TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in context
Summary: Background: Type 1 diabetes (T1D) is an autoimmune disease characterised by the attack of pancreatic β cells by “self” immune cells. Although previous studies demonstrated that B cells contribute to T1D through antigen presentation and autoantibody production, the involvement of different...
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Elsevier
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425000374 |
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| author | Siweier Luo Lina Zhang Chunfang Wei Chipeng Guo Zhe Meng Honghui Zeng Lele Hou Le Wang Zulin Liu Yufei Du Shiyu Tan Yating Zhang Xiaoding Xu Liyang Liang Yiming Zhou |
| author_facet | Siweier Luo Lina Zhang Chunfang Wei Chipeng Guo Zhe Meng Honghui Zeng Lele Hou Le Wang Zulin Liu Yufei Du Shiyu Tan Yating Zhang Xiaoding Xu Liyang Liang Yiming Zhou |
| author_sort | Siweier Luo |
| collection | DOAJ |
| description | Summary: Background: Type 1 diabetes (T1D) is an autoimmune disease characterised by the attack of pancreatic β cells by “self” immune cells. Although previous studies demonstrated that B cells contribute to T1D through antigen presentation and autoantibody production, the involvement of different populations of B cells, particularly in the early stages of T1D, has not been fully elucidated. Methods: In this study, we employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to investigate immune cell populations in patients with newly diagnosed T1D, their relative controls and age-matched healthy controls. Phosphoprotein microarray analysis was employed to investigate changes in protein phosphorylation in B cells. Furthermore, we developed a siRNA-based nanomedicine and evaluated its therapeutic potential in the NOD mouse. The integration of scRNA-seq, flow cytometry, phosphoprotein microarrays, and functional assays established a robust framework for understanding and targeting B cell-mediated autoimmunity in T1D. Findings: Using single-cell RNA sequencing, we discovered that patients with T1D exhibited increased humoural immunity in the early stage of T1D. Specifically, the population of naïve B cells increased in patients with newly diagnosed T1D who expressed elevated levels of the AKT kinase coactivator TCL1A. Using a protein phosphorylation microarray, we confirmed that TCL1A knockdown specifically impaired AKT2 phosphorylation and affected B cell survival and proliferation. Notably, we discovered that the naïve B cell population increased and TCL1A expression was upregulated in NOD mice that developed T1D. Both the levels of naïve B cells and TCL1A were strongly associated with glucose intolerance in T1D mice. Importantly, treatment with a siRNA-based nanomedicine targeting Tcl1a mRNA effectively reduced the number of naïve B cells, prevented the loss of pancreatic β cells, and improved glucose intolerance in T1D mice. Interpretation: Using single-cell RNA-seq, we have not only uncovered a naïve B cell specific gene that may contribute to the pathogenesis of T1D but also highlighted the potential of siRNA-based nanomedicine for treating T1D. The clinical translation of these findings offers a new approach for the treatment of T1D. Funding: See Acknowledgements. |
| format | Article |
| id | doaj-art-12e1997da71347ccb143715bc91e7166 |
| institution | DOAJ |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj-art-12e1997da71347ccb143715bc91e71662025-08-20T03:11:33ZengElsevierEBioMedicine2352-39642025-03-0111310559310.1016/j.ebiom.2025.105593TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in contextSiweier Luo0Lina Zhang1Chunfang Wei2Chipeng Guo3Zhe Meng4Honghui Zeng5Lele Hou6Le Wang7Zulin Liu8Yufei Du9Shiyu Tan10Yating Zhang11Xiaoding Xu12Liyang Liang13Yiming Zhou14Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaDepartment of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaDepartment of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330000, ChinaDepartment of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaDepartment of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Corresponding author. Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Corresponding author. Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, ChinaBasic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Corresponding author. Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.Summary: Background: Type 1 diabetes (T1D) is an autoimmune disease characterised by the attack of pancreatic β cells by “self” immune cells. Although previous studies demonstrated that B cells contribute to T1D through antigen presentation and autoantibody production, the involvement of different populations of B cells, particularly in the early stages of T1D, has not been fully elucidated. Methods: In this study, we employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to investigate immune cell populations in patients with newly diagnosed T1D, their relative controls and age-matched healthy controls. Phosphoprotein microarray analysis was employed to investigate changes in protein phosphorylation in B cells. Furthermore, we developed a siRNA-based nanomedicine and evaluated its therapeutic potential in the NOD mouse. The integration of scRNA-seq, flow cytometry, phosphoprotein microarrays, and functional assays established a robust framework for understanding and targeting B cell-mediated autoimmunity in T1D. Findings: Using single-cell RNA sequencing, we discovered that patients with T1D exhibited increased humoural immunity in the early stage of T1D. Specifically, the population of naïve B cells increased in patients with newly diagnosed T1D who expressed elevated levels of the AKT kinase coactivator TCL1A. Using a protein phosphorylation microarray, we confirmed that TCL1A knockdown specifically impaired AKT2 phosphorylation and affected B cell survival and proliferation. Notably, we discovered that the naïve B cell population increased and TCL1A expression was upregulated in NOD mice that developed T1D. Both the levels of naïve B cells and TCL1A were strongly associated with glucose intolerance in T1D mice. Importantly, treatment with a siRNA-based nanomedicine targeting Tcl1a mRNA effectively reduced the number of naïve B cells, prevented the loss of pancreatic β cells, and improved glucose intolerance in T1D mice. Interpretation: Using single-cell RNA-seq, we have not only uncovered a naïve B cell specific gene that may contribute to the pathogenesis of T1D but also highlighted the potential of siRNA-based nanomedicine for treating T1D. The clinical translation of these findings offers a new approach for the treatment of T1D. Funding: See Acknowledgements.http://www.sciencedirect.com/science/article/pii/S2352396425000374Type 1 diabetesSingle-cell RNA-sequencingB cellTCL1AKT signalling |
| spellingShingle | Siweier Luo Lina Zhang Chunfang Wei Chipeng Guo Zhe Meng Honghui Zeng Lele Hou Le Wang Zulin Liu Yufei Du Shiyu Tan Yating Zhang Xiaoding Xu Liyang Liang Yiming Zhou TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in context EBioMedicine Type 1 diabetes Single-cell RNA-sequencing B cell TCL1 AKT signalling |
| title | TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in context |
| title_full | TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in context |
| title_fullStr | TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in context |
| title_full_unstemmed | TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in context |
| title_short | TCL1A in naïve B cells as a therapeutic target for type 1 diabetesResearch in context |
| title_sort | tcl1a in naive b cells as a therapeutic target for type 1 diabetesresearch in context |
| topic | Type 1 diabetes Single-cell RNA-sequencing B cell TCL1 AKT signalling |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425000374 |
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