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postgraduate thesis: Plasmacytoid dendritic cells : their functional abnormalities and regulatory mechanisms in the development of systemic lupus erythematosus

TitlePlasmacytoid dendritic cells : their functional abnormalities and regulatory mechanisms in the development of systemic lupus erythematosus
Authors
Advisors
Advisor(s):Lau, WCS
Issue Date2013
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yan, S. [晏晟]. (2013). Plasmacytoid dendritic cells : their functional abnormalities and regulatory mechanisms in the development of systemic lupus erythematosus. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5108674
AbstractSystemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease that is characterised by diverse clinical manifestations. Immunologically, SLE features a prominent “interferon (IFN) signature” which is marked by an elevated expression of type I IFN-regulated genes in blood and tissue cells of patients with this condition. Plasmacytoid dendritic cells (pDCs), also known as the most potent type I IFN-producing cells, are therefore considered the major culprit in SLE pathogenesis. Previous studies from our group have demonstrated abnormalities in circulating and bone marrow (BM)-derived pDCs from SLE patients. In the light of this, the present study was undertaken to further evaluate the role of pDCs in SLE development and to seek for key mediator(s) that might lead to functional aberrations of pDCs in this condition. Recently, a growing attention has been drawn to microRNAs (miRNAs) for their critical role in regulating immune cell function and strong association with autoimmune diseases. Therefore, the current study hypothesised that microRNAs played an important role in modulating pDC response(s) to toll-like receptor (TLR) stimulation, and that dysregulated microRNA expression induction was responsible for pDC abnormalities in SLE pathogenesis. The spontaneous lupus mouse model, F1 hybrid of New Zealand Black and White strains (NZB/W F1), was used in this study. The disease profile of NZB/W F1 was characterised based on the development of serum antinuclear antibodies and proteinuria. Specifically, the development of lupus in these mice (symptomatic mice) was illustrated by high titres of serum antinuclear antibodies, persistent proteinuria, glomerular immune complex deposition and elevated expression of pro-inflammatory cytokine genes in the kidney. Young NZB/W F1 (pre-symptomatic) as well as age- and sex-matched non-lupus maternal NZW mice were used as controls. While the development of pDCs appeared to be unaffected by lupus, elevated upregulation of MHC class II and co-stimulatory molecules, and induction of IFN-stimulated gene Ifitm3 in TLR7-stimulated lupus pDCs suggested phenotypic and functional hypersensitivity of these cells. Furthermore, analysis of the expression profile of miRNAs in pDCs upon TLR7 activation identified six differentially regulated targets. Among these, miR-155 was the most highly induced and its induction was consistently higher in pDCs from symptomatic NZB/W F1 mice. Nevertheless, transfection of miR-155 mimics into pre-symptomatic pDCs resulted in a reduced expression of Ifitm3, suggesting that miR-155 has a negative regulatory role in IFN production in pDCs. The finding of upregulated induction of miR-155 in lupus pDCs reported in this thesis is in line with previous studies, which showed increased expression of miR-155 in splenic lymphocytes of lupus NZB/W F1 mice. Results obtained from the transfection experiments are also in accordance with other previous studies, which showed miR-155 functioned as a negative feedback regulator of IFN production in pDCs. However, the mechanism of the association between miR-155 expression and increased IFN response in SLE requires further investigations. It is hoped that findings from this study contribute to a better understanding of SLE pathogenesis and ignite future interests in evaluating the molecular layer of regulation in autoimmunity.
DegreeDoctor of Philosophy
SubjectDendritic cells
Systemic lupus erythematosus - Immunological aspects
Dept/ProgramMedicine
Persistent Identifierhttp://hdl.handle.net/10722/193512

 

DC FieldValueLanguage
dc.contributor.advisorLau, WCS-
dc.contributor.authorYan, Sheng-
dc.contributor.author晏晟-
dc.date.accessioned2014-01-10T09:45:57Z-
dc.date.available2014-01-10T09:45:57Z-
dc.date.issued2013-
dc.identifier.citationYan, S. [晏晟]. (2013). Plasmacytoid dendritic cells : their functional abnormalities and regulatory mechanisms in the development of systemic lupus erythematosus. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5108674-
dc.identifier.urihttp://hdl.handle.net/10722/193512-
dc.description.abstractSystemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease that is characterised by diverse clinical manifestations. Immunologically, SLE features a prominent “interferon (IFN) signature” which is marked by an elevated expression of type I IFN-regulated genes in blood and tissue cells of patients with this condition. Plasmacytoid dendritic cells (pDCs), also known as the most potent type I IFN-producing cells, are therefore considered the major culprit in SLE pathogenesis. Previous studies from our group have demonstrated abnormalities in circulating and bone marrow (BM)-derived pDCs from SLE patients. In the light of this, the present study was undertaken to further evaluate the role of pDCs in SLE development and to seek for key mediator(s) that might lead to functional aberrations of pDCs in this condition. Recently, a growing attention has been drawn to microRNAs (miRNAs) for their critical role in regulating immune cell function and strong association with autoimmune diseases. Therefore, the current study hypothesised that microRNAs played an important role in modulating pDC response(s) to toll-like receptor (TLR) stimulation, and that dysregulated microRNA expression induction was responsible for pDC abnormalities in SLE pathogenesis. The spontaneous lupus mouse model, F1 hybrid of New Zealand Black and White strains (NZB/W F1), was used in this study. The disease profile of NZB/W F1 was characterised based on the development of serum antinuclear antibodies and proteinuria. Specifically, the development of lupus in these mice (symptomatic mice) was illustrated by high titres of serum antinuclear antibodies, persistent proteinuria, glomerular immune complex deposition and elevated expression of pro-inflammatory cytokine genes in the kidney. Young NZB/W F1 (pre-symptomatic) as well as age- and sex-matched non-lupus maternal NZW mice were used as controls. While the development of pDCs appeared to be unaffected by lupus, elevated upregulation of MHC class II and co-stimulatory molecules, and induction of IFN-stimulated gene Ifitm3 in TLR7-stimulated lupus pDCs suggested phenotypic and functional hypersensitivity of these cells. Furthermore, analysis of the expression profile of miRNAs in pDCs upon TLR7 activation identified six differentially regulated targets. Among these, miR-155 was the most highly induced and its induction was consistently higher in pDCs from symptomatic NZB/W F1 mice. Nevertheless, transfection of miR-155 mimics into pre-symptomatic pDCs resulted in a reduced expression of Ifitm3, suggesting that miR-155 has a negative regulatory role in IFN production in pDCs. The finding of upregulated induction of miR-155 in lupus pDCs reported in this thesis is in line with previous studies, which showed increased expression of miR-155 in splenic lymphocytes of lupus NZB/W F1 mice. Results obtained from the transfection experiments are also in accordance with other previous studies, which showed miR-155 functioned as a negative feedback regulator of IFN production in pDCs. However, the mechanism of the association between miR-155 expression and increased IFN response in SLE requires further investigations. It is hoped that findings from this study contribute to a better understanding of SLE pathogenesis and ignite future interests in evaluating the molecular layer of regulation in autoimmunity.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshDendritic cells-
dc.subject.lcshSystemic lupus erythematosus - Immunological aspects-
dc.titlePlasmacytoid dendritic cells : their functional abnormalities and regulatory mechanisms in the development of systemic lupus erythematosus-
dc.typePG_Thesis-
dc.identifier.hkulb5108674-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5108674-
dc.date.hkucongregation2013-

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