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postgraduate thesis: Leptin modulates B cell responses in autoimmune arthritis
Title | Leptin modulates B cell responses in autoimmune arthritis |
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Authors | |
Advisors | |
Issue Date | 2018 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Chen, Q. [陳倩]. (2018). Leptin modulates B cell responses in autoimmune arthritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Rheumatoid arthritis (RA) is a systematic autoimmune disease characterized by symmetric polyarticular synovitis that primarily affects the small joints of hands and feet. A variety of immune cells including T cells, B cells, neutrophils, macrophages and dendritic cells infiltrate into the inflammatory lesions, establishing synovial inflammatory milieu that promote joint destruction. Ectopic lymphoid structures and functional germinal centers (GCs) containing plasma cell (PC) aggregates appear in the inflamed synovium of RA patients. Autoreactive B cells have been recognized to play pivotal roles in the pathogenesis of RA. Although studies show that B-cell depletion therapy with anti-CD20 antibodies results in RA clinical remission, the improvement is transient with the eventual relapse of this disease. The PC population does not express CD20 and has been considered as the main culprit for disease relapse. As terminally differentiated B cells, PCs are the producer of autoantibodies including rheumatoid factor and anti-citrullinated peptide antibody, two characteristic autoantibodies involved in the pathologic processes of RA. However, it remains largely unclear whether and how PCs are maintained and produce autoantibodies in synovial tissue during RA development.
Leptin, product of the obese gene, is mainly produced by adipose tissue. Leptin plays pleiotropic functions in metabolism, hematopoiesis and immunity. Moreover, leptin has been shown to modulate B cell maturation, but it is unclear how leptin regulates PC response and autoantibody production during the development of autoimmune arthritis. To determine the function of leptin in PC responses, I established collagen-induced arthritis (CIA) in DBA/1J mice as an animal model for human RA. In CIA mice, increased levels of leptin significantly correlated with the percentages of PCs in both synovial fluid and joint tissues. To determine how leptin signaling affects disease progression in CIA mice, I performed intra-articular injection of leptin or leptin blocker. Local leptin administration significantly enhanced PC responses and exacerbated arthritic damage. In contrast, local blockade of leptin reduced PC responses and ameliorated CIA development. In RA patients, I found no correlation of serum leptin levels with RA clinical parameters. However, synovial leptin concentrations significantly correlated with synovitis scores, synovial CD38 + PCs and synovial autoantibody levels.
Mechanistic studies revealed that leptin promoted PC generation from GC B cells. Moreover, I identified fibroblast-like synoviocyte (FLS) as a source of leptin in both mouse and human. In addition, B cells, when co-cultured with FLSs, vigorously differentiated into PCs, which was significantly inhibited by treatment with leptin blockade. In GC B cells, leptin was found to activate mammalian target of rapamycin (mTOR) and upregulate the expression of transcriptional factor IRF4, which could be attenuated by rapamycin treatment.
Taken together, these findings have demonstrated that leptin promotes PC generation via ObR-mTOR-IRF4 axis and exacerbates the development of autoimmune arthritis, which suggest that leptin blockade may serve a potential therapeutic strategy for the effective treatment of RA. |
Degree | Doctor of Philosophy |
Subject | Leptin B cells Arthritis Autoimmune diseases |
Dept/Program | Pathology |
Persistent Identifier | http://hdl.handle.net/10722/274666 |
DC Field | Value | Language |
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dc.contributor.advisor | Lu, L | - |
dc.contributor.advisor | Wong, CCL | - |
dc.contributor.author | Chen, Qian | - |
dc.contributor.author | 陳倩 | - |
dc.date.accessioned | 2019-09-09T07:21:28Z | - |
dc.date.available | 2019-09-09T07:21:28Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Chen, Q. [陳倩]. (2018). Leptin modulates B cell responses in autoimmune arthritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/274666 | - |
dc.description.abstract | Rheumatoid arthritis (RA) is a systematic autoimmune disease characterized by symmetric polyarticular synovitis that primarily affects the small joints of hands and feet. A variety of immune cells including T cells, B cells, neutrophils, macrophages and dendritic cells infiltrate into the inflammatory lesions, establishing synovial inflammatory milieu that promote joint destruction. Ectopic lymphoid structures and functional germinal centers (GCs) containing plasma cell (PC) aggregates appear in the inflamed synovium of RA patients. Autoreactive B cells have been recognized to play pivotal roles in the pathogenesis of RA. Although studies show that B-cell depletion therapy with anti-CD20 antibodies results in RA clinical remission, the improvement is transient with the eventual relapse of this disease. The PC population does not express CD20 and has been considered as the main culprit for disease relapse. As terminally differentiated B cells, PCs are the producer of autoantibodies including rheumatoid factor and anti-citrullinated peptide antibody, two characteristic autoantibodies involved in the pathologic processes of RA. However, it remains largely unclear whether and how PCs are maintained and produce autoantibodies in synovial tissue during RA development. Leptin, product of the obese gene, is mainly produced by adipose tissue. Leptin plays pleiotropic functions in metabolism, hematopoiesis and immunity. Moreover, leptin has been shown to modulate B cell maturation, but it is unclear how leptin regulates PC response and autoantibody production during the development of autoimmune arthritis. To determine the function of leptin in PC responses, I established collagen-induced arthritis (CIA) in DBA/1J mice as an animal model for human RA. In CIA mice, increased levels of leptin significantly correlated with the percentages of PCs in both synovial fluid and joint tissues. To determine how leptin signaling affects disease progression in CIA mice, I performed intra-articular injection of leptin or leptin blocker. Local leptin administration significantly enhanced PC responses and exacerbated arthritic damage. In contrast, local blockade of leptin reduced PC responses and ameliorated CIA development. In RA patients, I found no correlation of serum leptin levels with RA clinical parameters. However, synovial leptin concentrations significantly correlated with synovitis scores, synovial CD38 + PCs and synovial autoantibody levels. Mechanistic studies revealed that leptin promoted PC generation from GC B cells. Moreover, I identified fibroblast-like synoviocyte (FLS) as a source of leptin in both mouse and human. In addition, B cells, when co-cultured with FLSs, vigorously differentiated into PCs, which was significantly inhibited by treatment with leptin blockade. In GC B cells, leptin was found to activate mammalian target of rapamycin (mTOR) and upregulate the expression of transcriptional factor IRF4, which could be attenuated by rapamycin treatment. Taken together, these findings have demonstrated that leptin promotes PC generation via ObR-mTOR-IRF4 axis and exacerbates the development of autoimmune arthritis, which suggest that leptin blockade may serve a potential therapeutic strategy for the effective treatment of RA. | - |
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 | Leptin | - |
dc.subject.lcsh | B cells | - |
dc.subject.lcsh | Arthritis | - |
dc.subject.lcsh | Autoimmune diseases | - |
dc.title | Leptin modulates B cell responses in autoimmune arthritis | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Pathology | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_991044081525603414 | - |
dc.date.hkucongregation | 2019 | - |
dc.identifier.mmsid | 991044081525603414 | - |