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1
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Shi X, He X, Xu C. Charge-based immunoreceptor signalling in health and disease. Nat Rev Immunol 2025; 25:298-311. [PMID: 39528837 DOI: 10.1038/s41577-024-01105-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2024] [Indexed: 11/16/2024]
Abstract
Immunoreceptors have crucial roles in sensing environmental signals and initiating immune responses to protect the host. Dysregulation of immunoreceptor signalling can therefore lead to a range of diseases, making immunoreceptor-based therapies a promising frontier in biomedicine. A common feature of various immunoreceptors is the basic-residue-rich sequence (BRS), which is a largely unexplored aspect of immunoreceptor signalling. The BRS is typically located in the cytoplasmic juxtamembrane region of immunoreceptors, where it forms dynamic interactions with neighbouring charged molecules to regulate signalling. Loss or gain of the basic residues in an immunoreceptor BRS has been linked to severe human diseases, such as immunodeficiency and autoimmunity. In this Perspective, we describe the role of BRSs in various immunoreceptors, elucidating their signalling mechanisms and biological functions. Furthermore, we highlight pathogenic mutations in immunoreceptor BRSs and discuss the potential of leveraging BRS signalling in engineered T cell-based therapies.
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Affiliation(s)
- Xiaoshan Shi
- Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
| | - Xing He
- Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
| | - Chenqi Xu
- Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
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2
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He L, Zhan L, Yang Y, He W. Similarities and differences of a proliferation-inducing ligand expression in lacrimal gland lesions of patients with IgG4-associated ophthalmic diseases and mucosa-associated lymphoid tissue lymphoma. Front Immunol 2025; 16:1514003. [PMID: 40040702 PMCID: PMC11876129 DOI: 10.3389/fimmu.2025.1514003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 01/31/2025] [Indexed: 03/06/2025] Open
Abstract
Objective This study aimed to investigate the expression condition of a proliferation-inducing ligand (APRIL) in lacrimal gland lesions of patients with IgG4-associated ophthalmic diseases (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma. Patients and methods Fifteen patients with IgG4-ROD, 3 with MALT lymphoma, and 1 with elevated IgG4 with lacrimal gland lesions, treated in West China Hospital of Sichuan University from April 2022 to November 2023, were included. Immunofluorescence staining was used to detect the expression of APRIL in the specimen of lacrimal gland. Results The average expression level of APRIL in patients with lacrimal gland lesions of IgG4-ROD and MALT lymphoma were 8471.12 pixels/HPF and 2950.78 pixels/HPF respectively. The positive rates of APRIL were 10.49% and 7.23% respectively. CD138 and APRIL were colocalized, and the positive rate of their colocalization was 8.83%, and the positive areas of colocalization coincidence was 946.84 pixels/HPF in patients with IgG4-ROD. CD20 and APRIL were colocalized, and the positive rate of their colocalization was 7.04%, and the positive areas of colocalization coincidence was 949.78 pixels/HPF in patients with MALT lymphoma. We also found that the expression level and the positive rate of APRIL were positively correlated with the level of serum IgG4 in IgG4-ROD patients (r=0.5820, P=0.029; r= 0.6261, P=0.017; respectively). In addition, the positive rate and the positive areas of CD138 and APRIL colocalization were also positively correlated with serum IgG4 level (r=0.6420, P=0.013; r= 0.5673, P=0.034; respectively). Conclusion APRIL is highly expressed in lacrimal gland lesions of patients with IgG4-ROD and MALT lymphoma. This overexpression may facilitate the enrichment of CD138+ plasma cells and is associated with elevated serum IgG4 levels in patients with IgG4-ROD. Additionally, it may promote the proliferation of CD20+ B lymphocytes in patients with MALT lymphoma.APRIL may play a certain role in the possible transformation of IgG4-ROD into MALT lymphoma.
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Affiliation(s)
- Lvfu He
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Lisha Zhan
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Yu Yang
- Department of Ophthalmology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Weimin He
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Cheng J, Dávila Saldaña BJ, Chandrakasan S, Keller M. Pediatric lymphoproliferative disorders associated with inborn errors of immunity. Clin Immunol 2024; 266:110332. [PMID: 39069111 DOI: 10.1016/j.clim.2024.110332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/18/2024] [Accepted: 07/24/2024] [Indexed: 07/30/2024]
Abstract
Both non-malignant and malignant lymphoproliferative disorders (LPD) are commonly seen in patients with inborn errors of immunity (IEI), which may be the presenting manifestations or may develop during the IEI disease course. Here we review the clinical, histopathological, and molecular features of benign and malignant LPD associated with IEI and recognize the diagnostic challenges.
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Affiliation(s)
- Jinjun Cheng
- Department of Pathology and Laboratory Medicine, Children's National Hospital, Washington, DC, United States of America; Centers for Cancer & Blood Disorders and Cancer & Immunology Research, Children's National Hospital, Washington, DC, United States of America; The George Washington University School of Medicine and Health Sciences, Washington, DC, United States of America.
| | - Blachy J Dávila Saldaña
- Centers for Cancer & Blood Disorders and Cancer & Immunology Research, Children's National Hospital, Washington, DC, United States of America; The George Washington University School of Medicine and Health Sciences, Washington, DC, United States of America
| | - Shanmuganathan Chandrakasan
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States of America
| | - Michael Keller
- Centers for Cancer & Blood Disorders and Cancer & Immunology Research, Children's National Hospital, Washington, DC, United States of America; The George Washington University School of Medicine and Health Sciences, Washington, DC, United States of America
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4
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Balasubramaniam M, Mokhtar AMA. Past and present discovery of the BAFF/APRIL system - A bibliometric study from 1999 to 2023. Cell Signal 2024; 120:111201. [PMID: 38714287 DOI: 10.1016/j.cellsig.2024.111201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/30/2024] [Accepted: 05/01/2024] [Indexed: 05/09/2024]
Abstract
Cytokines from the Tumour Necrosis Factor (TNF) family are important regulators of both physiological and pathological processes. The discovery of novel TNF ligands and receptors, BAFF and APRIL, have opened up new possibilities for scientists to explore the effect of these cytokines on the human immune system. The role of BAFF/APRIL system in B lymphocytes is particularly important for survival and maintenance of homeostasis. Aberrant expression of the system is associated with various immunological disorders. Hence, this study provides a comprehensive overview of the past and present BAFF/APRIL system research development in a bibliometric perspective. To our best knowledge, this is the first ever bibliometric analysis conducted focusing on the BAFF/APRIL system. A total of 1055 relevant documents were retrieved from WoSCC. Microsoft Excel, VOSviewer, and Biblioshiny of R studio were bibliometric tools used to analyse the scientific literature. From 1999, the annual publications showed an upward trend, with Journal of Immunology being the most productive journal. USA leads the race for BAFF/APRIL system research developments. Pascal Schneider, a senior researcher affiliated with University of Lausanne, Switzerland was recognised as the most productive author and institution in the BAFF/APRIL system research field. The research focus transitioned from focusing on the role of the system in B cell biology, to immunological disorders and finally to development of BAFF/APRIL targeting drugs. Despite several studies elucidating briefly the pathway mechanism of BAFF/APRIL system in B-cell selection, substantial research on the mechanism of action in disease models and T cell activation and development of immunomodulating drugs from natural origins remains largely unexplored. Therefore, future research focusing on these areas are crucial for the deeper understanding of the system in disease manifestations and progression allowing a better treatment management for various immunological disorders.
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Affiliation(s)
- Muggunna Balasubramaniam
- Small G protein Research Group, Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia; Green Biopolymer Coating and Packaging Centre, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia
| | - Ana Masara Ahmad Mokhtar
- Small G protein Research Group, Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia; Green Biopolymer Coating and Packaging Centre, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia.
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5
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Garcia-Carmona Y, Fribourg M, Sowa A, Cerutti A, Cunningham-Rundles C. TACI and endogenous APRIL in B cell maturation. Clin Immunol 2023; 253:109689. [PMID: 37422057 PMCID: PMC10528899 DOI: 10.1016/j.clim.2023.109689] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/30/2023] [Accepted: 07/01/2023] [Indexed: 07/10/2023]
Abstract
While many of the genes and molecular pathways in the germinal center B cell response which initiate protective antibody production are known, the contributions of individual molecular players in terminal B cell differentiation remain unclear. We have previously investigated how mutations in TACI gene, noted in about 10% of patients with common variable immunodeficiency, impair B cell differentiation and often, lead to lymphoid hyperplasia and autoimmunity. Unlike mouse B cells, human B cells express TACI-L (Long) and TACI-S (Short) isoforms, but only TACI-S promotes terminal B cell differentiation into plasma cells. Here we show that the expression of intracellular TACI-S increases with B cell activation, and colocalizes with BCMA and their ligand, APRIL. We show that the loss of APRIL impairs isotype class switch and leads to distinct metabolic and transcriptional changes. Our studies suggest that intracellular TACI-S and APRIL along with BCMA direct long-term PC differentiation and survival.
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Affiliation(s)
- Yolanda Garcia-Carmona
- Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
| | - Miguel Fribourg
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
| | - Allison Sowa
- Microscopy CoRE and Advanced Bioimaging Center, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
| | - Andrea Cerutti
- Translational Clinical Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Charlotte Cunningham-Rundles
- Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
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6
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Abid N, Manaye S, Naushad H, Cheran K, Murthy C, Bornemann EA, Kamma HK, Alabbas M, Elashahab M. The Safety and Efficacy of Rituximab and Belimumab in Systemic Lupus Erythematosus: A Systematic Review. Cureus 2023; 15:e40719. [PMID: 37485087 PMCID: PMC10360028 DOI: 10.7759/cureus.40719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
There is a vital role of B cells in the pathogenesis of Systemic Lupus Erythematosus (SLE). Belimumab (Bel), an inhibitor of B cell activating factor (BAFF), and Rituximab (RTX), a monoclonal antibody targeting Cd20 antigen, have been used to manage systemic lupus. Several randomized controlled trials (RCTs) have evaluated these two agents' clinical efficacy and safety in different manifestations of SLE. This study aims to review the randomized control trials involving these two agents systematically and to explain if any disparity is noticed in the primary and secondary outcomes between these two agents. This study is done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After applying the inclusion criteria and quality assessment by independent reviewers and co-authors, relevant papers were identified, and data were extracted. The results have shown that RCTs involving Belimumab achieved primary endpoints; however, targeted endpoints were not achieved in studies involving Rituximab. It is concluded that despite the conflicting results obtained in clinical trials, both are effective in systemic lupus, as indicated in real-world clinical experience. However, better-designed multicenter studies evaluating these B-cell-targeting drugs are needed.
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Affiliation(s)
- Naushad Abid
- Internal Medicine, King Faisal University College of Medicine, Al-Ahsa, SAU
- Internal Medicine / Rheumatology, King Faisal University, Al-Ahsa, SAU
| | - Sara Manaye
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Hamzah Naushad
- Medicine and Surgery, Dow International Medical College, Dow University of Health Sciences, Karachi, PAK
| | - Kaaviya Cheran
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Chinmayee Murthy
- Internal Medicine, Bidar Institute of Medical Sciences, Bidar, IND
| | - Elisa A Bornemann
- Medicine and Surgery, Universidad Latina de Panama, Panama City, PAN
| | - Hari Krishna Kamma
- Psychiatry, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohammad Alabbas
- Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, HUN
| | - Mohammed Elashahab
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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7
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Ma A, Wang X, Li J, Wang C, Xiao T, Liu Y, Cheng H, Wang J, Li Y, Chang Y, Li J, Wang D, Jiang Y, Su L, Xin G, Gu S, Li Z, Liu B, Xu D, Ma Q. Single-cell biological network inference using a heterogeneous graph transformer. Nat Commun 2023; 14:964. [PMID: 36810839 PMCID: PMC9944243 DOI: 10.1038/s41467-023-36559-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 02/06/2023] [Indexed: 02/23/2023] Open
Abstract
Single-cell multi-omics (scMulti-omics) allows the quantification of multiple modalities simultaneously to capture the intricacy of complex molecular mechanisms and cellular heterogeneity. Existing tools cannot effectively infer the active biological networks in diverse cell types and the response of these networks to external stimuli. Here we present DeepMAPS for biological network inference from scMulti-omics. It models scMulti-omics in a heterogeneous graph and learns relations among cells and genes within both local and global contexts in a robust manner using a multi-head graph transformer. Benchmarking results indicate DeepMAPS performs better than existing tools in cell clustering and biological network construction. It also showcases competitive capability in deriving cell-type-specific biological networks in lung tumor leukocyte CITE-seq data and matched diffuse small lymphocytic lymphoma scRNA-seq and scATAC-seq data. In addition, we deploy a DeepMAPS webserver equipped with multiple functionalities and visualizations to improve the usability and reproducibility of scMulti-omics data analysis.
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Affiliation(s)
- Anjun Ma
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Xiaoying Wang
- School of Mathematics, Shandong University, Jinan, Shandong, China
| | - Jingxian Li
- School of Mathematics, Shandong University, Jinan, Shandong, China
| | - Cankun Wang
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Tong Xiao
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Yuntao Liu
- School of Mathematics, Shandong University, Jinan, Shandong, China
| | - Hao Cheng
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Juexin Wang
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Yang Li
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Yuzhou Chang
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jinpu Li
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO, USA
| | - Duolin Wang
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Yuexu Jiang
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Li Su
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO, USA
| | - Gang Xin
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Shaopeng Gu
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Bingqiang Liu
- School of Mathematics, Shandong University, Jinan, Shandong, China.
| | - Dong Xu
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA.
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO, USA.
| | - Qin Ma
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA.
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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8
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Cascalho M, Platt JL. TNFRSF13B in B cell responses to organ transplantation. Hum Immunol 2023; 84:27-33. [PMID: 36333165 PMCID: PMC10429825 DOI: 10.1016/j.humimm.2022.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/14/2022] [Accepted: 09/27/2022] [Indexed: 11/07/2022]
Abstract
Antibodies directed against organ transplants are thought to pose the most vexing hurdle to enduring function and survival of the transplants, particularly organ xenotransplants, and accordingly basic and clinical investigation has focused on elucidating the specificity and pathogenicity of graft-specific antibodies. While much has been learned about these matters, far less is known about the B cells producing graft-specific antibodies and why these antibodies appear to injure some grafts but not others. With the goal of addressing those questions, we have investigated the properties of tumor necrosis factor receptor super family-13B (TNFRSF13B), which regulates various aspects of B cell responses. A full understanding of the functions of TNFRSF13B however is hindered by extreme polymorphism and by diversity of interactions of the protein. Nevertheless, TNFRSF13B variants have been found to exert distinct impact on natural and elicited antibody responses and host defense and mutations of TNFRSF13B have been found to influence the propensity for development of antibody-mediated rejection of organ transplants. Because B cell responses potentially limit application of xenotransplantation, understanding how TNFRSF13B diversity and TNFRSF13B variants govern immunity in xenotransplantation could inspire development of novel therapeutics that could in turn accelerate clinical implementation of xenotransplantation.
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Affiliation(s)
- Marilia Cascalho
- Department of Surgery and Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States.
| | - Jeffrey L Platt
- Department of Surgery and Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States.
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9
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Goodman DB, Azimi CS, Kearns K, Talbot A, Garakani K, Garcia J, Patel N, Hwang B, Lee D, Park E, Vykunta VS, Shy BR, Ye CJ, Eyquem J, Marson A, Bluestone JA, Roybal KT. Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies. Sci Transl Med 2022; 14:eabm1463. [PMID: 36350984 PMCID: PMC9939256 DOI: 10.1126/scitranslmed.abm1463] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Chimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers but have shown limited efficacy in persistent, recurrent malignancies. Here, we introduce "CAR Pooling," a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with signaling domains derived from a range of immune cell lineages were evaluated in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several domains were identified from the tumor necrosis factor (TNF) receptor family that have been primarily associated with B cells. CD40 enhanced proliferation, whereas B cell-activating factor receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI) promoted cytotoxicity. These functions were enhanced relative to clinical benchmarks after prolonged antigen stimulation, and CAR T cell signaling through these domains fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic transcriptional signature previously associated with positive clinical outcomes. We also observed that replacing the 4-1BB intracellular signaling domain with the BAFF-R signaling domain in a clinically validated B cell maturation antigen (BCMA)-specific CAR resulted in enhanced activity in a xenotransplant model of multiple myeloma. Together, these results show that CAR Pooling is a general approach for rapid exploration of CAR architecture and activity to improve the efficacy of CAR T cell therapies.
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Affiliation(s)
- Daniel B. Goodman
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Gladstone UCSF Institute for Genetic Immunology; San Francisco, CA, 94107, USA
- School of Medicine, University of California, San Francisco; San Francisco, CA, USA
- Diabetes Center, University of California, San Francisco; San Francisco, CA 94143, USA
| | - Camillia S. Azimi
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
| | - Kendall Kearns
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
| | - Alexis Talbot
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Gladstone UCSF Institute for Genetic Immunology; San Francisco, CA, 94107, USA
- INSERM U976, Saint Louis Research Institute, Paris City University, Paris, France
| | - Kiavash Garakani
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
| | - Julie Garcia
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
| | - Nisarg Patel
- Department of Oral and Maxillofacial Surgery, University of California, San Francisco; San Francisco, CA, USA
- Bakar Computational Health Sciences Institute, University of California, San Francisco; San Francisco, CA, USA
- School of Medicine, University of California, San Francisco; San Francisco, CA, USA
| | - Byungjin Hwang
- Institute for Human Genetics (IHG), University of California, San Francisco; San Francisco, California, USA
- Department of Medicine, University of California, San Francisco; San Francisco, California, 94143, USA
| | - David Lee
- Institute for Human Genetics (IHG), University of California, San Francisco; San Francisco, California, USA
- Department of Medicine, University of California, San Francisco; San Francisco, California, 94143, USA
| | - Emily Park
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
| | - Vivasvan S. Vykunta
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; San Francisco, California, 94158, USA
- Gladstone UCSF Institute for Genetic Immunology; San Francisco, CA, 94107, USA
- School of Medicine, University of California, San Francisco; San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco; San Francisco, California, 94143, USA
| | - Brian R. Shy
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; San Francisco, California, 94158, USA
- Gladstone UCSF Institute for Genetic Immunology; San Francisco, CA, 94107, USA
- School of Medicine, University of California, San Francisco; San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco; San Francisco, California, 94143, USA
| | - Chun Jimmie Ye
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Chan Zuckerberg Biohub; San Francisco, California, 94158, USA
- Bakar Computational Health Sciences Institute, University of California, San Francisco; San Francisco, CA, USA
- Institute for Human Genetics (IHG), University of California, San Francisco; San Francisco, California, USA
- Department of Epidemiology and Biostatistics, San Francisco; San Francisco, CA 94143, USA
- Department of Medicine, University of California, San Francisco; San Francisco, California, 94143, USA
| | - Justin Eyquem
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Gladstone UCSF Institute for Genetic Immunology; San Francisco, CA, 94107, USA
| | - Alexander Marson
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; San Francisco, California, 94158, USA
- Chan Zuckerberg Biohub; San Francisco, California, 94158, USA
- Gladstone UCSF Institute for Genetic Immunology; San Francisco, CA, 94107, USA
- School of Medicine, University of California, San Francisco; San Francisco, CA, USA
- Institute for Human Genetics (IHG), University of California, San Francisco; San Francisco, California, USA
- Innovative Genomics Institute, University of California, Berkeley; Berkeley, CA 94720, USA
- Diabetes Center, University of California, San Francisco; San Francisco, CA 94143, USA
- Department of Medicine, University of California, San Francisco; San Francisco, California, 94143, USA
| | - Jeffrey A. Bluestone
- Diabetes Center, University of California, San Francisco; San Francisco, CA 94143, USA
- Sonoma Biotherapeutics; South San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco; San Francisco, California, 94143, USA
| | - Kole T. Roybal
- Department of Microbiology and Immunology, University of California, San Francisco; San Francisco, California, 94143, USA
- Parker Institute for Cancer Immunotherapy; San Francisco, California, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; San Francisco, California, 94158, USA
- Chan Zuckerberg Biohub; San Francisco, California, 94158, USA
- Gladstone UCSF Institute for Genetic Immunology; San Francisco, CA, 94107, USA
- UCSF Cell Design Institute; San Francisco, California, 94158, USA
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10
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Siegmund D, Wagner J, Wajant H. TNF Receptor Associated Factor 2 (TRAF2) Signaling in Cancer. Cancers (Basel) 2022; 14:cancers14164055. [PMID: 36011046 PMCID: PMC9406534 DOI: 10.3390/cancers14164055] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/05/2022] [Accepted: 08/19/2022] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) is an intracellular adapter protein with E3 ligase activity, which interacts with a plethora of other signaling proteins, including plasma membrane receptors, kinases, phosphatases, other E3 ligases, and deubiquitinases. TRAF2 is involved in various cancer-relevant cellular processes, such as the activation of transcription factors of the NFκB family, stimulation of mitogen-activated protein (MAP) kinase cascades, endoplasmic reticulum (ER) stress signaling, autophagy, and the control of cell death programs. In a context-dependent manner, TRAF2 promotes tumor development but it can also act as a tumor suppressor. Based on a general description, how TRAF2 in concert with TRAF2-interacting proteins and other TRAF proteins act at the molecular level is discussed for its importance for tumor development and its potential usefulness as a therapeutic target in cancer therapy. Abstract Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.
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11
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Smulski CR, Zhang L, Burek M, Teixidó Rubio A, Briem JS, Sica MP, Sevdali E, Vigolo M, Willen L, Odermatt P, Istanbullu D, Herr S, Cavallari M, Hess H, Rizzi M, Eibel H, Schneider P. Ligand-independent oligomerization of TACI is controlled by the transmembrane domain and regulates proliferation of activated B cells. Cell Rep 2022; 38:110583. [PMID: 35354034 DOI: 10.1016/j.celrep.2022.110583] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 11/03/2021] [Accepted: 03/07/2022] [Indexed: 12/23/2022] Open
Abstract
In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations.
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Affiliation(s)
- Cristian R Smulski
- Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland; Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany; Medical Physics Department, Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Avenida E- Bustillo 9500, R8402AGP Río Negro, San Carlos de Bariloche, Argentina.
| | - Luyao Zhang
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Malte Burek
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Ariadna Teixidó Rubio
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Jana-Susann Briem
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Mauricio P Sica
- Medical Physics Department, Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Avenida E- Bustillo 9500, R8402AGP Río Negro, San Carlos de Bariloche, Argentina; Instituto de Energía y Desarrollo Sustentable, Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Avenida E- Bustillo 9500, R8402AGP Río Negro, San Carlos de Bariloche, Argentina
| | - Eirini Sevdali
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Michele Vigolo
- Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland
| | - Laure Willen
- Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland
| | - Patricia Odermatt
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Duygu Istanbullu
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Stephanie Herr
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Marco Cavallari
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany
| | | | - Marta Rizzi
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Hermann Eibel
- Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany
| | - Pascal Schneider
- Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland.
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12
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Cascalho M, Platt JL. TNFRSF13B Diversification Fueled by B Cell Responses to Environmental Challenges-A Hypothesis. Front Immunol 2021; 12:634544. [PMID: 33679786 PMCID: PMC7925820 DOI: 10.3389/fimmu.2021.634544] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/21/2021] [Indexed: 12/30/2022] Open
Abstract
B cell differentiation and memory are controlled by the transmembrane activator and CAML interactor (TACI), a receptor encoded by TNFRSF13B. TNFRSF13B mutations are frequently found in common variable immunodeficiency (CVID) and in IgA -deficiency; yet, ~98% of those with mutant TNFRSF13B are healthy. Indeed, TNFRSF13B is among the 5% most polymorphic genes in man. Other mammals evidence polymorphism at comparable loci. We hypothesize that TNFRSF13B diversity might promote rather than detract from well-being by controlling key elements of innate immunity. We shall discuss how extraordinary diversity of TNFRSF13B could have evolved and persisted across diverse species of mammals by controlling innate and adaptive B cell responses in apparently paradoxical ways.
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Affiliation(s)
- Marilia Cascalho
- Department of Surgery and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States
| | - Jeffrey L Platt
- Department of Surgery and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States
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13
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Wang ZZ, Song J, Wang H, Li JX, Xiao Q, Yu Z, Liu JX, Liu Z. B Cell-Activating Factor Promotes B Cell Survival in Ectopic Lymphoid Tissues in Nasal Polyps. Front Immunol 2021; 11:625630. [PMID: 33552090 PMCID: PMC7854540 DOI: 10.3389/fimmu.2020.625630] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 12/01/2020] [Indexed: 11/13/2022] Open
Abstract
Ectopic lymphoid tissues (eLTs) characterized by B cell aggregation contribute to the local immunoglobulin production in nasal polyps (NPs). B cell-activating factor (BAFF) is vital for B cell survival, proliferation, and maturation. The purpose of this study is to investigate whether BAFF is involved in the B cell survival and eLT formation in NPs. The mRNA and protein levels of BAFF in NP tissues with and without eLTs were detected by PCR and ELISA assay, respectively. The cellular sources of BAFF and active caspase-3-positive B cells in NPs were studied by immunofluorescence staining. B cells purified from NP tissues were stimulated with BAFF and were analyzed by flow cytometry. Stromal cells purified from NP tissues were stimulated with lymphotoxin (LT) α1β2, and BAFF levels in culture supernatants were analyzed by ELISA. Compared with those in control tissues and NPs without eLTs, the BAFF levels were elevated in NPs with eLTs. Abundant BAFF-positive cells and few active caspase-3-positive apoptotic B cells were found in NPs with eLTs, in contrast to those in NPs without eLTs. There was a negative correlation between the numbers of BAFF-positive cells and frequencies of apoptotic B cells in total B cells in NP tissues. BAFF protected nasal polyp B cells from apoptosis in vitro. Stromal cells were an important cellular source of BAFF in NPs with eLTs. LTα1β2 induced BAFF production from nasal stromal cells in vitro. We propose that BAFF contribute to eLT formation in NPs by promoting B cell survival.
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Affiliation(s)
- Zhe-Zheng Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Song
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hai Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing-Xian Li
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiao Xiao
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ze Yu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin-Xin Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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14
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Wise LM, Stohl W. Belimumab and Rituximab in Systemic Lupus Erythematosus: A Tale of Two B Cell-Targeting Agents. Front Med (Lausanne) 2020; 7:303. [PMID: 32695790 PMCID: PMC7338653 DOI: 10.3389/fmed.2020.00303] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 05/27/2020] [Indexed: 12/24/2022] Open
Abstract
Given the centrality of B cells to systemic lupus erythematosus (SLE), it stands to reason that a candidate therapeutic agent that targets B cells could be efficacious. Both rituximab, a monoclonal antibody (mAb) that binds to CD20 on the surface of B cells, and belimumab, a mAb that binds and neutralizes the B cell survival factor BAFF, have been extensively studied for the treatment of SLE. Despite the greater ability of rituximab to deplete B cells than that of belimumab, randomized controlled trials of rituximab in SLE failed to reach their primary clinical endpoints, whereas the primary clinical endpoints were reached in four independent phase-III clinical trials of belimumab in SLE. Accordingly, belimumab has been approved for treatment of SLE, whereas use of rituximab in SLE remains off-label. Nevertheless, several case series of rituximab have pointed to some utility for rituximab in treating SLE. In this review, we provide a concise summary of the factors that led to belimumab's success in SLE as well an analysis of the elements that may have contributed to the lack of success seen in the rituximab randomized controlled trials in SLE.
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Affiliation(s)
- Leanna M Wise
- Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, United States
| | - William Stohl
- Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, United States
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15
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Kampa M, Notas G, Stathopoulos EN, Tsapis A, Castanas E. The TNFSF Members APRIL and BAFF and Their Receptors TACI, BCMA, and BAFFR in Oncology, With a Special Focus in Breast Cancer. Front Oncol 2020; 10:827. [PMID: 32612943 PMCID: PMC7308424 DOI: 10.3389/fonc.2020.00827] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/28/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor necrosis factor (TNF) superfamily consists of 19 ligands and 29 receptors and is related to multiple cellular events from proliferation and differentiation to apoptosis and tumor reduction. In this review, we overview the whole system, and we focus on A proliferation-inducing ligand (APRIL, TNFSF13) and B cell-activating factor (BAFF, TNFSF13B) and their receptors transmembrane activator and Ca2+ modulator (CAML) interactor (TACI, TNFRSF13B), B cell maturation antigen (BCMA, TNFRSF17), and BAFF receptor (BAFFR, TNFRSF13C). We explore their role in cancer and novel biological therapies introduced for multiple myeloma and further focus on breast cancer, in which the modulation of this system seems to be of potential interest, as a novel therapeutic target. Finally, we discuss some precautions which should be taken into consideration, while targeting the APRIL–BAFF system.
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Affiliation(s)
- Marilena Kampa
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
| | - George Notas
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
| | | | - Andreas Tsapis
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
| | - Elias Castanas
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
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16
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Xu S, Lam KP. Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma? Cancers (Basel) 2020; 12:cancers12041045. [PMID: 32340409 PMCID: PMC7226350 DOI: 10.3390/cancers12041045] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/17/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma (MM) has emerged as the next most likely oncological or hematological disease indication amenable for cellular immunotherapy. Much of the attention has been focused on B cell maturation antigen (BCMA) as a unique cell surface protein on myeloma cells that is available for monoclonal antibodies, antibody drug conjugates (ADCs), T-cell redirecting bispecific molecules, and chimeric antigen receptor (CAR) T cell targeting. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily that binds two ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and mediates the growth and survival of plasma and MM cells. Interestingly, transmembrane activator and CAML interactor (TACI), another TNFR superfamily member, also binds the same ligands and plays largely overlapping roles as BCMA in normal plasma and malignant MM cells. In this article, we review the biology of TACI, focusing on its role in normal B and plasma cells and malignant MM cells, and also discuss various ways to incorporate TACI as a potential target for immunotherapies against MM.
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Affiliation(s)
- Shengli Xu
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
- Correspondence: (S.X); (K.-P.L)
| | - Kong-Peng Lam
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
- Correspondence: (S.X); (K.-P.L)
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17
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Mulazzani M, Huber M, Borchard S, Langer S, Angele B, Schuh E, Meinl E, Dreyling M, Birnbaum T, Straube A, Koedel U, von Baumgarten L. APRIL and BAFF: novel biomarkers for central nervous system lymphoma. J Hematol Oncol 2019; 12:102. [PMID: 31615554 PMCID: PMC6792247 DOI: 10.1186/s13045-019-0796-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 09/25/2019] [Indexed: 12/22/2022] Open
Abstract
Background Early diagnosis of CNS lymphoma (CNSL) is essential for successful therapy of this rapidly progressing brain tumor. However, in patients presenting with focal brain lesions, fast and reliable diagnosis of PCNSL remains a challenge. A proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) are important factors in the pathophysiology, diagnosis, and prognosis of systemic B cell malignancies. However, their utility as biomarkers for the diagnosis of CNSL and their effects on CNSL cells remain unclear. Methods In this prospective study, we analyzed the levels of APRIL and BAFF in the cerebrospinal fluid (CSF) of 116 patients with suspected focal brain lesions, including 53 CNSL patients. Additionally, we serially measured their levels during chemotherapy and relapse. Furthermore, we analyzed the effect of APRIL and BAFF on two B cell lymphoma cell lines using proliferation, viability, and chemotaxis assays. Results CSF levels of APRIL and BAFF reliably differentiated CNSL from other focal brain lesions (including primary and metastatic brain tumors, autoimmune-inflammatory lesions, and neuroinfectious lesions) with a specificity of 93.7% (APRIL, BAFF) and a sensitivity of 62.3% (APRIL) and 47.1% (BAFF). Serial CSF analysis of CNSL patients during chemotherapy and relapse demonstrates a close correlation of APRIL CSF levels and the course of this disease. In vitro, APRIL and BAFF showed anti-apoptotic effects during MTX treatment and mediated chemotaxis of malignant B cells. Conclusion This study extends the spectrum of valuable diagnostic biomarkers in CNSL. In patients with focal brain lesions, measurement of APRIL in CSF could help accelerating the diagnosis of CNSL. Moreover, our results highlight an important role of APRIL and BAFF in the pathophysiology of CNSL.
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Affiliation(s)
| | - Marion Huber
- Department of Neurology, University Hospital, LMU, Munich, Germany
| | - Sabine Borchard
- Department of Neurology, University Hospital, LMU, Munich, Germany
| | - Sigrid Langer
- Department of Neurology, University Hospital, LMU, Munich, Germany
| | - Barbara Angele
- Department of Neurology, University Hospital, LMU, Munich, Germany
| | - Elisabeth Schuh
- Institute for Clinical Neuroimmunology, University Hospital, LMU, Munich, Germany
| | - Edgar Meinl
- Institute for Clinical Neuroimmunology, University Hospital, LMU, Munich, Germany
| | - Martin Dreyling
- Department of Oncology, University Hospital, LMU, Munich, Germany
| | - Tobias Birnbaum
- Department of Neurology, HELIOS Amper-Hospital Dachau, Dachau, Germany
| | - Andreas Straube
- Department of Neurology, University Hospital, LMU, Munich, Germany
| | - Uwe Koedel
- Department of Neurology, University Hospital, LMU, Munich, Germany
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18
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Abo-Elfadl MT, Gamal-Eldeen AM, Ismail MF, Shahin NN. Silencing of the cytokine receptor TNFRSF13B: A new therapeutic target for triple-negative breast cancer. Cytokine 2019; 125:154790. [PMID: 31400636 DOI: 10.1016/j.cyto.2019.154790] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/20/2019] [Accepted: 07/23/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND TNFRSF13B, TACI, is a member of the TNF receptor superfamily; it plays a key role in cancer cell proliferation and progression. METHOD Influence of silencing of human cytokine receptors on cell viability was screened by Luminescent Cell Viability Assay, after transfection of the siRNA library to find the maximum cell death superhits in both triple-negative MDA-MB-231 and double-positive MCF7 breast cells. The mode of cell death was investigated by dual DNA fluorescence staining. The expression of mRNAs of TACI, BAFF, BAFF-R, and APRIL was explored by qPCR. Immunocytofluorescence analysis was used to evaluate changes in TACI, Bcl-2, TNFR2, cyclin-D2, and PCNA. NF-kB p65, cell cycle, and necrosis/apoptosis (late and early) were analyzed by flow cytometry. RESULTS TACI is the most potent cytotoxic superhit resulted from high-throughput screening of the siRNA library, in both types of cells. Our findings indicated that silencing receptor TACI in both types of breast cancer cells led to significant cell death, after different intervals from siRNA transfection. Cell death mediators (TNFR2, Bcl-2, and NF-κB) were significantly decreased after TACI silencing. The key factors for cell division (Cyclin-D2 and PCNA) were significantly increased in silenced cells of both types but the cell cycle was arrested before the completion of mitosis. Expression of BAFF, BAFF-R and APRIL mRNA in TACI-silenced cells showed significant upregulation in MDA-MB-231 cells, while only BAFF-R and APRIL showed significant downregulation in MCF7 cells. CONCLUSION TACI silencing can be a new and promising therapeutic target for mesenchymal-stem like triple-negative breast cancer subtype.
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Affiliation(s)
- Mahmoud T Abo-Elfadl
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, 12622 Cairo, Egypt; Biochemistry Department, National Research Centre, Dokki, Cairo, Egypt
| | - Amira M Gamal-Eldeen
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, 12622 Cairo, Egypt; Biochemistry Department, National Research Centre, Dokki, Cairo, Egypt; Clinical Laboratory Department, College of Applied Medical Sciences, Taif University, Al Mutamarat Rd, Al Mathnah, At Taif 26521, Saudi Arabia.
| | - Manal F Ismail
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nancy N Shahin
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Garcia-Carmona Y, Ting AT, Radigan L, Athuluri Divakar SK, Chavez J, Meffre E, Cerutti A, Cunningham-Rundles C. TACI Isoforms Regulate Ligand Binding and Receptor Function. Front Immunol 2018; 9:2125. [PMID: 30333819 PMCID: PMC6176016 DOI: 10.3389/fimmu.2018.02125] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/29/2018] [Indexed: 12/12/2022] Open
Abstract
TACI signals activate B cell proliferation, isotype switch and antibody production in both normal immunity and autoimmune states. In contrast to murine TACI, the human TACI gene undergoes alternative splicing to produce short and long isoforms (TACI-S and TACI-L). In previous studies, we showed that transduction of the short, but not long isoform, into murine B cells or human pre-B cells lacking TACI, caused them to become transcriptional and morphologically identical to plasma cells. These data suggest that the expression of different isoforms in humans provides unique controls on B cell maturation. In these studies we show that TACI-S and TACI-L form complexes in a ligand-independent manner, not dependent on a single extracellular domain. Both TACI isoforms are detectable in the endosomal cellular compartment where they co-localize with MyD88, TRAF6, and the activated 65 kDa form of TLR9, depending on a conserved intracellular TACI sequence. In contrast to TACI-L expressing cells, or cells bearing both isoforms, TACI-S binds ligands BAFF and APRIL with substantially greater affinity and promotes enhanced NF-kB activation. Using isoform-specific monoclonal antibodies, we show that while TACI-L is predominant as a surface receptor surface on human B cells, significantly more TACI-S is noted in the intracellular compartment and also in marginal zone, isotype switched and plasmablast in resting B cells. TACI-S is increased in tonsillar B cells and also in the intracellular compartment of activated peripheral B cells. These data shows that alternative splicing of the human TACI gene leads to two isoforms both of which intersect with MyD88 and TRAF6 and form complexes with TLR9, but the two isoforms have different ligand binding capacities, subcellular locations and activation capabilities.
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Affiliation(s)
- Yolanda Garcia-Carmona
- Department of Clinical Immunology, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Adrian T Ting
- Department of Clinical Immunology, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Lin Radigan
- Department of Clinical Immunology, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | | | - Jose Chavez
- Department of Clinical Immunology, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Eric Meffre
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Andrea Cerutti
- Department of Clinical Immunology, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Catalan Institute for Research and Advance Studies (ICREA), Barcelona, Spain.,Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Charlotte Cunningham-Rundles
- Department of Clinical Immunology, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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20
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Beekman R, Chapaprieta V, Russiñol N, Vilarrasa-Blasi R, Verdaguer-Dot N, Martens JHA, Duran-Ferrer M, Kulis M, Serra F, Javierre BM, Wingett SW, Clot G, Queirós AC, Castellano G, Blanc J, Gut M, Merkel A, Heath S, Vlasova A, Ullrich S, Palumbo E, Enjuanes A, Martín-García D, Beà S, Pinyol M, Aymerich M, Royo R, Puiggros M, Torrents D, Datta A, Lowy E, Kostadima M, Roller M, Clarke L, Flicek P, Agirre X, Prosper F, Baumann T, Delgado J, López-Guillermo A, Fraser P, Yaspo ML, Guigó R, Siebert R, Martí-Renom MA, Puente XS, López-Otín C, Gut I, Stunnenberg HG, Campo E, Martin-Subero JI. The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia. Nat Med 2018; 24:868-880. [PMID: 29785028 PMCID: PMC6363101 DOI: 10.1038/s41591-018-0028-4] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 03/23/2018] [Indexed: 12/11/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.
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Affiliation(s)
- Renée Beekman
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
| | - Vicente Chapaprieta
- Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
| | - Núria Russiñol
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Roser Vilarrasa-Blasi
- Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
| | - Núria Verdaguer-Dot
- Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
| | - Joost H A Martens
- Molecular Biology, NCMLS, FNWI, Radboud University, Nijmegen, The Netherlands
| | - Martí Duran-Ferrer
- Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
| | - Marta Kulis
- Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain
| | - François Serra
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Structural Genomics Group, CNAG-CRG, The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Biola M Javierre
- Nuclear Dynamics Program, Babraham Institute, Babraham Research Campus, Cambridge, UK
| | - Steven W Wingett
- Nuclear Dynamics Program, Babraham Institute, Babraham Research Campus, Cambridge, UK
| | - Guillem Clot
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
| | - Ana C Queirós
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | | | - Julie Blanc
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Marta Gut
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Angelika Merkel
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Simon Heath
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Anna Vlasova
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology and UPF, Barcelona, Spain
| | - Sebastian Ullrich
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology and UPF, Barcelona, Spain
| | - Emilio Palumbo
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology and UPF, Barcelona, Spain
| | - Anna Enjuanes
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
| | - David Martín-García
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
| | - Sílvia Beà
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
| | - Magda Pinyol
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
| | - Marta Aymerich
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
| | - Romina Royo
- Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
| | - Montserrat Puiggros
- Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
| | - David Torrents
- Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Avik Datta
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK
| | - Ernesto Lowy
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK
| | - Myrto Kostadima
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK
| | - Maša Roller
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK
| | - Laura Clarke
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK
| | - Paul Flicek
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK
| | - Xabier Agirre
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Felipe Prosper
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain
| | - Tycho Baumann
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - Julio Delgado
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - Armando López-Guillermo
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - Peter Fraser
- Nuclear Dynamics Program, Babraham Institute, Babraham Research Campus, Cambridge, UK
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | | | - Roderic Guigó
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology and UPF, Barcelona, Spain
| | - Reiner Siebert
- Institute of Human Genetics, University of Ulm and University Hospital of Ulm, Ulm, Germany
| | - Marc A Martí-Renom
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Structural Genomics Group, CNAG-CRG, The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Xose S Puente
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Carlos López-Otín
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Ivo Gut
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | | | - Elias Campo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain
- Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
- Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain
- Hematopathology Section, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Jose I Martin-Subero
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain.
- Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
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21
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Wen L, Zhu C, Zhu Z, Yang C, Zheng X, Liu L, Zuo X, Sheng Y, Tang H, Liang B, Zhou Y, Li P, Zhu J, Ding Y, Chen G, Gao J, Tang L, Cheng Y, Sun J, Elango T, Kafle A, Yu R, Xue K, Zhang Y, Li F, Li Z, Guo J, Zhang X, Zhou C, Tang Y, Shen N, Wang M, Yu X, Liu S, Fan X, Gao M, Xiao F, Wang P, Wang Z, Zhang A, Zhou F, Sun L, Yang S, Xu J, Yin X, Cui Y, Zhang X. Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population. Ann Rheum Dis 2018; 77:417. [PMID: 29233832 DOI: 10.1136/annrheumdis-2017-211823] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 11/11/2017] [Accepted: 11/19/2017] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. METHODS We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. RESULTS We discovered four novel SLE gene regions (LCT, TPCN2, AHNAK2 and TNFRSF13B) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (pmeta <5.00×10-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38×10-3) whose expression level was reduced significantly in patients with SLE (P<2.53×10-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10-5) in ex vivo experiments. CONCLUSIONS This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE.
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Affiliation(s)
- Leilei Wen
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Caihong Zhu
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Zhengwei Zhu
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Chao Yang
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiaodong Zheng
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Lu Liu
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xianbo Zuo
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Yujun Sheng
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Huayang Tang
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Bo Liang
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Yi Zhou
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Pan Li
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jun Zhu
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Yantao Ding
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Gang Chen
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinping Gao
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Lili Tang
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Yuyan Cheng
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jingying Sun
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Tamilselvi Elango
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Anjana Kafle
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Ruixing Yu
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Ke Xue
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Yaohua Zhang
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
| | - Feng Li
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - Jianping Guo
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuanjia Tang
- Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Nan Shen
- Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng Wang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Key Laboratory of Nephrology, Ministry of Health, Guangdong, China
| | - Xueqing Yu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Key Laboratory of Nephrology, Ministry of Health, Guangdong, China
| | - Shengxiu Liu
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xing Fan
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Min Gao
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Fengli Xiao
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Peiguang Wang
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Zaixing Wang
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Anping Zhang
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Fusheng Zhou
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Liangdan Sun
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Sen Yang
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhua Xu
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
| | - Xianyong Yin
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
- Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - Yong Cui
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Xuejun Zhang
- Department of Dermatology, Institute of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
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22
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Dou H, Yan Z, Zhang M, Xu X. APRIL promotes non-small cell lung cancer growth and metastasis by targeting ERK1/2 signaling. Oncotarget 2017; 8:109289-109300. [PMID: 29312608 PMCID: PMC5752521 DOI: 10.18632/oncotarget.22672] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 11/09/2017] [Indexed: 12/12/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the most common cause of cancer-related mortality in the world. It is a complex disease involving multiple genetic alterations. As a cytokine belonging to the Tumor Necrosis Factor-α (TNF- α) family, the - a proliferation-inducing ligand (APRIL) expression and its signaling have been studied in many human solid tumor types, but the data on APRIL signaling in NSCLC are lacking. The aim of this study was to evaluate the APRIL expression and investigate its signaling in NSCLC. The expression of APRIL and its receptors, B cell maturation antigen (BCMA) and transmembrane activator and calcium-modulatorand cyclophilin ligand interactor (TACI), was analyzed by using immunohistochemistry in NSCLC samples. Quantitative RT-PCR was performed to evaluate mRNA expression of APRIL, BCMA and TACI in human lung adenocarcinoma cell lines A549, H1299, and H1650. Cell proliferation was measured by using the cell proliferation and cytotoxicity assay kit 8 (CCK8) assay, cell migration by using wound healing assay, and cell invasion by using transwall assay. The protein level of APRIL, BCMA and TAC, and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) signaling, were determined by western blot. Our results indicated, APRIL and its receptors BCMA and TACI, were overexpressed in most of human NSCLC samples and cell lines; APRIL promoted tumor proliferation, migration and metastasis in A549 and H1299 cells via BCMA and TACI. Furthermore, ERK1/2 activation was involved in APRIL signaling through TACI but not BCMA in A549 and H1299 cells. APRIL might serve as a potential prognostic biomarker for NSCLC, and APRIL related signaling pathway could be a therapeutic target for NSCLC.
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Affiliation(s)
- Hengli Dou
- Department of Neurosurgery, The Fourth Hospital of Jinan, Jinan 250013, Shandong, China
| | - Zhaohua Yan
- Department of Neurosurgery, The Fourth Hospital of Jinan, Jinan 250013, Shandong, China
| | - Meng Zhang
- Department of Neurosurgery, The Fourth Hospital of Jinan, Jinan 250013, Shandong, China
| | - Xiaoxin Xu
- Department of Neurosurgery, The Fourth Hospital of Jinan, Jinan 250013, Shandong, China
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23
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Borhis G, Trovato M, Chaoul N, Ibrahim HM, Richard Y. B-Cell-Activating Factor and the B-Cell Compartment in HIV/SIV Infection. Front Immunol 2017; 8:1338. [PMID: 29163465 PMCID: PMC5663724 DOI: 10.3389/fimmu.2017.01338] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/03/2017] [Indexed: 12/12/2022] Open
Abstract
With the goal to design effective HIV vaccines, intensive studies focused on broadly neutralizing antibodies, which arise in a fraction of HIV-infected people. Apart from identifying new vulnerability sites in the viral envelope proteins, these studies have shown that a fraction of these antibodies are produced by self/poly-reactive B-cells. These findings prompted us to revisit the B-cell differentiation and selection process during HIV/SIV infection and to consider B-cells as active players possibly shaping the helper T-cell program within germinal centers (GCs). In this context, we paid a particular attention to B-cell-activating factor (BAFF), a key cytokine in B-cell development and immune response that is overproduced during HIV/SIV infection. As it does in autoimmune diseases, BAFF excess might contribute to the abnormal rescue of self-reactive B-cells at several checkpoints of the B-cell development and impair memory B-cell generation and functions. In this review, we first point out what is known about the functions of BAFF/a proliferation-inducing ligand and their receptors [B-cell maturation, transmembrane activator and CAML interactor (TACI), and BAFF-R], in physiological and pathophysiological settings, in mice and humans. In particular, we highlight recent results on the previously underappreciated regulatory functions of TACI and on the highly regulated production of soluble TACI and BAFF-R that act as decoy receptors. In light of recent data on BAFF, TACI, and BAFF-R, we then revisit the altered phenotypes and functions of B-cell subsets during the acute and chronic phase of HIV/SIV infection. Given the atypical phenotype and reduced functions of memory B-cells in HIV/SIV infection, we particularly discuss the GC reaction, a key checkpoint where self-reactive B-cells are eliminated and pathogen-specific memory B-cells and plasmablasts/cells are generated in physiological settings. Through its capacity to differentially bind and process BAFF-R and TACI on GC B-cells and possibly on follicular helper T-cells, BAFF appears as a key regulator of the physiological GC reaction. Its local excess during HIV/SIV infection could play a key role in B-cell dysregulations.
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Affiliation(s)
- Gwenoline Borhis
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
| | - Maria Trovato
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
| | - Nada Chaoul
- Commissariat à l’Energie Atomique, Institut des maladies Emergentes et Thérapies innovantes, Service d’Immuno-Virologie, Fontenay-aux Roses, France
| | - Hany M. Ibrahim
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
| | - Yolande Richard
- INSERM u1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris-Descartes, Paris, France
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24
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Haley SL, Tzvetkov EP, Lytle AG, Alugupalli KR, Plummer JR, McGettigan JP. APRIL:TACI axis is dispensable for the immune response to rabies vaccination. Antiviral Res 2017; 144:130-137. [PMID: 28619678 DOI: 10.1016/j.antiviral.2017.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 06/07/2017] [Accepted: 06/08/2017] [Indexed: 12/25/2022]
Abstract
There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation-inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell maturation antigen (BCMA)-expressed by B cells in various stages of maturation-with high affinity. We discovered that RABV-infected primary murine B cells upregulate APRIL ex vivo. Cytokines present at the time of antigen exposure affect the outcome of vaccination by influencing T and B cell activation and GC formation. Therefore, we hypothesized that the presence of APRIL at the time of RABV-based vaccine antigen exposure would support the generation of protective antibodies against RABV glycoprotein (G). In an effort to improve the response to RABV vaccination, we constructed and characterized a live recombinant RABV-based vaccine vector which expresses murine APRIL (rRABV-APRIL). Immunogenicity testing in mice demonstrated that expressing APRIL from the RABV genome does not impact the primary antibody response against RABV G compared to RABV alone. In order to evaluate the necessity of APRIL for the response to rabies vaccination, we compared the responses of APRIL-deficient and wild-type mice to immunization with rRABV. APRIL deficiency does not affect the primary antibody response to vaccination. Furthermore, APRIL expression by the vaccine did not improve the generation of long-lived antibody-secreting plasma cells (PCs) as serum antibody levels were equivalent in response to rRABV-APRIL and the vector eight weeks after immunization. Moreover, APRIL is dispensable for the long-lived antibody-secreting PC response to rRABV vaccination as anti-RABV G IgG levels were similar in APRIL-deficient and wild-type mice six months after vaccination. Mice lacking the APRIL receptor TACI demonstrated primary anti-RABV G antibody responses similar to wild-type mice following immunization with the vaccine vector indicating that this response is independent of TACI-mediated signals. Collectively, our findings demonstrate that APRIL and associated TACI signaling is dispensable for the immune response to RABV-based vaccination.
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Affiliation(s)
- Shannon L Haley
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Evgeni P Tzvetkov
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Andrew G Lytle
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Kishore R Alugupalli
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Joseph R Plummer
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, United States
| | - James P McGettigan
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, United States; Jefferson Vaccine Center, Thomas Jefferson University, Philadelphia, PA, United States.
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25
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Rand KA, Song C, Dean E, Serie DJ, Curtin K, Sheng X, Hu D, Huff CA, Bernal-Mizrachi L, Tomasson MH, Ailawadhi S, Singhal S, Pawlish K, Peters ES, Bock CH, Stram A, Van Den Berg DJ, Edlund CK, Conti DV, Zimmerman T, Hwang AE, Huntsman S, Graff J, Nooka A, Kong Y, Pregja SL, Berndt SI, Blot WJ, Carpten J, Casey G, Chu L, Diver WR, Stevens VL, Lieber MR, Goodman PJ, Hennis AJM, Hsing AW, Mehta J, Kittles RA, Kolb S, Klein EA, Leske C, Murphy AB, Nemesure B, Neslund-Dudas C, Strom SS, Vij R, Rybicki BA, Stanford JL, Signorello LB, Witte JS, Ambrosone CB, Bhatti P, John EM, Bernstein L, Zheng W, Olshan AF, Hu JJ, Ziegler RG, Nyante SJ, Bandera EV, Birmann BM, Ingles SA, Press MF, Atanackovic D, Glenn MJ, Cannon-Albright LA, Jones B, Tricot G, Martin TG, Kumar SK, Wolf JL, Deming Halverson SL, Rothman N, Brooks-Wilson AR, Rajkumar SV, Kolonel LN, Chanock SJ, Slager SL, Severson RK, Janakiraman N, Terebelo HR, Brown EE, De Roos AJ, Mohrbacher AF, Colditz GA, Giles GG, Spinelli JJ, Chiu BC, Munshi NC, Anderson KC, Levy J, Zonder JA, Orlowski RZ, Lonial S, Camp NJ, Vachon CM, Ziv E, Stram DO, Hazelett DJ, et alRand KA, Song C, Dean E, Serie DJ, Curtin K, Sheng X, Hu D, Huff CA, Bernal-Mizrachi L, Tomasson MH, Ailawadhi S, Singhal S, Pawlish K, Peters ES, Bock CH, Stram A, Van Den Berg DJ, Edlund CK, Conti DV, Zimmerman T, Hwang AE, Huntsman S, Graff J, Nooka A, Kong Y, Pregja SL, Berndt SI, Blot WJ, Carpten J, Casey G, Chu L, Diver WR, Stevens VL, Lieber MR, Goodman PJ, Hennis AJM, Hsing AW, Mehta J, Kittles RA, Kolb S, Klein EA, Leske C, Murphy AB, Nemesure B, Neslund-Dudas C, Strom SS, Vij R, Rybicki BA, Stanford JL, Signorello LB, Witte JS, Ambrosone CB, Bhatti P, John EM, Bernstein L, Zheng W, Olshan AF, Hu JJ, Ziegler RG, Nyante SJ, Bandera EV, Birmann BM, Ingles SA, Press MF, Atanackovic D, Glenn MJ, Cannon-Albright LA, Jones B, Tricot G, Martin TG, Kumar SK, Wolf JL, Deming Halverson SL, Rothman N, Brooks-Wilson AR, Rajkumar SV, Kolonel LN, Chanock SJ, Slager SL, Severson RK, Janakiraman N, Terebelo HR, Brown EE, De Roos AJ, Mohrbacher AF, Colditz GA, Giles GG, Spinelli JJ, Chiu BC, Munshi NC, Anderson KC, Levy J, Zonder JA, Orlowski RZ, Lonial S, Camp NJ, Vachon CM, Ziv E, Stram DO, Hazelett DJ, Haiman CA, Cozen W. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiol Biomarkers Prev 2016; 25:1609-1618. [PMID: 27587788 PMCID: PMC5524541 DOI: 10.1158/1055-9965.epi-15-1193] [Show More Authors] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 06/20/2016] [Accepted: 07/05/2016] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. METHODS We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. RESULTS We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. IMPACT A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.
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Affiliation(s)
- Kristin A Rand
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Chi Song
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | | | | | - Karen Curtin
- University of Utah School of Medicine, Salt Lake City, Utah
| | - Xin Sheng
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Donglei Hu
- University of California at San Francisco, San Francisco, California
| | - Carol Ann Huff
- Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | | | - Michael H Tomasson
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri
| | | | - Seema Singhal
- Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois
| | - Karen Pawlish
- New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, New Jersey
| | - Edward S Peters
- Louisiana State University School of Public Health, Louisiana State University, New Orleans, Louisiana
| | - Cathryn H Bock
- Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
| | - Alex Stram
- Genomic Health, Inc., Redwood City, California
| | - David J Van Den Berg
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Christopher K Edlund
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - David V Conti
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | | | - Amie E Hwang
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Scott Huntsman
- University of California at San Francisco, San Francisco, California
| | - John Graff
- Rutgers-Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey
| | - Ajay Nooka
- Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Yinfei Kong
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Silvana L Pregja
- Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
| | - William J Blot
- International Epidemiology Institute, Rockville, Maryland
- Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - John Carpten
- The Translational Genomics Research Institute, Phoenix, Arizona
| | - Graham Casey
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Lisa Chu
- Cancer Prevention Institute of California, Fremont, California
- Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California
| | | | | | - Michael R Lieber
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | | | - Anselm J M Hennis
- Stony Brook University, Stony Brook, New York
- Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados
| | - Ann W Hsing
- Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California
| | - Jayesh Mehta
- Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois
| | - Rick A Kittles
- Department of Surgery, University of Arizona, Tucson, Arizona
| | - Suzanne Kolb
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Eric A Klein
- Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
| | | | - Adam B Murphy
- Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois
| | | | | | - Sara S Strom
- The University of Texas MD Anderson Cancer Center, University of Texas, Houston, Texas
| | - Ravi Vij
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri
| | | | - Janet L Stanford
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Lisa B Signorello
- Harvard School of Public Health, Harvard University, Boston, Massachusetts
| | - John S Witte
- Institute for Human Genetics, University of California, San Francisco, San Francisco, California
| | | | - Parveen Bhatti
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Esther M John
- Cancer Prevention Institute of California, Fremont, California
- Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California
| | - Leslie Bernstein
- Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California
| | - Wei Zheng
- International Epidemiology Institute, Rockville, Maryland
| | - Andrew F Olshan
- Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
| | - Jennifer J Hu
- Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida
| | - Regina G Ziegler
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
| | - Sarah J Nyante
- Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
| | - Elisa V Bandera
- Rutgers-Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey
| | - Brenda M Birmann
- Harvard School of Public Health, Harvard University, Boston, Massachusetts
| | - Sue A Ingles
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Michael F Press
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | | | - Martha J Glenn
- University of Utah School of Medicine, Salt Lake City, Utah
| | | | - Brandt Jones
- University of Utah School of Medicine, Salt Lake City, Utah
| | | | - Thomas G Martin
- University of California at San Francisco, San Francisco, California
| | | | - Jeffrey L Wolf
- University of California at San Francisco, San Francisco, California
| | | | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
| | | | | | - Laurence N Kolonel
- University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
| | | | - Richard K Severson
- Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
| | | | | | | | | | - Ann F Mohrbacher
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Graham A Colditz
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri
| | - Graham G Giles
- Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria, Australia
- School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia
- Monash University, Melbourne, Melbourne, Victoria, Australia
| | - John J Spinelli
- BC Cancer Agency, Vancouver, Canada
- School of Population and Public Health, University of British Columbia, Vancouver, Canada
| | | | - Nikhil C Munshi
- Dana Farber Cancer Institute, Harvard School of Medicine, Harvard University, Boston, Massachusetts
| | - Kenneth C Anderson
- Dana Farber Cancer Institute, Harvard School of Medicine, Harvard University, Boston, Massachusetts
| | - Joan Levy
- Multiple Myeloma Research Foundation, Norwalk, Connecticut
| | - Jeffrey A Zonder
- Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
| | - Robert Z Orlowski
- The University of Texas MD Anderson Cancer Center, University of Texas, Houston, Texas
| | - Sagar Lonial
- Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Nicola J Camp
- University of Utah School of Medicine, Salt Lake City, Utah
| | | | - Elad Ziv
- University of California at San Francisco, San Francisco, California
| | - Daniel O Stram
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Dennis J Hazelett
- Center for Bioinformatics and Computational Biology, Cedars Sinai Medical Center, Los Angeles, California.
| | - Christopher A Haiman
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
| | - Wendy Cozen
- Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
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Uzzan M, Colombel JF, Cerutti A, Treton X, Mehandru S. B Cell-Activating Factor (BAFF)-Targeted B Cell Therapies in Inflammatory Bowel Diseases. Dig Dis Sci 2016; 61:3407-3424. [PMID: 27655102 DOI: 10.1007/s10620-016-4317-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 09/13/2016] [Indexed: 12/23/2022]
Abstract
Inflammatory bowel diseases (IBD) involve dysregulated immune responses to gut antigens in genetically predisposed individuals. While a better elucidation of IBD pathophysiology has considerably increased the number of treatment options, the need for more effective therapeutic strategies remains a pressing priority. Defects of both non-hematopoietic (epithelial and stromal) and hematopoietic (lymphoid and myeloid) cells have been described in patients with IBD. Within the lymphoid system, alterations of the T cell compartment are viewed as essential in the pathogenesis of IBD. However, growing evidence points to the additional perturbations of the B cell compartment. Indeed, the intestinal lamina propria from IBD patients shows an increased presence of antibody-secreting plasma cells, which correlates with enhanced pro-inflammatory immunoglobulin G production and changes in the quality of non-inflammatory IgA responses. These B cell abnormalities are compounded by the emergence of systemic antibody responses to various autologous and microbial antigens, which predates the clinical diagnosis of IBD and identifies patients with complicated disease. It is presently unclear whether such antibody responses play a pathogenetic role, as B cell depletion with the CD20-targeting monoclonal antibody rituximab did not ameliorate ulcerative colitis in a clinical trial. However, it must be noted that unresponsiveness to rituximab is also observed also in some patients with autoimmune disorders usually responsive to B cell-depleting therapies. In this review, we discussed mechanistic aspects of B cell-based therapies and their potential role in IBD with a special interest on BAFF and BAFF-targeting therapies buoyed by the success of anti-BAFF treatments in rheumatologic disorders.
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Affiliation(s)
- Mathieu Uzzan
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .,The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Departments of Medicine and Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrea Cerutti
- The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Xavier Treton
- Department of Gastroenterology, Beaujon Hospital, APHP, Denis Diderot University, Paris, France
| | - Saurabh Mehandru
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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27
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Jabara HH, Lee JJ, Janssen E, Ullas S, Liadaki K, Garibyan L, Benson H, Sannikova T, Bram R, Hammarstrom L, Cruz AC, Siegel R, Manis J, Malley R, Geha RS. Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice. J Allergy Clin Immunol 2016; 139:1293-1301.e4. [PMID: 27609654 DOI: 10.1016/j.jaci.2016.07.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 07/18/2016] [Accepted: 07/26/2016] [Indexed: 01/22/2023]
Abstract
BACKGROUND The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation. OBJECTIVE We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice. METHODS Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge. RESULTS Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI+/- mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand-driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge. CONCLUSION These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers.
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Affiliation(s)
- Haifa H Jabara
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - John J Lee
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Erin Janssen
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Sumana Ullas
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Kyriaki Liadaki
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Lilit Garibyan
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Halli Benson
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Tatyana Sannikova
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Richard Bram
- Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minn
| | | | - Anthony C Cruz
- Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - Richard Siegel
- Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - John Manis
- Division of Transfusion Medicine, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Richard Malley
- Division of Infectious Diseases, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass
| | - Raif S Geha
- Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
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Abstract
B lymphocytestimulator (BLyS) is a vital B cell survivalfactor. Overexpressionof BLyS in mice may lead to systemic lupus erythematosus (SLE)-like disease, and treatment of bona fide SLE mice with BLyS antagonists ameliorates disease progression and enhances survival. BLyS overexpression is common in human SLE, and results from a phase I clinical trial with a BLyS antagonistin human SLE have shown the antagonist to be biologicallyactive and safe. These features collectivelypoint to BLyS as an attractive therapeutic target in human disease.
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Affiliation(s)
- W Stohl
- Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles 90033, USA.
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Bosello S, Pers JO, Rochas C, Devauchelle V, De Santis M, Daridon C, Saraux A, Ferraccioli GF, Youinou P. Baff and Rheumatic Autoimmune Disorders: Implications for Disease Management and Therapy. Int J Immunopathol Pharmacol 2016; 20:1-8. [PMID: 17346422 DOI: 10.1177/039463200702000101] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.
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Affiliation(s)
- S Bosello
- Laboratory of Immunology, Medical School, Brest, France
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Abstract
The signaling adapter protein tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) is both modified by and contributes to several types of ubiquitination events. TRAF3 plays a variety of context-dependent regulatory roles in all types of immune cells. In B lymphocytes, TRAF3 contributes to regulation of signaling by members of both the TNFR superfamily and innate immune receptors. TRAF3 also plays a unique cell type-specific and critical role in the restraint of B-cell homeostatic survival, a role with important implications for both B-cell differentiation and the pathogenesis of B-cell malignancies. This review focuses upon the relationship between ubiquitin and TRAF3, and how this contributes to multiple functions of TRAF3 in the regulation of signal transduction, transcriptional activation, and effector functions of B lymphocytes.
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Affiliation(s)
- Wai W Lin
- The Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA
| | - Bruce S Hostager
- Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | - Gail A Bishop
- The Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA.,Department of Microbiology, University of Iowa, Iowa City, IA, USA.,Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.,VA Medical Center, University of Iowa, Iowa City, IA, USA
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31
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Liu H, Zhang J, Li J, Song J, Zhang S. Molecular structure, distribution, and immunology function of TNFSF13B (BAFF) in Nile tilapia (Oreochromis niloticus). FISH & SHELLFISH IMMUNOLOGY 2016; 51:240-250. [PMID: 26915306 DOI: 10.1016/j.fsi.2016.02.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 02/19/2016] [Accepted: 02/19/2016] [Indexed: 06/05/2023]
Abstract
B cell-activating factor (BAFF)is a member of the tumor necrosis factor (TNF) family and plays roles in B cell survival and maturation. In this study, the full-length cDNA of Nile tilapia (Oreochromis niloticus) BAFF (tBAFF) was amplified from the spleen by reverse transcription PCR (RT-PCR). The open reading frame of this cDNA encodes a protein of 261 amino acids containing a predicted transmembrane domain and a furin protease cleavage site, similar to mammalian, avian, and reptile BAFF. Real-time quantitative PCR (qPCR) analysis revealed that tBAFF is present in various tissues and is predominantly expressed in the spleen. The predicted three-dimensional (3D) structure of the Nile tilapia (Oreochromis niloticus) soluble BAFF (tsBAFF) monomer was determined by (3D) structure modeling monomeranalyzed by (3D) structure mouse counterpart. Both tsBAFF and EGFP/tsBAFF were efficiently expressed in Escherichia coli BL21 (DE3), as confirmed by SDS-PAGE and Western blot analysis. After purification, the EGFP/tsBAFF fusion protein showed a fluorescence spectrum similar to that of EGFP. Laser scanning confocal microscopy showed that EGFP/tsBAFF bound to its receptor. In vitro, tsBAFF promoted the proliferation of Nile tilapia and mouse splenic B cells together with/without a priming agent (Staphylococcus aureus Cowan 1, SAC) or anti-mouse IgM. Furthermore, tsBAFF showed a similar proliferation-stimulating effect on mouse B cells compared to msBAFF. These findings indicate that tsBAFF plays an important role in the proliferation of Nile tilapia B cells and has functional cross-reactivity among Nile tilapia and mammals. Therefore, BAFF may represent a useful factor for enhancing immunological efficacy in animals.
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Affiliation(s)
- Hongzhen Liu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Life Sciences College, Nanjing Normal University, Nanjing, 210046, China
| | - Jiaxin Zhang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Life Sciences College, Nanjing Normal University, Nanjing, 210046, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, 210037, China.
| | - Jianfeng Li
- Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310036, China
| | - Jinyun Song
- Central Laboratory, The Second Affiliated Hospital of Southeast University, 210003, Nanjing, China
| | - Shuangquan Zhang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Life Sciences College, Nanjing Normal University, Nanjing, 210046, China.
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B-Cell Activating Factor as a Cancer Biomarker and Its Implications in Cancer-Related Cachexia. BIOMED RESEARCH INTERNATIONAL 2015; 2015:792187. [PMID: 26339644 PMCID: PMC4538579 DOI: 10.1155/2015/792187] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 04/28/2015] [Indexed: 01/21/2023]
Abstract
B-cell activating factor (BAFF) is a cytokine and adipokine of the TNF ligand superfamily. The main biological function of BAFF in maintaining the maturation of B-cells to plasma cells has recently made it a target of the first FDA-approved selective BAFF antibody, belimumab, for the therapy of systemic lupus erythematosus. Concomitantly, the role of BAFF in cancer has been a subject of research since its discovery. Here we review BAFF as a biomarker of malignant disease activity and prognostic factor in B-cell derived malignancies such as multiple myeloma. Moreover, anti-BAFF therapy seems to be a promising approach in treatment of B-cell derived leukemias/lymphomas. In nonhematologic solid tumors, BAFF may contribute to cancer progression by mechanisms both dependent on and independent of BAFF's proinflammatory role. We also describe ongoing research into the pathophysiological link between BAFF and cancer-related cachexia. BAFF has been shown to contribute to inflammation and insulin resistance which are known to worsen cancer cachexia syndrome. Taking all the above together, BAFF is emerging as a biomarker of several malignancies and a possible hallmark of cancer cachexia.
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Abstract
Rheumatoid arthritis (RA) is a common autoimmune disease that is marked by a systemic inflammatory reaction and joint erosions. Elevated levels of B cell activating factor (BAFF) have been detected in the serum and synovial fluid of RA patients. Moreover, the levels of BAFF increase in cases of autoimmune disease and are correlated with the level of disease activity. As an innate cytokine mediator, BAFF affects the immune response of the synovial microenvironment. In this review, we consider recent observations of BAFF and its receptors in RA progression, as well as the effects of BAFF on the cell-cell interactions network. We also summarize the clinical development of BAFF antagonists for the treatment of RA.
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Sathkumara HD, De Silva NR, Handunnetti S, De Silva AD. Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor. Int J Immunogenet 2015; 42:239-53. [DOI: 10.1111/iji.12217] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 04/27/2015] [Accepted: 05/25/2015] [Indexed: 12/25/2022]
Affiliation(s)
- H. D. Sathkumara
- Genetech Research Institute; Colombo Sri Lanka
- Institute of Biochemistry, Molecular Biology and Biotechnology; University of Colombo; Colombo Sri Lanka
| | | | - S. Handunnetti
- Institute of Biochemistry, Molecular Biology and Biotechnology; University of Colombo; Colombo Sri Lanka
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He XQ, Guan J, Liu F, Li J, He MR. Identification of the sAPRIL binding peptide and its growth inhibition effects in the colorectal cancer cells. PLoS One 2015; 10:e0120564. [PMID: 25826583 PMCID: PMC4380366 DOI: 10.1371/journal.pone.0120564] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 02/05/2015] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) super family. It binds to its specific receptors and is involved in multiple processes during tumorigenesis and tumor cells proliferation. High levels of APRIL expression are closely correlated to the growth, metastasis, and 5-FU drug resistance of colorectal cancer. The aim of this study was to identify a specific APRIL binding peptide (BP) able to block APRIL activity that could be used as a potential treatment for colorectal cancer. METHODS A phage display library was used to identify peptides that bound selectively to soluble recombinant human APRIL (sAPRIL). The peptides with the highest binding affinity for sAPRIL were identified using ELISA. The effects of sAPRIL-BP on cell proliferation and cell cycle/apoptosis in vitro were evaluated using the CCK-8 assay and flow cytometry, respectively. An in vivo mouse model of colorectal cancer was used to determine the anti-tumor efficacy of the sAPRIL-BP. RESULTS Three candidate peptides were characterized from eight phage clones with high binding affinity for sAPRIL. The peptide with the highest affinity was selected for further characterization. The identified sAPRIL-BP suppressed tumor cell proliferation and cell cycle progression in LOVO cells in a dose-dependent manner. In vivo in a mouse colorectal challenge model, the sAPRIL-BP reduced the growth of tumor xenografts in nude mice by inhibiting proliferation and inducing apoptosis intratumorally. Moreover, in an in vivo metastasis model, sAPRIL-BP reduced liver metastasis of colorectal cancer cells. CONCLUSIONS sAPRIL-BP significantly suppressed tumor growth in vitro and in vivo and might be a candidate for treating colorectal cancers that express high levels of APRIL.
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Affiliation(s)
- Xiao-qing He
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Digestive Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Oncology Department, Wuzhou Red Cross Hospital, Wuzhou 543002, Guangxi Province, China
| | - Jing Guan
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Digestive Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Army Reserve Anti-aircraft Artillery Hospital, Zhengzhou 450002, Henan Province, China
| | - Fang Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Digestive Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jing Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Digestive Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Mei-rong He
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Digestive Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- * E-mail:
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García-Castro A, Zonca M, Florindo-Pinheiro D, Carvalho-Pinto CE, Cordero A, Gutiérrez del Burgo B, García-Grande A, Mañes S, Hahne M, González-Suárez E, Planelles L. APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer. Carcinogenesis 2015; 36:574-84. [DOI: 10.1093/carcin/bgv020] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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37
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Lascano V, Hahne M, Papon L, Cameron K, Röeder C, Schafmayer C, Driessen L, van Eenennaam H, Kalthoff H, Medema JP. Circulating APRIL levels are correlated with advanced disease and prognosis in rectal cancer patients. Oncogenesis 2015; 4:e136. [PMID: 25622308 PMCID: PMC5520648 DOI: 10.1038/oncsis.2014.50] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 11/10/2014] [Accepted: 11/14/2014] [Indexed: 12/22/2022] Open
Abstract
We have previously shown that the tumor necrosis factor family member a proliferation-inducing ligand (APRIL) enhances intestinal tumor growth in various preclinical tumor models. Here, we have investigated whether APRIL serum levels at time of surgery predict survival in a large cohort of colorectal cancer (CRC) patients. We measured circulating APRIL levels in a cohort of CRC patients (n=432) using a novel validated monoclonal APRIL antibody (hAPRIL.133) in an enzyme-linked immunosorbent assay (ELISA) setup. APRIL levels were correlated with clinicopathological features and outcome. Overall survival was examined with Kaplan–Meier survival analysis, and Cox proportional hazards ratios were calculated. We observed that circulating APRIL levels were normally distributed among CRC patients. High APRIL expression correlated significantly with poor outcome measures, such as higher stage at presentation and development of lymphatic and distant metastases. Within the group of rectal cancer patients, higher circulating APRIL levels at time of surgery were correlated with poor survival (log-rank analysis P-value 0.008). Univariate Cox regression analysis for overall survival in rectal cancer patients showed that patients with elevated circulating APRIL levels had an increased risk of poor outcome (hazard ratio (HR) 1.79; 95% confidence interval (CI) 1.16–2.76; P-value 0.009). Multivariate analysis in rectal cancer patients showed that APRIL as a prognostic factor was dependent on stage of disease (HR 1.25; 95% CI 0.79–1.99; P-value 0.340), which was related to the fact that stage IV rectal cancer patients had significantly higher levels of APRIL. Our results revealed that APRIL serum levels at time of surgery were associated with features of advanced disease and prognosis in rectal cancer patients, which strengthens the previously reported preclinical observation of increased APRIL levels correlating with disease progression.
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Affiliation(s)
- V Lascano
- LEXOR (Lab of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - M Hahne
- 1] LEXOR (Lab of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands [2] Institut de Génétique Moléculaire (IGMM), CNRS UMR5535, Montpellier, France [3] Université Montpellier Sud de France, Montpellier, France
| | - L Papon
- 1] Institut de Génétique Moléculaire (IGMM), CNRS UMR5535, Montpellier, France [2] Université Montpellier Sud de France, Montpellier, France
| | - K Cameron
- LEXOR (Lab of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - C Röeder
- Institute for Experimental Cancer Research, University Clinic Schleswig-Holstein (UKSH), Kiel, Germany
| | - C Schafmayer
- Clinic for General Surgery, Visceral-, Thoracic-, Transplantation-, and Pediatric Surgery, UKSH, Kiel, Germany
| | | | | | - H Kalthoff
- Institute for Experimental Cancer Research, University Clinic Schleswig-Holstein (UKSH), Kiel, Germany
| | - J P Medema
- LEXOR (Lab of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
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38
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Hoffmann FS, Kuhn PH, Laurent SA, Hauck SM, Berer K, Wendlinger SA, Krumbholz M, Khademi M, Olsson T, Dreyling M, Pfister HW, Alexander T, Hiepe F, Kümpfel T, Crawford HC, Wekerle H, Hohlfeld R, Lichtenthaler SF, Meinl E. The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity. THE JOURNAL OF IMMUNOLOGY 2014; 194:542-52. [PMID: 25505277 DOI: 10.4049/jimmunol.1402070] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.
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Affiliation(s)
- Franziska S Hoffmann
- Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany
| | - Peer-Hendrik Kuhn
- Neuroproteomics, Technical University Munich and Hospital Rechts der Isar, Munich D-81675, Germany; German Center for Neurodegenerative Diseases, Bonn D-53175, Germany; Institute for Advanced Study, Technical University, Munich D-85748, Germany
| | - Sarah A Laurent
- Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg D-85764, Germany
| | - Kerstin Berer
- Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried D-82152, Germany
| | - Simone A Wendlinger
- Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany
| | - Markus Krumbholz
- Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany
| | - Mohsen Khademi
- Division of Clinical Neuroscience, Karolinska University Hospital, Stockholm 14186, Sweden
| | - Tomas Olsson
- Division of Clinical Neuroscience, Karolinska University Hospital, Stockholm 14186, Sweden
| | - Martin Dreyling
- Department of Medicine III, Ludwig Maximilian University, Munich D-81377, Germany
| | - Hans-Walter Pfister
- Department of Neurology, Ludwig Maximilian University, Munich D-81377, Germany
| | - Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin D-10117, Germany
| | - Falk Hiepe
- Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin D-10117, Germany
| | - Tania Kümpfel
- Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany
| | - Howard C Crawford
- Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL 32224; and
| | - Hartmut Wekerle
- Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried D-82152, Germany
| | - Reinhard Hohlfeld
- Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich D-81377, Germany
| | - Stefan F Lichtenthaler
- Neuroproteomics, Technical University Munich and Hospital Rechts der Isar, Munich D-81675, Germany; German Center for Neurodegenerative Diseases, Bonn D-53175, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich D-81377, Germany
| | - Edgar Meinl
- Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany;
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Liu Y, Liu H, Peng Y, Liu F. New insights into the pathogenesis of IgA nephropathy: do toll like receptor 9-B cell activation factor-IgA class switching recombination signaling axis induce IgA hyper-production? Ren Fail 2014; 36:970-3. [DOI: 10.3109/0886022x.2014.916578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Reduced BAFF-R and increased TACI expression in common variable immunodeficiency. J Clin Immunol 2014; 34:573-83. [PMID: 24809296 DOI: 10.1007/s10875-014-0047-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 04/15/2014] [Indexed: 10/25/2022]
Abstract
PURPOSE B-cell survival and differentiation critically depend on the interaction of BAFF-R and TACI with their ligands, BAFF and APRIL. Mature B-cell defects lead to Common Variable Immunodeficiency (CVID), which is associated with elevated serum levels of BAFF and APRIL. Nevertheless, BAFF-R and TACI expression in CVID and their relationship with ligand availability remain poorly understood. METHODS AND RESULTS We found that BAFF-R expression was dramatically reduced on B cells of CVID patients, relative to controls. BAFF-R levels inversely correlated with serum BAFF concentration both in CVID and healthy subjects. We also found that recombinant BAFF stimulation reduced BAFF-R expression on B cells without decreasing transcript levels. On the other hand, CVID subjects had increased TACI expression on B cells in direct association with serum BAFF but not APRIL levels. Moreover, splenomegaly was associated with higher TACI expression, suggesting that perturbations of TACI function may underlie lymphoproliferation in CVID. CONCLUSIONS Our results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAFF-R expression is controlled by BAFF binding. Identification of the factors governing BAFF-R and TACI is crucial to understanding CVID pathogenesis, and B-cell biology in general, as well as to explore their potential as therapeutic targets.
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Secreto F, Manske M, Price-Troska T, Ziesmer S, Hodge LS, Ansell SM, Cerhan JR, Novak AJ. B-cell activating factor-receptor specific activation of tumor necrosis factor receptor associated factor 6 and the phosphatidyl inositol 3-kinase pathway in lymphoma B cells. Leuk Lymphoma 2014; 55:1884-92. [PMID: 24206092 DOI: 10.3109/10428194.2013.862619] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
B-cell activating factor-receptor (BAFF-R) is the primary BAFF receptor that is responsible for promoting B-cell development and survival. Malignant B-cells exploit the BAFF/BAFF-R system, and high serum BAFF levels or genetic alterations in BAFF receptors have been found in B-cell cancers. BAFF signaling impacts pro-survival pathways. However, other than nuclear factor-κB2 (NF-κB2), little is known about the specific pathways activated by individual BAFF receptors. Using a novel BAFF-R expression model we have demonstrated that activation of BAFF-R, independent of transmembrane activator and cytophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), can induce phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β). Expression of an activated form of BAFF-R also enhanced a pro-survival gene expression pattern, including the novel BAFF-regulated gene Pin1, whose expression was phosphatidyl inositol 3-kinase (PI3K)-dependent. Additionally, we showed that TRAF6 is essential for mediating BAFF-R dependent activation of Akt. Together these data describe a novel role for TRAF6 in BAFF-R-specific activation of the PI3K pathway and provide evidence suggesting a new role for Pin1 in BAFF-R signaling.
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Affiliation(s)
- Frank Secreto
- Division of Hematology, Mayo Clinic , Rochester, MN , USA
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42
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Stohl W. Therapeutic targeting of the BAFF/APRIL axis in systemic lupus erythematosus. Expert Opin Ther Targets 2014; 18:473-89. [DOI: 10.1517/14728222.2014.888415] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Gardam S, Brink R. Non-Canonical NF-κB Signaling Initiated by BAFF Influences B Cell Biology at Multiple Junctures. Front Immunol 2014; 4:509. [PMID: 24432023 PMCID: PMC3880999 DOI: 10.3389/fimmu.2013.00509] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 12/24/2013] [Indexed: 01/13/2023] Open
Abstract
It has been more than a decade since it was recognized that the nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) transcription factor family was activated by two distinct pathways: the canonical pathway involving NF-κB1 and the non-canonical pathway involving NF-κB2. During this time a great deal of evidence has been amassed on the ligands and receptors that activate these pathways, the cytoplasmic adapter molecules involved in transducing the signals from receptors to nucleus, and the resulting physiological outcomes within body tissues. In contrast to NF-κB1 signaling, which can be activated by a wide variety of receptors, the NF-κB2 pathway is typically only activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor (TNF) family. Amongst these is B cell activating factor of the TNF family (BAFF) and its receptor BAFFR. Whilst BAFF is produced by many cell types throughout the body, BAFFR expression appears to be restricted to the hematopoietic lineage and B cells in particular. For this reason, the main physiological outcomes of BAFF mediated NF-κB2 activation are confined to B cells. Indeed BAFF mediated NF-κB2 signaling contributes to peripheral B cell survival and maturation as well as playing a role in antibody responses and long term maintenance plasma cells. Thus the importance BAFF and NF-κB2 permeates the entire B cell lifespan and impacts on this important component of the immune system in a variety of ways.
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Affiliation(s)
- Sandra Gardam
- Immunology Division, Garvan Institute of Medical Research , Darlinghurst, NSW , Australia
| | - Robert Brink
- Immunology Division, Garvan Institute of Medical Research , Darlinghurst, NSW , Australia ; St. Vincent's Clinical School, University of New South Wales , Darlinghurst, NSW , Australia
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44
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Roles for TNF-receptor associated factor 3 (TRAF3) in lymphocyte functions. Cytokine Growth Factor Rev 2013; 25:147-56. [PMID: 24433987 DOI: 10.1016/j.cytogfr.2013.12.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 12/15/2013] [Indexed: 12/27/2022]
Abstract
TRAF3 is an adapter protein that serves and regulates the functions of several types of receptors, located both inside the cell and at the plasma membrane. These include members of the TNF receptor superfamily (TNFR-SF), toll-like receptors (TLR), and cytokine receptors. It has become increasingly evident that the roles and functions of TRAF3 are highly context-dependent. TRAF3 can serve distinct roles for different receptors in the same cell, and also has highly cell-type-dependent functions. This review focuses upon the current state of knowledge regarding how TRAF3 regulates the biology and effector functions of B and T lymphocytes, two major cell types of the adaptive immune response in which TRAF3 has markedly distinct roles.
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Ferrer G, Bosch R, Hodgson K, Tejero R, Roué G, Colomer D, Montserrat E, Moreno C. B cell activation through CD40 and IL4R ligation modulates the response of chronic lymphocytic leukaemia cells to BAFF and APRIL. Br J Haematol 2013; 164:570-8. [PMID: 24245956 DOI: 10.1111/bjh.12645] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Accepted: 10/02/2013] [Indexed: 11/26/2022]
Abstract
The two tumour necrosis factor family proteins BAFF (TNFSF13B) and APRIL (TNFSF13) and their receptors [BAFF-R (TNFRSF13C), TACI (TNFRSF13B), BCMA (TNFRSF17)] play a critical role in the survival of normal B cells. The sensitivity of normal B cells to BAFF and APRIL can be modulated by signals regulated by their receptors. This modulation, however, has not been extensively investigated in chronic lymphocytic leukaemia (CLL) cells. We evaluated the expression, regulation and signalling of BAFF and APRIL receptors in normal and in CLL cells upon stimulation through CD40+IL4R and BCR. We further analysed the prognostic value of BAFF and APRIL receptors expression in patients with CLL. BCMA expression was significantly higher on CLL cells than on normal B cells. BCR and CD40+IL4R stimulation promoted an increase in TACI and BCMA expression, cell viability and activation in normal B cells. A similar effect was observed in CLL cells after CD40+IL4R but not BCR stimulation. BCMA expression correlated with unmutated IGHV genes, poor-risk cytogenetics, and short progression-free survival. These findings further characterize the link between CD40+IL4R regulatory signals, BAFF, APRIL and their receptors and the survival of leukaemic cells and clinical features of CLL.
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Affiliation(s)
- Gerardo Ferrer
- Department of Haematology, Institute of Haematology and Oncology, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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B cell activating factor inhibition impairs bacterial immunity by reducing T cell-independent IgM secretion. Infect Immun 2013; 81:4490-7. [PMID: 24082070 DOI: 10.1128/iai.00998-13] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
B cell activating factor of the tumor necrosis factor family (BAFF) is an essential survival factor for B cells and has been shown to regulate T cell-independent (TI) IgM production. During Ehrlichia muris infection, TI IgM secretion in the spleen was BAFF dependent, and antibody-mediated BAFF neutralization led to an impairment of IgM-mediated host defense. The failure of TI plasmablasts to secrete IgM was not a consequence of alterations in their generation, survival, or early differentiation, since all occurred normally in infected mice following BAFF neutralization. Gene expression characteristic of plasma cell differentiation was also unaffected by BAFF neutralization in vivo, and except for CD138, plasmablast cell surface marker expression was unaffected. IgM was produced, since it was detected intracellularly, and impaired secretion was not due to a failure to express the IgM secretory exon. Addition of BAFF to plasmablasts in vitro rescued IgM secretion, suggesting that BAFF signaling can directly regulate secretory processes. Our findings indicate that BAFF signaling can modulate TI host defense by acting at a late stage in B cell differentiation, via its regulation of terminal plasmablast differentiation and/or IgM secretion.
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47
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So T, Croft M. Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family Molecules. Front Immunol 2013; 4:139. [PMID: 23760533 PMCID: PMC3675380 DOI: 10.3389/fimmu.2013.00139] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 05/25/2013] [Indexed: 12/22/2022] Open
Abstract
Activation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B) is a common response triggered by a range of membrane-bound receptors on many cell types. In T lymphocytes, the PI3K-Akt pathway promotes clonal expansion, differentiation, and survival of effector cells and suppresses the generation of regulatory T cells. PI3K activation is tightly controlled by signals through the T cell receptor (TCR) and the co-stimulatory receptor CD28, however sustained and periodic signals from additional co-receptors are now being recognized as critical contributors to the activation of this pathway. Accumulating evidence suggests that many members of the Tumor Necrosis Factor receptor (TNFR) superfamily, TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), that are constitutive or inducible on T cells, can directly or indirectly promote activity in the PI3K-Akt pathway. We discuss recent data which suggests that ligation of one TNFR family molecule organizes a signalosome, via TNFR-associated factor (TRAF) adapter proteins in T cell membrane lipid microdomains, that results in the subsequent accumulation of highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units. We propose this may be a generalizable mechanism applicable to other TNFR family molecules that will result in a quantitative contribution of these signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR. We also review data that other TNFR molecules, such as CD40 (TNFRSF5), RANK (TNFRSF11A), FN14 (TNFRSF12A), TACI (TNFRSF13B), BAFFR (TNFRSF13C), and NGFR (TNFRSF16), contribute to the activation of this pathway in diverse cell types through a similar ability to recruit PI3K or Akt into their signaling complexes.
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Affiliation(s)
- Takanori So
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine , Sendai , Japan
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Almejun MB, Cols M, Zelazko M, Oleastro M, Cerutti A, Oppezzo P, Cunningham-Rundles C, Danielian S. Naturally occurring mutation affecting the MyD88-binding site of TNFRSF13B impairs triggering of class switch recombination. Eur J Immunol 2013; 43:805-14. [PMID: 23225259 DOI: 10.1002/eji.201242945] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Revised: 10/22/2012] [Accepted: 12/04/2012] [Indexed: 11/06/2022]
Abstract
Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) were previously found to be associated with hypogammaglobulinemia in humans. It has been shown that proliferation inducing ligand (APRIL) elicits class switch recombination (CSR) by inducing recruitment of MyD88 to a TACI highly conserved cytoplasmic domain (THC). We have identified a patient with hypogammaglobulinemia carrying a missense mutation (S231R) predicted to affect the THC. Aiming to evaluate the relevance of this novel mutation of TACI in CSR induction, we tested the ability of TACI, TLR9, or/and CD40 ligands to trigger CSR in naive B cells and B-cell lines carrying S231R. IgG secretion was impaired when triggered by TACI or/and TLR9 ligands on S231R-naive B cells. Likewise, these stimuli induced less expression of activation-induced cytidine deaminase, I(γ)1-C(μ), and I(γ)1-C(μ), while induction by optimal CD40 stimulation was indistinguishable from controls. These cells also showed an impaired cooperation between TACI and TLR9 pathways, as well as a lack of APRIL-mediated enhancement of CD40 activation in suboptimal conditions. Finally, after APRIL ligation, S231R-mutated TACI failed to colocalize with MyD88. Collectively, these results highlight the requirement of an intact MyD88-binding site in TACI to trigger CSR.
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Affiliation(s)
- Maria B Almejun
- Servicio de Inmunología y Reumatología, Hospital Nacional de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
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Yang M, Wu Y, Lu Y, Liu C, Sun J, Liao M, Qin M, Mo L, Gao Y, Lu Z, Wu C, Zhang Y, Zhang H, Qin X, Hu Y, Zhang S, Li J, Dong M, Zheng SL, Xu J, Yang X, Tan A, Mo Z. Genome-wide scan identifies variant in TNFSF13 associated with serum IgM in a healthy Chinese male population. PLoS One 2012; 7:e47990. [PMID: 23118916 PMCID: PMC3485370 DOI: 10.1371/journal.pone.0047990] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2012] [Accepted: 09/19/2012] [Indexed: 01/09/2023] Open
Abstract
IgM provides a first line of defense during microbial infections. Serum IgM levels are detected routinely in clinical practice. And IgM is a genetically complex trait. We conducted a two-stage genome-wide association study (GWAS) to identify genetic variants affecting serum IgM levels in a Chinese population of 3495, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Our data show that a common single nucleotide polymorphism (SNP), rs11552708 located in the TNFSF13 gene was significantly associated with IgM levels (p = 5.00×10−7 in first stage, p = 1.34×10−3 in second stage, and p = 4.22×10−9 when combined). Besides, smoking was identified to be associated with IgM levels in both stages (P<0.05), but there was no significant interaction between smoking and the identified SNP (P>0.05). It is suggested that TNFSF13 may be a susceptibility gene affecting serum IgM levels in Chinese male population.
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Affiliation(s)
- Ming Yang
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Yongming Wu
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Yanmei Lu
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Changyuan Liu
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jielin Sun
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Ming Liao
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Min Qin
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Linjian Mo
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Yong Gao
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Zheng Lu
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Chunlei Wu
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Youjie Zhang
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Haiying Zhang
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Department of Occupational Health and Environmental Health, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Xue Qin
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Yanling Hu
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Medical Scientific Research Center, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Shijun Zhang
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Department of Pharmacology, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jianling Li
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Cardiovascular Disease, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Min Dong
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - S. Lilly Zheng
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Jianfeng Xu
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- Center for Genetic Epidemiology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America
- Fudan-VARI Center for Genetic Epidemiology, Fudan University, Shanghai, People's Republic of China
- Fudan University Institute of Urology, Huashan Hospital, Shanghai, People's Republic of China
| | - Xiaobo Yang
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Department of Occupational Health and Environmental Health, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- * E-mail: (ZM); (AT); (XY)
| | - Aihua Tan
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Department of Chemotherapy, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- * E-mail: (ZM); (AT); (XY)
| | - Zengnan Mo
- Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
- * E-mail: (ZM); (AT); (XY)
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Kimberley FC, van der Sloot AM, Guadagnoli M, Cameron K, Schneider P, Marquart JA, Versloot M, Serrano L, Medema JP. The design and characterization of receptor-selective APRIL variants. J Biol Chem 2012; 287:37434-46. [PMID: 22961987 DOI: 10.1074/jbc.m112.406090] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily with an important role in humoral immunity, is also implicated in several cancers as a prosurvival factor. APRIL binds two different TNF receptors, B cell maturation antigen (BCMA) and transmembrane activator and cylclophilin ligand interactor (TACI), and also interacts independently with heparan sulfate proteoglycans. Because APRIL shares binding of the TNF receptors with B cell activation factor, separating the precise signaling pathways activated by either ligand in a given context has proven quite difficult. In this study, we have used the protein design algorithm FoldX to successfully generate a BCMA-specific variant of APRIL, APRIL-R206E, and two TACI-selective variants, D132F and D132Y. These APRIL variants show selective activity toward their receptors in several in vitro assays. Moreover, we have used these ligands to show that BCMA and TACI have a distinct role in APRIL-induced B cell stimulation. We conclude that these ligands are useful tools for studying APRIL biology in the context of individual receptor activation.
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Affiliation(s)
- Fiona C Kimberley
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, University of Amsterdam, Amsterdam 1105 A2, The Netherlands
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