLE research on the characterization of immune system dysfunction and its link with heritable and environmental factors. Dendritic cells (DCs) are immune cells that express pattern recognition receptors (PRRs) for the recognition of pathogen associated molecular patterns (PAMPs). Aberrant functions of DCs have been reported in SLE including recognition of self-nucleic acids, presentation of self-antigens and strong induction of interferon response, depending on their expression of PRRs. Dectin-1 is a non-toll like receptor PRR that is highly expressed in DCs for the recognition of pathogenic carbohydrates found mostly in fungi. Recognition of fungal carbohydrates by dectin-1 promotes DC maturation and production of pro-inflammatory cytokines that preferentially skew towards a T helper-17 (Th17) response which has been found to be engaged in the pathogenesis of SLE and other autoimmune diseases. Therefore, the current investigation aimed to study the expression of dectin-1 and the effect of dectin-1 activation in DCs from SLE patients.

Dectin-1 expression on CD14+ monocytes from peripheral blood of SLE patients and healthy controls was measured by flow cytometry. SLE patients (mean+/-SD = 92.05+/-3.471%) were found to have higher dectin-1 expression on CD14+ monocytes compared to controls (mean+/-SD = 83.7+/-14.64%) (p=0.02). Monocyte derived DCs (MoDCs) were then derived from CD14+ monocytes in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4. Pre-treated moDCs with curdlan, a dectin-1 specific ligand, showed increased expression of costimulatory molecules including CD83 and CD86 and enhanced production of IL-1&#946; compared with healthy controls (all p&lt;0.05). Curdlan treated moDCs were further co-cultured with CD4+ na?ve T cells and polarization into Th17 cells was subsequently evaluated by measuring the percentage of Th17 per moDCs-na?ve T cells and expression of intracellular IL-17. Curdlan treated moDCs from SLE patients were found to have enhanced Th17 polarization capacity (mean+/-SEM = 28.33+/-5.64%) compared with controls (mean+/-SEM = 12.77+/-2.56%) (p&lt;0.05). To address the mechanism of Th17 polarization, expression of caspase-1 which promotes the production of IL-1&#946; was measured. Curdlan treated moDCs in SLE patients expressed higher levels of caspase-1 detected in the cell lysate as measured using Western Blot compared with healthy controls (p&lt;0.05).

In conclusion, compared with healthy individuals, SLE moDCs were more matured and activated in response to &#946;-glucan as shown by their higher expression of co-stimulatory molecules, enhanced production of IL-1&#946; and stronger Th17 polarizing effect. These findings suggest functional dysregulation of dectin-1 expressing DCs in patients with SLE which may be involved in the pathogenesis of this condition.</description.abstract>
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<publisher>The University of Hong Kong (Pokfulam, Hong Kong)</publisher>
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<rights>Creative Commons: Attribution 3.0 Hong Kong License</rights>
<source.uri>http://hub.hku.hk/bib/B47869999</source.uri>
<subject.lcsh>Dendritic cells.</subject.lcsh>
<subject.lcsh>Systemic lupus erythematosus - Pathogenesis.</subject.lcsh>
<title>The role of dectin-1 expressing dendritic cells in the pathogenesis ofsystemic lupus erythematosus</title>
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<date.hkucongregation>2012</date.hkucongregation>
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