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postgraduate thesis: Perturbations in the frequency and function of exhausted and classical memory B cells : role in systemic lupus erythematosus and lupus nephritis
Title | Perturbations in the frequency and function of exhausted and classical memory B cells : role in systemic lupus erythematosus and lupus nephritis |
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Authors | |
Issue Date | 2024 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Zhu, L. [朱立同]. (2024). Perturbations in the frequency and function of exhausted and classical memory B cells : role in systemic lupus erythematosus and lupus nephritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Various B cell abnormalities have been implicated in the pathogenesis of SLE and LN. These include an elevated number of classical memory B cells, which are strongly related to disease activity and relapse in SLE and LN. Another B cell disturbance is B cell exhaustion, which was initially reported in chronic human immunodeficiency virus (HIV) infection, chronic infection and autoimmune conditions. The pathogenic roles of exhausted and classical memory B cells in SLE and LN, especially their effect on disease relapse remains poorly understood.
In the first part of this thesis, we measured classical memory B cells (CD19+CD21+CD27+) and exhausted B cells (CD19+CD21–CD27–) in healthy controls (HC) as well as LN patients with multiple relapses (MR) (n=15) or no relapse (NR) (n=15) during disease remission. B cell-related cytokines, homing and inhibitory receptors, proliferation and calcium mobilization in classical and exhausted memory B cells were also assessed. Our results showed that the MR group exhibited higher proportion of peripheral exhausted and classical memory B cells compared to NR group and HC. The circulating levels of B cell-related cytokines (IL-6, BAFF and IL-21) and homing/adhesion molecules (Siglec-6, CXCR3 and CD62L) were all higher in the MR group. MR patients also had increased expression of inhibitory receptors (CD22, CD85j, CD183 and FCRL4) but reduced CD62L expression on exhausted B cell surface compared to the other two groups. Exhausted B cells from MR patients also showed decreased cellular proliferation and impaired calcium mobilization in response to B-cell receptor activation compared to the NR group.
To further understand the genetic control of exhausted and classical memory B cells homeostasis, we used single-cell RNA sequencing data from two separate SLE and LN datasets and performed bioinformatics analysis to identify genes and pathways relevant to memory and exhausted B cells biology in SLE and LN. IFI44L, XAF1 and MX1 were differentially expressed genes (DEGs) identified in both exhausted and classical memory B cells in SLE and LN patients. Their increased expression were also verified in classical and exhausted memory B cells obtained from LN patients during remission. Protein-protein interaction network analysis suggested that STAT1 showed the highest eigenvector centrality for these DEGs. IFI44L, XAF1 and MX1 were involved in distinct biological processes and immune pathways (especially the JAK-STAT), which may contribute to the development of SLE and LN. Classical memory B cells showed significant associations with arginine, proline, and beta-alanine metabolism, while exhausted B cells were inversely correlated with linoleic acid metabolism and biosynthesis of fatty acids and glycosaminoglycans.
Our findings suggested that perturbations in the number and function of exhausted and classical memory B cells may be related to the pathogenesis of LN and the tendency for disease relapse. Dysregulations in distinct DEGs can affect homeostasis of exhausted and classical memory B cells, and hence the propensity for lupus development. These data can help improve our new strategies for disease monitoring and treatment in SLE and LN.
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Degree | Doctor of Philosophy |
Subject | B cells Systemic lupus erythematosus - Pathogenesis Lupus nephritis - Pathogenesis |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/352627 |
DC Field | Value | Language |
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dc.contributor.author | Zhu, Litong | - |
dc.contributor.author | 朱立同 | - |
dc.date.accessioned | 2024-12-19T09:26:49Z | - |
dc.date.available | 2024-12-19T09:26:49Z | - |
dc.date.issued | 2024 | - |
dc.identifier.citation | Zhu, L. [朱立同]. (2024). Perturbations in the frequency and function of exhausted and classical memory B cells : role in systemic lupus erythematosus and lupus nephritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/352627 | - |
dc.description.abstract | Various B cell abnormalities have been implicated in the pathogenesis of SLE and LN. These include an elevated number of classical memory B cells, which are strongly related to disease activity and relapse in SLE and LN. Another B cell disturbance is B cell exhaustion, which was initially reported in chronic human immunodeficiency virus (HIV) infection, chronic infection and autoimmune conditions. The pathogenic roles of exhausted and classical memory B cells in SLE and LN, especially their effect on disease relapse remains poorly understood. In the first part of this thesis, we measured classical memory B cells (CD19+CD21+CD27+) and exhausted B cells (CD19+CD21–CD27–) in healthy controls (HC) as well as LN patients with multiple relapses (MR) (n=15) or no relapse (NR) (n=15) during disease remission. B cell-related cytokines, homing and inhibitory receptors, proliferation and calcium mobilization in classical and exhausted memory B cells were also assessed. Our results showed that the MR group exhibited higher proportion of peripheral exhausted and classical memory B cells compared to NR group and HC. The circulating levels of B cell-related cytokines (IL-6, BAFF and IL-21) and homing/adhesion molecules (Siglec-6, CXCR3 and CD62L) were all higher in the MR group. MR patients also had increased expression of inhibitory receptors (CD22, CD85j, CD183 and FCRL4) but reduced CD62L expression on exhausted B cell surface compared to the other two groups. Exhausted B cells from MR patients also showed decreased cellular proliferation and impaired calcium mobilization in response to B-cell receptor activation compared to the NR group. To further understand the genetic control of exhausted and classical memory B cells homeostasis, we used single-cell RNA sequencing data from two separate SLE and LN datasets and performed bioinformatics analysis to identify genes and pathways relevant to memory and exhausted B cells biology in SLE and LN. IFI44L, XAF1 and MX1 were differentially expressed genes (DEGs) identified in both exhausted and classical memory B cells in SLE and LN patients. Their increased expression were also verified in classical and exhausted memory B cells obtained from LN patients during remission. Protein-protein interaction network analysis suggested that STAT1 showed the highest eigenvector centrality for these DEGs. IFI44L, XAF1 and MX1 were involved in distinct biological processes and immune pathways (especially the JAK-STAT), which may contribute to the development of SLE and LN. Classical memory B cells showed significant associations with arginine, proline, and beta-alanine metabolism, while exhausted B cells were inversely correlated with linoleic acid metabolism and biosynthesis of fatty acids and glycosaminoglycans. Our findings suggested that perturbations in the number and function of exhausted and classical memory B cells may be related to the pathogenesis of LN and the tendency for disease relapse. Dysregulations in distinct DEGs can affect homeostasis of exhausted and classical memory B cells, and hence the propensity for lupus development. These data can help improve our new strategies for disease monitoring and treatment in SLE and LN. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | B cells | - |
dc.subject.lcsh | Systemic lupus erythematosus - Pathogenesis | - |
dc.subject.lcsh | Lupus nephritis - Pathogenesis | - |
dc.title | Perturbations in the frequency and function of exhausted and classical memory B cells : role in systemic lupus erythematosus and lupus nephritis | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2024 | - |
dc.identifier.mmsid | 991044891407103414 | - |