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postgraduate thesis: Role of B-1 cells in the development of murine lupus

TitleRole of B-1 cells in the development of murine lupus
Authors
Advisors
Advisor(s):Lu, L
Issue Date2019
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yang, X. [楊希]. (2019). Role of B-1 cells in the development of murine lupus. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractSystemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by disorders of both the cellular and humoral immune responses. Loss of B-cell tolerance and production of pathogenic autoantibodies are the hallmarks of the pathogenesis of SLE, which are also associated with the formation of immune complexes and tissue damages in multiple organs. B-1 cells represent a distinct B- cell subset with unique phenotypic, developmental and physiological properties. Increasing evidence indicates that B-1 cells may play pivotal roles in B-cell dysregulation and pathogenesis of autoimmune diseases, but the specific contribution of B-1 cells to the development of SLE remains largely unclear. This study was undertaken to investigate the role of B-1 cells in the development of lupus by using MRL/lpr mice as the animal model of SLE. Levels of autoantibodies and the kinetic changes of B-cell subsets were dissected after characterising the lupus development in MRL/lpr mice. Enzyme-linked immunosorbent assay (ELISA) results showed that the levels of anti- phosphatidylserine (PS) autoantibodies were significantly elevated in both serum and peritoneal lavage fluid (PLF) of MRL/lpr mice. The phenotypic features of B- 1 cells in various lymphoid organs indicated that B-1a cells were the dominant infiltrated B-cell subset in murine kidney. Besides, lupus progression was attenuated in B-1 cell-depleted mice. Enzyme-Linked ImmunoSpot assay (ELISpot) was used to monitor the frequencies of autoantibody-secreting cells within various B-cell subsets. Notably, specific autoantibodies against PS were observed mainly generated from B-1a cells. Moreover, further investigation revealed that the accelerated disease development and exacerbated renal inflammation were observed in PS-specific B-1a cells adoptive transferred mice, indicating the contribution of PS-specific B-1a cells to the lupus pathogenesis. To elucidate how PS-specific B-1a cells affect the lupus progression. In vitro studies showed that Toll-like receptor 9 (TLR9) was a critical signal in activating PS-specific B-1a cells. Treatment of B-1 cells with either TLR-9 antagonist (inhibitory CpG sODN 2088) or deoxyribonuclease (DNase) inhibited the secretion of anti-PS antibody, and the activations of pSyK and Blimp-1 were involved in the process of PS-specific B-1a cells production. As T cell immunoglobulin mucin protein 4 (Tim-4) is the receptor of PS. To determine whether Tim-4 participates in B-1 cell-induced lupus pathogenesis, the phenotypic analysis of Tim-4+B-1 was performed, and the defects of Tim-4+B-1a cells were identified in lupus-prone mice. Functionally, reduced level of anti-PS antibody secretion was found in Tim-4+B-1a cells. In addition, the involvement of Tim-4+B-1a cells in the phagocytic process was demonstrated by both in vivo and in vitro phagocytosis assays. Taken together, these findings not only reveal a novel pathogenic function of PS- specific B-1a cells and the engagement of TLR9-pSyK signal in the development of murine lupus, but also identify the phagocytic property of Tim-4+B-1a cells in immune response. Therefore, there is an imbalanced immune response of B-1a cells in the lupus pathogenesis, which may contribute to the development of effective therapies for SLE. (472 words)
DegreeDoctor of Philosophy
SubjectB cells
Systemic lupus erythematosus
Dept/ProgramPathology
Persistent Identifierhttp://hdl.handle.net/10722/273757

 

DC FieldValueLanguage
dc.contributor.advisorLu, L-
dc.contributor.authorYang, Xi-
dc.contributor.author楊希-
dc.date.accessioned2019-08-14T03:29:46Z-
dc.date.available2019-08-14T03:29:46Z-
dc.date.issued2019-
dc.identifier.citationYang, X. [楊希]. (2019). Role of B-1 cells in the development of murine lupus. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/273757-
dc.description.abstractSystemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by disorders of both the cellular and humoral immune responses. Loss of B-cell tolerance and production of pathogenic autoantibodies are the hallmarks of the pathogenesis of SLE, which are also associated with the formation of immune complexes and tissue damages in multiple organs. B-1 cells represent a distinct B- cell subset with unique phenotypic, developmental and physiological properties. Increasing evidence indicates that B-1 cells may play pivotal roles in B-cell dysregulation and pathogenesis of autoimmune diseases, but the specific contribution of B-1 cells to the development of SLE remains largely unclear. This study was undertaken to investigate the role of B-1 cells in the development of lupus by using MRL/lpr mice as the animal model of SLE. Levels of autoantibodies and the kinetic changes of B-cell subsets were dissected after characterising the lupus development in MRL/lpr mice. Enzyme-linked immunosorbent assay (ELISA) results showed that the levels of anti- phosphatidylserine (PS) autoantibodies were significantly elevated in both serum and peritoneal lavage fluid (PLF) of MRL/lpr mice. The phenotypic features of B- 1 cells in various lymphoid organs indicated that B-1a cells were the dominant infiltrated B-cell subset in murine kidney. Besides, lupus progression was attenuated in B-1 cell-depleted mice. Enzyme-Linked ImmunoSpot assay (ELISpot) was used to monitor the frequencies of autoantibody-secreting cells within various B-cell subsets. Notably, specific autoantibodies against PS were observed mainly generated from B-1a cells. Moreover, further investigation revealed that the accelerated disease development and exacerbated renal inflammation were observed in PS-specific B-1a cells adoptive transferred mice, indicating the contribution of PS-specific B-1a cells to the lupus pathogenesis. To elucidate how PS-specific B-1a cells affect the lupus progression. In vitro studies showed that Toll-like receptor 9 (TLR9) was a critical signal in activating PS-specific B-1a cells. Treatment of B-1 cells with either TLR-9 antagonist (inhibitory CpG sODN 2088) or deoxyribonuclease (DNase) inhibited the secretion of anti-PS antibody, and the activations of pSyK and Blimp-1 were involved in the process of PS-specific B-1a cells production. As T cell immunoglobulin mucin protein 4 (Tim-4) is the receptor of PS. To determine whether Tim-4 participates in B-1 cell-induced lupus pathogenesis, the phenotypic analysis of Tim-4+B-1 was performed, and the defects of Tim-4+B-1a cells were identified in lupus-prone mice. Functionally, reduced level of anti-PS antibody secretion was found in Tim-4+B-1a cells. In addition, the involvement of Tim-4+B-1a cells in the phagocytic process was demonstrated by both in vivo and in vitro phagocytosis assays. Taken together, these findings not only reveal a novel pathogenic function of PS- specific B-1a cells and the engagement of TLR9-pSyK signal in the development of murine lupus, but also identify the phagocytic property of Tim-4+B-1a cells in immune response. Therefore, there is an imbalanced immune response of B-1a cells in the lupus pathogenesis, which may contribute to the development of effective therapies for SLE. (472 words)-
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.lcshB cells-
dc.subject.lcshSystemic lupus erythematosus-
dc.titleRole of B-1 cells in the development of murine lupus-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePathology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2019-
dc.identifier.mmsid991044128170503414-

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