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postgraduate thesis: Dendritic cell abnormalities and their contributions in systemic lupus erythematosus pathogenesis

TitleDendritic cell abnormalities and their contributions in systemic lupus erythematosus pathogenesis
Authors
Issue Date2017
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yim, L. [嚴樂欣]. (2017). Dendritic cell abnormalities and their contributions in systemic lupus erythematosus pathogenesis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractSystemic lupus erythematosus (SLE) is a heavily female-biased, chronic and multifactorial autoimmune disease that affects various organ systems. Etiologically, SLE is triggered by genetic predisposition together with environmental factors, leading to the dysregulation of innate immunity, and subsequently the activation of adaptive immunity and tolerance breakdown. Dendritic cells (DCs) are the innate immune cells that activate T cells and B cells, thus playing essential roles in SLE pathogenesis. Clinically, peripheral leukocytes of SLE patients display a molecular “interferon signature” with up-regulation of various interferon (IFN) responsive genes, suggesting that plasmacytoid DCs (pDCs), being a potent type I IFN producer, maybe involved in pathogenesis. On the other hand, myeloid DCs (mDCs), being potent antigen presenting cells, have been shown to have enhanced T cell stimulating ability in SLE. Using the murine BWF1 lupus model, this study aimed to further dissect the roles of mDC and pDC in SLE pathogenesis by evaluating their abundance and properties before and after disease onset. Results showed that pDC abundance did not change significantly over the disease course. Although the frequency of CD80-expressing pDCs was increased slightly in disease mice, the basal and TLR7/9-induced expression of CD40, CD80, CD86 and MHC II remained similar. Functionally, the production of IFNα upon CpG stimulation by pDCs was also similar. In contrast, splenic mDCs were expanded after disease onset and surprisingly, although they expressed lower levels of CD80 and MHC II, mDCs’ ability in inducing allogeneic T cell proliferation were not impaired. BWF1 mDCs also expressed higher levels of TLR7 and TLR9 when compared with age- and sex-matched non-lupus parental NZW controls. Moreover, the basal mRNA expression of TNFα, BAFF, IL-10 and CXCL13 were increased in mDCs after disease onset. Subsequent findings showed that mDCs displayed heightened TLR9 responses with increased IL-10 and CXCL13 production, and TLR7-stimulated mDCs also produced more IL-10 after disease onset. It was therefore hypothesized that mDCs might attract Tfh cells via CXCL13 binding to its receptor CXCR5 on Tfh and modulate their functions. Results showed that Tfh cells were also expanded and positively correlated with mDC abundance after disease onset. The interaction between mDCs and Tfh was further evaluated by in vitro co-culture assays. Results showed that TLR9-primed mDCs from symptomatic mice could enhance Tfh functions with higher IL-21 and IFNγ expressions, and blocking IL-10 in the co-culture further augmented Tfh functions. In summary, this study demonstrated that mDCs from symptomatic mice displayed elevated TLR7/9 responses and led to an increase in IL-10 and CXCL13 production. On one hand, these mDCs could promote Tfh functions, however, the IL-10 produced by them could be inhibitory. Further experiments are needed to delineate the novel interactions between mDCs and Tfh in SLE via IL-10. In particular, in vivo experiments should be done to confirm in vitro findings; and the adoptive transfer of mDCs or Tfh into pre-symptomatic BWF1 mice may reveal clearly the roles of these cells in SLE disease progression.
DegreeDoctor of Philosophy
SubjectDendritic cells
Systemic lupus erythematosus - Pathogenesis
Dept/ProgramMedicine
Persistent Identifierhttp://hdl.handle.net/10722/241425
HKU Library Item IDb5864189

 

DC FieldValueLanguage
dc.contributor.authorYim, Lok-yan-
dc.contributor.author嚴樂欣-
dc.date.accessioned2017-06-13T02:07:50Z-
dc.date.available2017-06-13T02:07:50Z-
dc.date.issued2017-
dc.identifier.citationYim, L. [嚴樂欣]. (2017). Dendritic cell abnormalities and their contributions in systemic lupus erythematosus pathogenesis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/241425-
dc.description.abstractSystemic lupus erythematosus (SLE) is a heavily female-biased, chronic and multifactorial autoimmune disease that affects various organ systems. Etiologically, SLE is triggered by genetic predisposition together with environmental factors, leading to the dysregulation of innate immunity, and subsequently the activation of adaptive immunity and tolerance breakdown. Dendritic cells (DCs) are the innate immune cells that activate T cells and B cells, thus playing essential roles in SLE pathogenesis. Clinically, peripheral leukocytes of SLE patients display a molecular “interferon signature” with up-regulation of various interferon (IFN) responsive genes, suggesting that plasmacytoid DCs (pDCs), being a potent type I IFN producer, maybe involved in pathogenesis. On the other hand, myeloid DCs (mDCs), being potent antigen presenting cells, have been shown to have enhanced T cell stimulating ability in SLE. Using the murine BWF1 lupus model, this study aimed to further dissect the roles of mDC and pDC in SLE pathogenesis by evaluating their abundance and properties before and after disease onset. Results showed that pDC abundance did not change significantly over the disease course. Although the frequency of CD80-expressing pDCs was increased slightly in disease mice, the basal and TLR7/9-induced expression of CD40, CD80, CD86 and MHC II remained similar. Functionally, the production of IFNα upon CpG stimulation by pDCs was also similar. In contrast, splenic mDCs were expanded after disease onset and surprisingly, although they expressed lower levels of CD80 and MHC II, mDCs’ ability in inducing allogeneic T cell proliferation were not impaired. BWF1 mDCs also expressed higher levels of TLR7 and TLR9 when compared with age- and sex-matched non-lupus parental NZW controls. Moreover, the basal mRNA expression of TNFα, BAFF, IL-10 and CXCL13 were increased in mDCs after disease onset. Subsequent findings showed that mDCs displayed heightened TLR9 responses with increased IL-10 and CXCL13 production, and TLR7-stimulated mDCs also produced more IL-10 after disease onset. It was therefore hypothesized that mDCs might attract Tfh cells via CXCL13 binding to its receptor CXCR5 on Tfh and modulate their functions. Results showed that Tfh cells were also expanded and positively correlated with mDC abundance after disease onset. The interaction between mDCs and Tfh was further evaluated by in vitro co-culture assays. Results showed that TLR9-primed mDCs from symptomatic mice could enhance Tfh functions with higher IL-21 and IFNγ expressions, and blocking IL-10 in the co-culture further augmented Tfh functions. In summary, this study demonstrated that mDCs from symptomatic mice displayed elevated TLR7/9 responses and led to an increase in IL-10 and CXCL13 production. On one hand, these mDCs could promote Tfh functions, however, the IL-10 produced by them could be inhibitory. Further experiments are needed to delineate the novel interactions between mDCs and Tfh in SLE via IL-10. In particular, in vivo experiments should be done to confirm in vitro findings; and the adoptive transfer of mDCs or Tfh into pre-symptomatic BWF1 mice may reveal clearly the roles of these cells in SLE disease progression.-
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.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshDendritic cells-
dc.subject.lcshSystemic lupus erythematosus - Pathogenesis-
dc.titleDendritic cell abnormalities and their contributions in systemic lupus erythematosus pathogenesis-
dc.typePG_Thesis-
dc.identifier.hkulb5864189-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-

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