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Kögl T, Chang HF, Staniek J, Chiang SC, Thoulass G, Lao J, Weißert K, Dettmer-Monaco V, Geiger K, Manna PT, Beziat V, Momenilandi M, Tu SM, Keppler SJ, Pattu V, Wolf P, Kupferschmid L, Tholen S, Covill LE, Ebert K, Straub T, Groß M, Gather R, Engel H, Salzer U, Schell C, Maier S, Lehmberg K, Cornu TI, Pircher H, Shahrooei M, Parvaneh N, Elling R, Rizzi M, Bryceson YT, Ehl S, Aichele P, Ammann S. Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect. J Exp Med 2024; 221:e20221122. [PMID: 38722309 PMCID: PMC11082451 DOI: 10.1084/jem.20221122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 03/08/2024] [Accepted: 04/17/2024] [Indexed: 05/12/2024] Open
Abstract
SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.
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Affiliation(s)
- Tamara Kögl
- Institute for Immunology, Center for Microbiology and Hygiene, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
| | - Hsin-Fang Chang
- Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany
| | - Julian Staniek
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center— University of Freiburg, Freiburg, Germany
| | - Samuel C.C. Chiang
- Division of Bone Marrow Transplantation and Immune Deficiency, and Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
- Department of Medicine, Center for Hematology and Regenerative Medicine Huddinge, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Gudrun Thoulass
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Jessica Lao
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Kristoffer Weißert
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
| | - Viviane Dettmer-Monaco
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Institute for Transfusion Medicine and Gene Therapy—University of Freiburg, Freiburg, Germany
| | - Kerstin Geiger
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Institute for Transfusion Medicine and Gene Therapy—University of Freiburg, Freiburg, Germany
| | - Paul T. Manna
- Department of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Vivien Beziat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, University of Paris-Cité, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Mana Momenilandi
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, University of Paris-Cité, Paris, France
| | - Szu-Min Tu
- Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany
| | - Selina J. Keppler
- Division of Rheumatology and Immunology, Medical University of Graz, Graz, Austria
| | - Varsha Pattu
- Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany
| | - Philipp Wolf
- Department of Urology, Faculty of Medicine, Medical Center—University of Freiburg, Freiburg, Germany
| | - Laurence Kupferschmid
- Institute of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany
| | - Stefan Tholen
- Department of Pathology, Institute of Surgical Pathology, University Medical Center, University of Freiburg, Freiburg, Germany
| | - Laura E. Covill
- Department of Medicine, Center for Hematology and Regenerative Medicine Huddinge, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Karolina Ebert
- Institute for Immunology, Center for Microbiology and Hygiene, Medical Center—University of Freiburg, Freiburg, Germany
| | - Tobias Straub
- Institute for Immunology, Center for Microbiology and Hygiene, Medical Center—University of Freiburg, Freiburg, Germany
| | - Miriam Groß
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
| | - Ruth Gather
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
| | - Helena Engel
- Institute for Immunology, Center for Microbiology and Hygiene, Medical Center—University of Freiburg, Freiburg, Germany
| | - Ulrich Salzer
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center— University of Freiburg, Freiburg, Germany
| | - Christoph Schell
- Department of Pathology, Institute of Surgical Pathology, University Medical Center, University of Freiburg, Freiburg, Germany
| | - Sarah Maier
- Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kai Lehmberg
- Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tatjana I. Cornu
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Institute for Transfusion Medicine and Gene Therapy—University of Freiburg, Freiburg, Germany
| | - Hanspeter Pircher
- Institute for Immunology, Center for Microbiology and Hygiene, Medical Center—University of Freiburg, Freiburg, Germany
| | - Mohammad Shahrooei
- Department of Microbiology, Immunology, and Transplantation, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium
- Dr. Shahrooei Laboratory, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Parvaneh
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran
| | - Roland Elling
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty for Medicine, Center for Pediatrics and Adolescent Medicine, Medical Center—University of Freiburg, Freiburg, Germany
| | - Marta Rizzi
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center— University of Freiburg, Freiburg, Germany
- Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Clinical Immunology, Medical Center—University of Freiburg, Freiburg, Germany
| | - Yenan T. Bryceson
- Department of Medicine, Center for Hematology and Regenerative Medicine Huddinge, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Division of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Broegelmann Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway
| | - Stephan Ehl
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
| | - Peter Aichele
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
| | - Sandra Ammann
- Faculty of Medicine, Institute for Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Freiburg, Germany
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Silva FS, Barros-Lima A, Souza-Barros M, Crespo-Neto JA, Santos VGR, Pereira DS, Alves-Hanna FS, Magalhães-Gama F, Faria JAQA, Costa AG. A dual-role for IL-10: From leukemogenesis to the tumor progression in acute lymphoblastic leukemia. Cytokine 2023; 171:156371. [PMID: 37725872 DOI: 10.1016/j.cyto.2023.156371] [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: 06/28/2023] [Revised: 09/10/2023] [Accepted: 09/12/2023] [Indexed: 09/21/2023]
Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in the world, and accounts for 25% of all childhood cancers among children under 15 years of age. Longitudinal studies have shown that children with ALL are born with a deregulated immune response that, together with postnatal environmental exposures, favor the onset of the disease. In this context, IL-10, a key cytokine in the regulation of the immune response, presents itself as a paradoxical mediator, initially influencing the development of ALL through the regulation of inflammatory processes and later on the progression of malignancy, with the increase of this molecule in the leukemia microenvironment. According to the literature, this cytokine plays a critical role in the natural history of the disease and plays an important role in two different though complex scenarios. Thus, in this review, we explore the dual role of IL-10 in ALL, and describe its biological characteristics, immunological mechanisms and genetics, as well as its impact on the leukemia microenvironment and its clinical implications.
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Affiliation(s)
- Flavio Souza Silva
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
| | - Amanda Barros-Lima
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
| | - Mateus Souza-Barros
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
| | - Juniel Assis Crespo-Neto
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
| | | | - Daniele Sá Pereira
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Brazil
| | - Fabíola Silva Alves-Hanna
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
| | - Fábio Magalhães-Gama
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil; Programa de Pós-Graduação em Ciências da Saúde, Instituto René Rachou - Fundação Oswaldo Cruz (FIOCRUZ) Minas, Belo Horizonte, Brazil
| | - Jerusa Araújo Quintão Arantes Faria
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
| | - Allyson Guimarães Costa
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil; Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Escola de Enfermagem de Manaus, UFAM, Manaus, Brazil.
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Glass MC, Glass DR, Oliveria JP, Mbiribindi B, Esquivel CO, Krams SM, Bendall SC, Martinez OM. Human IL-10-producing B cells have diverse states that are induced from multiple B cell subsets. Cell Rep 2022; 39:110728. [PMID: 35443184 PMCID: PMC9107325 DOI: 10.1016/j.celrep.2022.110728] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 02/13/2022] [Accepted: 03/31/2022] [Indexed: 02/04/2023] Open
Abstract
Regulatory B cells (Bregs) suppress immune responses through the secretion of interleukin-10 (IL-10). This immunomodulatory capacity holds therapeutic potential, yet a definitional immunophenotype for enumeration and prospective isolation of B cells capable of IL-10 production remains elusive. Here, we simultaneously quantify cytokine production and immunophenotype in human peripheral B cells across a range of stimulatory conditions and time points using mass cytometry. Our analysis shows that multiple functional B cell subsets produce IL-10 and that no phenotype uniquely identifies IL-10+ B cells. Further, a significant portion of IL-10+ B cells co-express the pro-inflammatory cytokines IL-6 and tumor necrosis factor alpha (TNFα). Despite this heterogeneity, operationally tolerant liver transplant recipients have a unique enrichment of IL-10+, but not TNFα+ or IL-6+, B cells compared with transplant recipients receiving immunosuppression. Thus, human IL-10-producing B cells constitute an induced, transient state arising from a diversity of B cell subsets that may contribute to maintenance of immune homeostasis.
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Affiliation(s)
- Marla C Glass
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA; Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - David R Glass
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Immunology Graduate Program, Stanford University, Stanford, CA, USA
| | - John-Paul Oliveria
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Respirology, McMaster University, Hamilton, ON, Canada
| | - Berenice Mbiribindi
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA; Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Carlos O Esquivel
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Sheri M Krams
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA; Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Sean C Bendall
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Olivia M Martinez
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA; Immunology, Stanford University School of Medicine, Stanford, CA, USA.
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Isolation of primary human B lymphocytes from tonsils compared to blood as alternative source for ex vivo application. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1179:122853. [PMID: 34325309 DOI: 10.1016/j.jchromb.2021.122853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 06/28/2021] [Accepted: 06/30/2021] [Indexed: 01/18/2023]
Abstract
B lymphocytes ('B cells') are components of the human immune system with obvious potential for medical and biotechnological applications. Here, we discuss the isolation of primary human B cells from both juvenile and adult tonsillar material using a two-step procedure based on gradient centrifugation followed by separation on a nylon wool column as alternative to the current gold standard, i.e., negative immunosorting from buffy coats by antibody-coated magnetic beads. We show that the nylon wool separation is a low-cost method well suited to the isolation of large amounts of primary B cells reaching purities ≥ 80%. More importantly, this method allows the preservation of all B cell subsets, while MACS sorting seems to be biased against a certain B cell subtype, namely the CD27+ B cells. Importantly, compared to blood, the excellent recovery yield during purification of tonsillar B cells provides high number of cells, hence increases the number of subsequent experiments feasible with identical cell material, consequently improving comparability of results. The cultivability of the isolated B cells was demonstrated using pokeweed mitogen (PWM) as a stimulatory substance. Our results showed for the first time that the proliferative response of tonsillar B cells to mitogens declines with the age of the donor. Furthermore, we observed that PWM treatment stimulates the proliferation of a dedicated subpopulation and induces some terminal differentiation with ASCs signatures. Taken together this indicates that the proposed isolation procedure preserves the proliferative capability as well as the differentiation capacity of the B cells.
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Abos B, Wang T, Secombes CJ, Tafalla C. Distinct modes of action of CD40L and adaptive cytokines IL-2, IL-4/13, IL-10 and IL-21 on rainbow trout IgM + B cells. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 111:103752. [PMID: 32447012 PMCID: PMC7397517 DOI: 10.1016/j.dci.2020.103752] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 05/04/2023]
Abstract
In mammals, conventional B (B2) cells are activated within lymphoid follicles through a close relationship with T follicular helper (Tfh) cells. The interaction between CD40 expressed on B cells and its ligand (CD40L) expressed on Tfh cells is a key signal that regulates the formation of germinal centers (GCs), B cell survival, proliferation and differentiation to plasma cells (PCs) or memory cells. Additionally, certain soluble cytokines produced by T cells also strongly condition the outcome of this interaction. Despite the many differences found between fish B cells and mammalian B2 cells, and the lack of conventional GCs, rainbow trout IgM+ B cells have been shown to be stimulated by CD40L, however, whether cytokines commonly produced by T cells can further modulate this response has never been addressed to date. Thus, in this study, we determined the effects of recombinant rainbow trout adaptive cytokines interleukin 2B (IL-2B), IL-4/13A, IL-4/13B, IL-10 and IL-21 (cytokines known to activate B cells in mammals) on splenic IgM+ B cells alone or in combination with CD40L. We studied how these cytokines and CD40L cooperated to promote IgM+ B cell survival, proliferation and IgM secretion. The results obtained provide valuable information for the first time in teleost fish on how different T cell signals cooperate to activate B cells in the absence of GCs.
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Affiliation(s)
- Beatriz Abos
- Animal Health Research Center (CISA-INIA), Valdeolmos, 28130, Madrid, Spain
| | - Tiehui Wang
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB24 2TZ, United Kingdom
| | - Christopher J Secombes
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB24 2TZ, United Kingdom
| | - Carolina Tafalla
- Animal Health Research Center (CISA-INIA), Valdeolmos, 28130, Madrid, Spain.
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Geng Y, Shen F, Wu W, Zhang L, Luo L, Fan Z, Hou R, Yue B, Zhang X. First demonstration of giant panda's immune response to canine distemper vaccine. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 102:103489. [PMID: 31473266 DOI: 10.1016/j.dci.2019.103489] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 08/28/2019] [Accepted: 08/28/2019] [Indexed: 06/10/2023]
Abstract
The Canine Distemper Virus (CDV) is a high fatal virus to the giant panda (Ailuropoda melanoleuca), where CDV vaccination is a key preventative measure in captive giant pandas. However, the immune response of giant pandas to CDV vaccination has been little studied. In this study, we investigated the blood transcriptome expression profiles of five giant panda cubs after three inoculations, 21 days apart. Blood samples were collected before vaccination (0 Day), and 24 h after each of the three inoculations; defined here as 1 Day, 21 Day, and 42 Day. Compared to 0 Day, we obtained 1262 differentially expressed genes (DEGs) during inoculations. GO and KEGG pathways enrichment analysis of these DEGs found 222 GO terms and 40 pathways. The maximum immune-related terms were enriched by DEGs from comparisons of 21 Day and 0 Day. In the PPI analysis, we identified RSAD2, IL18, ISG15 immune-related hub genes from 1 Day and 21 Day comparison. Compared to 0 Day, innate immune-related genes, TLR4 and TLR8, were up-regulated at 1 Day, and the expressions of IRF1, RSAD2, MX1, and OAS2 were highest at 21 Day. Of the adaptive immune-related genes, IL15, promoting T cell differentiation into CD8+T cells, was up-regulated after the first two inoculations, IL12β, promoting T cell differentiation into memory cells, and IL10, promoting B cell proliferation and differentiation, were down-regulated during three inoculations. Our results indicated that the immune response of five giant panda cubs was strongest after the second inoculation, most likely protected against CDV infection through innate immunity and T cells, but did not produce enough memory cells to maintain long-term immunity after CDV vaccination.
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Affiliation(s)
- Yang Geng
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, 610064, China.
| | - Fujun Shen
- The Sichuan Key Laboratory for Conservation Biology of Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, 610081, China.
| | - Wei Wu
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, 610064, China.
| | - Liang Zhang
- The Sichuan Key Laboratory for Conservation Biology of Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, 610081, China.
| | - Li Luo
- The Sichuan Key Laboratory for Conservation Biology of Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, 610081, China.
| | - Zhenxin Fan
- Sichuan Key Laboratory of Conservation Biology on Endangered Wildlife, College of Life Sciences, Sichuan University, Chengdu, 610064, PR China.
| | - Rong Hou
- The Sichuan Key Laboratory for Conservation Biology of Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, 610081, China.
| | - Bisong Yue
- Sichuan Key Laboratory of Conservation Biology on Endangered Wildlife, College of Life Sciences, Sichuan University, Chengdu, 610064, PR China.
| | - Xiuyue Zhang
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, 610064, China.
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Nolan LS, Parks OB, Good M. A Review of the Immunomodulating Components of Maternal Breast Milk and Protection Against Necrotizing Enterocolitis. Nutrients 2019; 12:E14. [PMID: 31861718 PMCID: PMC7019368 DOI: 10.3390/nu12010014] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/05/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023] Open
Abstract
Breast milk contains immunomodulating components that are beneficial to newborns during maturation of their immune system. Human breast milk composition is influenced by an infant's gestational and chronological age, lactation stage, and the mother and infant's health status. Major immunologic components in human milk, such as secretory immunoglobulin A (IgA) and growth factors, have a known role in regulating gut barrier integrity and microbial colonization, which therefore protect against the development of a life-threatening gastrointestinal illness affecting newborn infants called necrotizing enterocolitis (NEC). Breast milk is a known protective factor in the prevention of NEC when compared with feeding with commercial formula. Breast milk supplements infants with human milk oligosaccharides, leukocytes, cytokines, nitric oxide, and growth factors that attenuate inflammatory responses and provide immunological defenses to reduce the incidence of NEC. This article aims to review the variety of immunomodulating components in breast milk that protect the infant from the development of NEC.
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Affiliation(s)
- Lila S. Nolan
- Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Olivia B. Parks
- University of Pittsburgh School of Medicine, Medical Scientist Training Program, Pittsburgh, PA 15213, USA;
| | - Misty Good
- Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;
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Heterogeneity and coexistence of oncogenic mechanisms involved in HCV-associated B-cell lymphomas. Crit Rev Oncol Hematol 2019; 138:156-171. [PMID: 31092372 DOI: 10.1016/j.critrevonc.2019.04.005] [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: 11/08/2018] [Revised: 04/02/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022] Open
Abstract
The association of HCV-infection with B-lymphomas is supported by the regression of most indolent/low-grade lymphomas following anti-viral therapy. Studies on direct and indirect oncogenic mechanisms have elucidated the pathogenesis of HCV-associated B-lymphoma subtypes. These include B-lymphocyte proliferation and sustained clonal expansion by HCV-envelope protein stimulation of B-cell receptors, and prolonged HCV-infected B-cell growth by overexpression of an anti-apoptotic BCL-2 oncogene caused by the increased frequency of t(14;18) chromosomal translocations in follicular lymphomas. HCV has been implicated in lymphomagenesis by a "hit-and-run" mechanism, inducing enhanced mutation rate in immunoglobulins and anti-oncogenes favoring immune escape, due to permanent genetic damage by double-strand DNA-breaks. More direct oncogenic mechanisms have been identified in cytokines and chemokines in relation to NS3 and Core expression, particularly in diffuse large B-cell lymphoma. By reviewing genetic alterations and disrupted signaling pathways, we intend to highlight how mutually non-contrasting mechanisms cooperate with environmental factors toward progression of HCV-lymphoma.
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9
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Wang X, Hao GL, Wang BY, Gao CC, Wang YX, Li LS, Xu JD. Function and dysfunction of plasma cells in intestine. Cell Biosci 2019; 9:26. [PMID: 30911371 PMCID: PMC6417281 DOI: 10.1186/s13578-019-0288-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/01/2019] [Indexed: 12/23/2022] Open
Abstract
As the main player in humoral immunity, antibodies play indispensable roles in the body's immune system. Plasma cells (PCs), as antibody factories, are important contributors to humoral immunity. PCs, recognized by their unique marker CD138, are always discovered in the medullary cords of spleen and lymph nodes and in bone marrow and mucosal lymphoid tissue. This article will review the origin and differentiation of PCs, characteristics of short- and long-lived PCs, and the secretion of antibodies, such as IgA, IgM, and IgG. PCs play a crucial role in the maintenance of intestinal homeostasis using immunomodulation though complex mechanisms. Clearly, PCs play functional roles in maintaining intestinal health, but more details are needed to fully understand all the other effects of intestinal PCs.
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Affiliation(s)
- Xue Wang
- School of Basic Medical Sciences, Xuanwu Hospital, Beijing Capital Medical University, Beijing, 100069 China
| | - Gui-liang Hao
- School of Basic Medical Sciences, Xuanwu Hospital, Beijing Capital Medical University, Beijing, 100069 China
| | - Bo-ya Wang
- Peking University Health Science Center, Beijing, 100081 China
| | - Chen-chen Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, No. 10, Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Yue-xiu Wang
- Department of Teaching Office, International School, Capital Medical University, Beijing, 100069 China
| | - Li-sheng Li
- Function Platform Center, School of Basic Medical Science, Capital Medical University, Beijing, 100069 China
| | - Jing-dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, No. 10, Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
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10
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Darwiche W, Gubler B, Marolleau JP, Ghamlouch H. Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective. Front Immunol 2018; 9:683. [PMID: 29670635 PMCID: PMC5893869 DOI: 10.3389/fimmu.2018.00683] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/20/2018] [Indexed: 12/20/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells.
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Affiliation(s)
- Walaa Darwiche
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Laboratoire d'Hématologie, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Brigitte Gubler
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Laboratoire d'Oncobiologie Moléculaire, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Jean-Pierre Marolleau
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Service d'Hématologie Clinique et Thérapie cellulaire, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Hussein Ghamlouch
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1170, Gustave Roussy, Villejuif, France.,Institut Gustave Roussy, Villejuif, France.,Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France
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11
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Dietrich S, Oleś M, Lu J, Sellner L, Anders S, Velten B, Wu B, Hüllein J, da Silva Liberio M, Walther T, Wagner L, Rabe S, Ghidelli-Disse S, Bantscheff M, Oleś AK, Słabicki M, Mock A, Oakes CC, Wang S, Oppermann S, Lukas M, Kim V, Sill M, Benner A, Jauch A, Sutton LA, Young E, Rosenquist R, Liu X, Jethwa A, Lee KS, Lewis J, Putzker K, Lutz C, Rossi D, Mokhir A, Oellerich T, Zirlik K, Herling M, Nguyen-Khac F, Plass C, Andersson E, Mustjoki S, von Kalle C, Ho AD, Hensel M, Dürig J, Ringshausen I, Zapatka M, Huber W, Zenz T. Drug-perturbation-based stratification of blood cancer. J Clin Invest 2018; 128:427-445. [PMID: 29227286 PMCID: PMC5749541 DOI: 10.1172/jci93801] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 10/31/2017] [Indexed: 12/11/2022] Open
Abstract
As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
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MESH Headings
- Antineoplastic Agents/therapeutic use
- Chromosomes, Human, Pair 12/genetics
- Chromosomes, Human, Pair 12/metabolism
- Databases, Factual
- Female
- Hematologic Neoplasms/classification
- Hematologic Neoplasms/drug therapy
- Hematologic Neoplasms/genetics
- Hematologic Neoplasms/pathology
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/classification
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Male
- Models, Biological
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Signal Transduction
- Trisomy/genetics
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Affiliation(s)
- Sascha Dietrich
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
- Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Małgorzata Oleś
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Junyan Lu
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Leopold Sellner
- Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Simon Anders
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Britta Velten
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Bian Wu
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Jennifer Hüllein
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Michelle da Silva Liberio
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Tatjana Walther
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Lena Wagner
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Sophie Rabe
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
- Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | | | | | - Andrzej K. Oleś
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Mikołaj Słabicki
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Andreas Mock
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Christopher C. Oakes
- Division of Hematology, Departments of Internal Medicine and Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Centre, Heidelberg, Germany
| | - Shihui Wang
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Sina Oppermann
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Marina Lukas
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Vladislav Kim
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Martin Sill
- Division of Biostatistics, German Cancer Research Centre, Heidelberg, Germany
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Centre, Heidelberg, Germany
| | - Anna Jauch
- Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
| | - Lesley Ann Sutton
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Emma Young
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Richard Rosenquist
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Xiyang Liu
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Alexander Jethwa
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Kwang Seok Lee
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
| | - Joe Lewis
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, Heidelberg, Germany
| | - Kerstin Putzker
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, Heidelberg, Germany
| | - Christoph Lutz
- Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
| | - Davide Rossi
- Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Andriy Mokhir
- Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry II, Erlangen, Germany
| | - Thomas Oellerich
- Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, Frankfurt, Germany; Department of Haematology, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Katja Zirlik
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Hematology/Oncology, University Hospital Freiburg, Freiburg, Germany and Tumorzentrum ZeTuP Chur, Chur, Schweiz
| | - Marco Herling
- Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany
| | - Florence Nguyen-Khac
- INSERM U1138, Université Pierre et Marie Curie-Paris and Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, Paris, France
| | - Christoph Plass
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Centre, Heidelberg, Germany
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Emma Andersson
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland and Department of Hematology, Comprehensive Cancer Centre, Helsinki University Hospital, Helsinki, Finland
| | - Satu Mustjoki
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland and Department of Hematology, Comprehensive Cancer Centre, Helsinki University Hospital, Helsinki, Finland
| | - Christof von Kalle
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Heidelberg Centre for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany
| | - Anthony D. Ho
- Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Jan Dürig
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Hematology, University Hospital Essen, Essen, Germany
| | - Ingo Ringshausen
- Department of Hematology, University of Cambridge, Cambridge, United Kingdom
| | - Marc Zapatka
- Division of Molecular Genetics, German Cancer Research Centre, Heidelberg, Germany
| | - Wolfgang Huber
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Thorsten Zenz
- Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
- Molecular Therapy in Hematology and Oncology, and Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Hematology, University of Zürich, Zürich, Switzerland
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12
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CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation? Cell Immunol 2017; 321:8-17. [PMID: 28838763 DOI: 10.1016/j.cellimm.2017.07.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 07/18/2017] [Indexed: 01/30/2023]
Abstract
CD11c+ T-bet+ B cells have now been detected and characterized in different experimental and clinical settings, in both mice and humans. Whether such cells are monolithic, or define subsets of B cells with different functions is not yet known. Our studies have identified CD11c+ IgM+ CD19hi splenic IgM memory B cells that appear at approximately three weeks post-ehrlichial infection, and persist indefinitely, during low-level chronic infection. Although the CD11c+ T-bet+ B cells we have described are distinct, they appear to share many features with similar cells detected under diverse conditions, including viral infections, aging, and autoimmunity. We propose that CD11c+ T-bet+ B cells as a group share characteristics of memory B cells that are maintained under conditions of inflammation and/or low-level chronic antigen stimulation. In some cases, these cells may be advantageous, by providing immunity to re-infection, but in others may be deleterious, by contributing to aged-associated autoimmune responses.
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13
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Herek TA, Cutucache CE. Using Murine Models to Investigate Tumor-Lymphoid Interactions: Spotlight on Chronic Lymphocytic Leukemia and Angioimmunoblastic T-Cell Lymphoma. Front Oncol 2017; 7:86. [PMID: 28512625 PMCID: PMC5411430 DOI: 10.3389/fonc.2017.00086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 04/18/2017] [Indexed: 12/15/2022] Open
Abstract
The role of the tumor microenvironment in leukemias and lymphomas is well established, yet the intricacies of how the malignant cells regulate and influence their non-malignant counterparts remain elusive. For example, chronic lymphocytic leukemia (CLL) is an expansion of malignant CD5+CD19+ B cells, yet the non-malignant T cells play just as large of a role in disease presentation and etiology. Herein, we review the dynamic tumor cell to lymphoid repertoire interactions found in two non-Hodgkin's lymphoma subtypes: CLL and angioimmunoblastic T-cell lymphoma. We aim to highlight the pivot work done in the murine models which recapitulate these diseases and explore the insights that can be gained from studying the immuno-oncological regulation of non-malignant lymphoid counterparts.
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Affiliation(s)
- Tyler A Herek
- Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA
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14
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Crassini K, Shen Y, Mulligan S, Giles Best O. Modeling the chronic lymphocytic leukemia microenvironment in vitro. Leuk Lymphoma 2016; 58:266-279. [PMID: 27756161 DOI: 10.1080/10428194.2016.1204654] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Microenvironments within the lymph node and bone marrow promote proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Successful treatment of CLL must therefore target the leukemic cells within these compartments. A better understanding of the interaction between CLL cells and the tumor microenvironment has led to the development of in vitro models that mimic the mechanisms that support leukemic cell survival and proliferation in vivo. Employing these models as part of the pre-clinical evaluation of novel therapeutic agents enables a better approximation of their potential clinical efficacy. In this review we summarize the current literature describing how different aspects of the tumor microenvironment have been modeled in vitro and detail how these models have been employed to study the biology of the disease and potential efficacy of novel therapeutic agents.
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Affiliation(s)
- Kyle Crassini
- a Northern Blood Research Centre , Kolling Institute of Medical Research, Royal North Shore Hospital , Sydney , Australia
| | - Yandong Shen
- a Northern Blood Research Centre , Kolling Institute of Medical Research, Royal North Shore Hospital , Sydney , Australia
| | - Stephen Mulligan
- a Northern Blood Research Centre , Kolling Institute of Medical Research, Royal North Shore Hospital , Sydney , Australia.,b Chronic Lymphocytic Leukemia Research Consortium (CLLARC) , Australia
| | - O Giles Best
- a Northern Blood Research Centre , Kolling Institute of Medical Research, Royal North Shore Hospital , Sydney , Australia.,b Chronic Lymphocytic Leukemia Research Consortium (CLLARC) , Australia
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15
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Khoury T, Chen S, Adar T, Jacob EO, Mizrahi M. Hepatitis C infection and lymphoproliferative disease: accidental comorbidities? World J Gastroenterol 2014; 20:16197-16202. [PMID: 25473174 PMCID: PMC4239508 DOI: 10.3748/wjg.v20.i43.16197] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 06/04/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection has been associated with liver cancer and cirrhosis, autoimmune disorders such as thyroiditis and mixed cryoglobulinema, and alterations in immune function and chronic inflammation, both implicated in B cell lymphoproliferative diseases that may progress to non-Hodgkin lymphoma (NHL). HCV bound to B cell surface receptors can induce lymphoproliferation, leading to DNA mutations and/or lower antigen response thresholds. These findings and epidemiological reports suggest an association between HCV infection and NHL. We performed a systematic review of the literature to clarify this potential relationship. We searched the English-language literature utilizing Medline, Embase, Paper First, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews, with search terms broadly defined to capture discussions of HCV and its relationship with NHL and/or lymphoproliferative diseases. References were screened to further identify relevant studies and literature in the basic sciences. A total of 62 reports discussing the relationship between HCV, NHL, and lymphoproliferative diseases were identified. Epidemiological studies suggest that at least a portion of NHL may be etiologically attributable to HCV, particularly in areas with high HCV prevalence. Studies that showed a lack of association between HCV infection and lymphoma may have been influenced by small sample size, short follow-up periods, and database limitations. The association appears strongest with the B-cell lymphomas relative to other lymphoproliferative diseases. Mechanisms by which chronic HCV infection promotes lymphoproliferative disease remains unclear. Lymphomagenesis is a multifactorial process involving genetic, environmental, and infectious factors. HCV most probably have a role in the lymphomagenesis but further study to clarify the association and underlying mechanisms is warranted.
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16
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Parola C, Salogni L, Vaira X, Scutera S, Somma P, Salvi V, Musso T, Tabbia G, Bardessono M, Pasquali C, Mantovani A, Sozzani S, Bosisio D. Selective activation of human dendritic cells by OM-85 through a NF-kB and MAPK dependent pathway. PLoS One 2013; 8:e82867. [PMID: 24386121 PMCID: PMC3875422 DOI: 10.1371/journal.pone.0082867] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 11/06/2013] [Indexed: 01/08/2023] Open
Abstract
OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), a product made of the water soluble fractions of 21 inactivated bacterial strain patterns responsible for respiratory tract infections, is used for the prevention of recurrent upper respiratory tract infections and acute exacerbations in chronic obstructive pulmonary disease patients. OM-85 is able to potentiate both innate and adaptive immune responses. However, the molecular mechanisms responsible for OM-85 activation are still largely unknown. Purpose of this study was to investigate the impact of OM-85 stimulation on human dendritic cell functions. We show that OM-85 selectively induced NF-kB and MAPK activation in human DC with no detectable action on the interferon regulatory factor (IRF) pathway. As a consequence, chemokines (i.e. CXCL8, CXCL6, CCL3, CCL20, CCL22) and B-cell activating cytokines (i.e. IL-6, BAFF and IL-10) were strongly upregulated. OM-85 also synergized with the action of classical pro-inflammatory stimuli used at suboptimal concentrations. Peripheral blood mononuclear cells from patients with COPD, a pathological condition often associated with altered PRR expression pattern, fully retained the capability to respond to OM-85. These results provide new insights on the molecular mechanisms of OM-85 activation of the immune response and strengthen the rational for its use in clinical settings.
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Affiliation(s)
- Carmen Parola
- Dept. Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy
| | - Laura Salogni
- Dept. Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy
| | - Xenia Vaira
- Dept. Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy
| | - Sara Scutera
- Dept. Public Health and Pediatric Sciences, Università degli Studi di Torino, Torino, Italy
| | - Paolo Somma
- Dept. Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy
| | - Valentina Salvi
- Dept. Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy
| | - Tiziana Musso
- Dept. Public Health and Pediatric Sciences, Università degli Studi di Torino, Torino, Italy
| | - Giuseppe Tabbia
- Pulmonary Division, Ospedale S. Giovanni Battista, Torino, Italy
| | - Marco Bardessono
- Pulmonary Division, Ospedale S. Giovanni Battista, Torino, Italy
| | | | - Alberto Mantovani
- Humanitas Clinical and Research Center, Rozzano, Italy
- Dept. Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano, Italy
| | - Silvano Sozzani
- Dept. Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy
- Humanitas Clinical and Research Center, Rozzano, Italy
| | - Daniela Bosisio
- Dept. Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy
- * E-mail:
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17
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Berglund LJ, Avery DT, Ma CS, Moens L, Deenick EK, Bustamante J, Boisson-Dupuis S, Wong M, Adelstein S, Arkwright PD, Bacchetta R, Bezrodnik L, Dadi H, Roifman CM, Fulcher DA, Ziegler JB, Smart JM, Kobayashi M, Picard C, Durandy A, Cook MC, Casanova JL, Uzel G, Tangye SG. IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts. Blood 2013; 122:3940-50. [PMID: 24159173 PMCID: PMC3854113 DOI: 10.1182/blood-2013-06-506865] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 10/10/2013] [Indexed: 12/19/2022] Open
Abstract
B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common γ chain (γc)-binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Rα) in normal, but not STAT3-deficient, CD40L-stimulated naïve B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naïve B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21.
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Affiliation(s)
- Lucinda J Berglund
- Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
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T-helper I immunity, specific for the breast cancer antigen insulin-like growth factor-I receptor (IGF-IR), is associated with increased adiposity. Breast Cancer Res Treat 2013; 139:657-65. [DOI: 10.1007/s10549-013-2577-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Accepted: 05/22/2013] [Indexed: 12/14/2022]
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Kalli F, Machiorlatti R, Battaglia F, Parodi A, Conteduca G, Ferrera F, Proietti M, Tardito S, Sanguineti M, Millo E, Fenoglio D, De Palma R, Inghirami G, Filaci G. Comparative analysis of cancer vaccine settings for the selection of an effective protocol in mice. J Transl Med 2013; 11:120. [PMID: 23663506 PMCID: PMC3659084 DOI: 10.1186/1479-5876-11-120] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 05/08/2013] [Indexed: 12/31/2022] Open
Abstract
Background Cancer vaccines are considered a promising therapeutic approach. However, their clinical results are not yet satisfactory. This may be due to the the difficulty of selection of an efficient tumor associated antigen (TAA) and immunization protocol. Indeed, the weak antigenicity of many TAA impairs the design of robust procedures, therefore a systematic analysis to identify the most efficient TAA is mandatory. Here, we performed a study to compare different gp100 vaccination strategies to identify the best strategy to provide a 100% protection against experimental melanoma in a reproducible manner. Methods C57BL/6J mice were challenged subcutaneously with B16F10 melanoma cells, after vaccination with: a) mouse or human gp10025-33 peptide plus CpG adjuvant; b) mouse or human gp100 gene; c) mouse or human gp10025-33 peptide-pulsed dendritic cells (DC). Alternatively, a neutralizing anti-IL-10 monoclonal antibody (mAb) was subcutaneously administered at the site of tumor challenge to counteract regulatory cells. Finally, combinatorial treatment was performed associating human gp10025-33 peptide-pulsed DC vaccination with administration of the anti-IL-10 mAb. Results Vaccination with human gp10025-33 peptide-pulsed DC was the most effective immunization protocol, although not achieving a full protection. Administration of the anti-IL-10 mAb showed also a remarkable protective effect, replicated in mice challenged with a different tumor, Anaplastic Large Cell Lymphoma. When immunization with gp10025-33 peptide-pulsed DC was associated with IL-10 counteraction, a 100% protective effect was consistently achieved. The analysis on the T-cell tumor infiltrates showed an increase of CD4+granzyme+ T-cells and a decreased number of CD4+CD25+Foxp3+ Treg elements from mice treated with either gp10025-33 peptide-pulsed DC vaccination or anti-IL-10 mAb administration. These data suggest that processes of intratumoral re-balance between effector and regulatory T cell subpopulations may play a critical protective role in immunotherapy protocols. Conclusions Here we demonstrate that, in the setting of a cancer vaccine strategy, a comparative analysis of different personalized approaches may favour the unveiling of the most effective protocol. Moreover, our findings suggest that counteraction of IL-10 activity may be critical to revert the intratumoral environment promoting Treg polarization, thus increasing the effects of a vaccination against selected TAA.
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Affiliation(s)
- Francesca Kalli
- Centre of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV n. 7, 16132, Genoa, Italy
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A combination of cytokines rescues highly purified leukemic CLL B-cells from spontaneous apoptosis in vitro. PLoS One 2013; 8:e60370. [PMID: 23555960 PMCID: PMC3608602 DOI: 10.1371/journal.pone.0060370] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 02/26/2013] [Indexed: 12/16/2022] Open
Abstract
B-chronic lymphocytic leukemia (B-CLL), the most common human leukemia, is characterized by predominantly non-dividing malignant mature CD5+ B lymphocytes with an apoptosis defect. Various microenvironmental stimuli confer a growth advantage on these leukemic cells and extend their survival in vivo. Nevertheless, when cultured in vitro, CLL B-cells rapidly die from apoptosis. Certain cytokines may extend the survival capacity of CLL B-cells in vitro and individual anti-apoptotic effects of several cytokines have been reported. The potential cumulative effect of such cytokines has not been studied. We therefore investigated the effects on CLL B-cells survival in vitro of humoral factors, polyclonal lymphocyte activators and a combination of cytokines known for their anti-apoptotic effects. Purified CLL B-cells were cultured in the presence or absence of various soluble molecules and the leukemic cell response was assessed in terms of viability. Apoptotic cell death was detected by flow cytometry using annexinV and 7-amino-actinomycin. The survival of CLL B-cells in vitro was highly variable. When tested separately, cytokines (IL-2, -6, -10, -12, -15, -21, BAFF and APRIL) improved CLL B cell survival moderately; in combination, they significantly enhanced survival of these cells, even up to 7 days of culture. We also report that humoral factors from autologous serum are important for survival of these malignant cells. Our findings support the concept that the CLL microenvironment is critical and suggest that soluble factors may contribute directly to the prolonged survival of CLL B-cells. Therefore, the combination of cytokines we describe as providing strong resistance to apoptosis in vitro might be used to improve the treatment of CLL.
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Duell BL, Tan CK, Carey AJ, Wu F, Cripps AW, Ulett GC. Recent insights into microbial triggers of interleukin-10 production in the host and the impact on infectious disease pathogenesis. ACTA ACUST UNITED AC 2012; 64:295-313. [PMID: 22268692 DOI: 10.1111/j.1574-695x.2012.00931.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 01/17/2012] [Accepted: 01/17/2012] [Indexed: 02/06/2023]
Abstract
Since its initial description as a Th2-cytokine antagonistic to interferon-alpha and granulocyte-macrophage colony-stimulating factor, many studies have shown various anti-inflammatory actions of interleukin-10 (IL-10), and its role in infection as a key regulator of innate immunity. Studies have shown that IL-10 induced in response to microorganisms and their products plays a central role in shaping pathogenesis. IL-10 appears to function as both sword and shield in the response to varied groups of microorganisms in its capacity to mediate protective immunity against some organisms but increase susceptibility to other infections. The nature of IL-10 as a pleiotropic modulator of host responses to microorganisms is explained, in part, by its potent and varied effects on different immune effector cells which influence antimicrobial activity. A new understanding of how microorganisms trigger IL-10 responses is emerging, along with recent discoveries of how IL-10 produced during disease might be harnessed for better protective or therapeutic strategies. In this review, we summarize studies from the past 5 years that have reported the induction of IL-10 by different classes of pathogenic microorganisms, including protozoa, nematodes, fungi, viruses and bacteria and discuss the impact of this induction on the persistence and/or clearance of microorganisms in the host.
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Affiliation(s)
- Benjamin L Duell
- School of Medical Sciences, Centre for Medicine and Oral Health, Griffith University, Gold Coast Campus, Gold Coast, Qld, Australia
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de Paula Careta F, Gobessi S, Panepucci RA, Bojnik E, Morato de Oliveira F, Mazza Matos D, Falcão RP, Laurenti L, Zago MA, Efremov DG. The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets. Haematologica 2012; 97:1246-54. [PMID: 22331265 DOI: 10.3324/haematol.2011.054668] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The malignant B cells in chronic lymphocytic leukemia receive signals from the bone marrow and lymph node microenvironments which regulate their survival and proliferation. Characterization of these signals and the pathways that propagate them to the interior of the cell is important for the identification of novel potential targets for therapeutic intervention. DESIGN AND METHODS We compared the gene expression profiles of chronic lymphocytic leukemia B cells purified from bone marrow and peripheral blood to identify genes that are induced by the bone marrow microenvironment. Two of the differentially expressed genes were further studied in cell culture experiments and in an animal model to determine whether they could represent appropriate therapeutic targets in chronic lymphocytic leukemia. RESULTS Functional classification analysis revealed that the majority of differentially expressed genes belong to gene ontology categories related to cell cycle and mitosis. Significantly up-regulated genes in bone marrow-derived tumor cells included important cell cycle regulators, such as Aurora A and B, survivin and CDK6. Down-regulation of Aurora A and B by RNA interference inhibited proliferation of chronic lymphocytic leukemia-derived cell lines and induced low levels of apoptosis. A similar effect was observed with the Aurora kinase inhibitor VX-680 in primary chronic lymphocytic leukemia cells that were induced to proliferate by CpG-oligonucleotides and interleukin-2. Moreover, VX-680 significantly blocked leukemia growth in a mouse model of chronic lymphocytic leukemia. CONCLUSIONS Aurora A and B are up-regulated in proliferating chronic lymphocytic leukemia cells and represent potential therapeutic targets in this disease.
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Affiliation(s)
- Francisco de Paula Careta
- Hematology Division and Center for Cell-Based Therapy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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Tsukiyama-Kohara K, Sekiguchi S, Kasama Y, Salem NE, Machida K, Kohara M. Hepatitis C virus-related lymphomagenesis in a mouse model. ISRN HEMATOLOGY 2011; 2011:167501. [PMID: 22084693 PMCID: PMC3195281 DOI: 10.5402/2011/167501] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Accepted: 06/02/2011] [Indexed: 01/30/2023]
Abstract
B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection. The mechanism by which HCV infection leads to lymphoproliferative disorder remains unclear. Our group established HCV transgenic mice that expressed the full HCV genome in B cells (RzCD19Cre mice). We observed a 25.0% incidence of diffuse large B cell non-Hodgkin lymphomas (22.2% in male and 29.6% in female mice) within 600 days of birth. Interestingly, RzCD19Cre mice with substantially elevated serum-soluble interleukin-2 receptor α-subunit (sIL-2Rα) levels (>1000 pg/mL) developed B cell lymphomas. Another mouse model of lymphoproliferative disorder was established by persistent expression of HCV structural proteins through disruption of interferon regulatory factor-1 (irf-1_/_/CN2 mice). Irf-1_/_/CN2 mice showed extremely high incidences of lymphomas and lymphoproliferative disorders. Moreover, these mice showed increased levels of interleukin (IL)-2, IL-10, and Bcl-2 as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes.
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Affiliation(s)
- Kyoko Tsukiyama-Kohara
- Department of Experimental Phylaxiology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto-shi, Kumamoto 860-8556, Japan
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Teodorczyk-Injeyan JA, McGregor M, Ruegg R, Injeyan HS. Interleukin 2-regulated in vitro antibody production following a single spinal manipulative treatment in normal subjects. CHIROPRACTIC & OSTEOPATHY 2010; 18:26. [PMID: 20825650 PMCID: PMC2945351 DOI: 10.1186/1746-1340-18-26] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Accepted: 09/08/2010] [Indexed: 11/24/2022]
Abstract
Background Our recent investigations have demonstrated that cell cultures from subjects, who received a single spinal manipulative treatment in the upper thoracic spine, show increased capacity for the production of the key immunoregulatory cytokine, interleukin-2. However, it has not been determined if such changes influence the response of the immune effector cells. Thus, the purpose of the present study was to determine whether, in the same subjects, spinal manipulation-related augmentation of the in vitro interleukin-2 synthesis is associated with the modulation of interleukin 2-dependent and/or interleukin-2-induced humoral immune response (antibody synthesis). Methods A total of seventy-four age and sex-matched healthy asymptomatic subjects were studied. The subjects were assigned randomly to: venipuncture control (n = 22), spinal manipulative treatment without cavitation (n = 25) or spinal manipulative treatment associated with cavitation (n = 27) groups. Heparinized blood samples were obtained from the subjects before (baseline) and then at 20 minutes and 2 hours post-treatment. Immunoglobulin (antibody) synthesis was induced in cultures of peripheral blood mononuclear cells by stimulation with conventional pokeweed mitogen or by application of human recombinant interleukin-2. Determinations of the levels of immunoglobulin G and immunoglobulin M production in culture supernatants were performed by specific immunoassays. Results The baseline levels of immunoglobulin synthesis induced by pokeweed mitogen or human recombinant interleukin-2 stimulation were comparable in all groups. No significant changes in the production of pokeweed mitogen-induced immunoglobulins were observed during the post-treatment period in any of the study groups. In contrast, the production of interleukin-2 -induced immunoglobulin G and immunoglobulin M was significantly increased in cultures from subjects treated with spinal manipulation. At 20 min post-manipulation, immunoglobulin G synthesis was significantly elevated in subjects who received manipulation with cavitation, relative to that in cultures from subjects who received manipulation without cavitation and venipuncture alone. At 2 hr post-treatment, immunoglobulin M synthesis was significantly elevated in subjects who received manipulation with cavitation relative to the venipuncture group. There were no quantitative alterations within the population of peripheral blood B or T lymphocytes in the studied cultures. Conclusion Spinal manipulative treatment does not increase interleukin-2 -dependent polyclonal immunoglobulin synthesis by mitogen-activated B cells. However, antibody synthesis induced by interleukin-2 alone can be, at least temporarily, augmented following spinal manipulation. Thus, under certain physiological conditions spinal manipulative treatment might influence interleukin-2 -regulated biological responses.
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Affiliation(s)
- Julita A Teodorczyk-Injeyan
- Professor and Chair, Department of Pathology and Microbiology, Canadian Memorial Chiropractic College, Canada.
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Persistent expression of the full genome of hepatitis C virus in B cells induces spontaneous development of B-cell lymphomas in vivo. Blood 2010; 116:4926-33. [PMID: 20733156 DOI: 10.1182/blood-2010-05-283358] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Extrahepatic manifestations of hepatitis C virus (HCV) infection occur in 40%-70% of HCV-infected patients. B-cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with HCV infection. The mechanism by which HCV infection of B cells leads to lymphoma remains unclear. Here we established HCV transgenic mice that express the full HCV genome in B cells (RzCD19Cre mice) and observed a 25.0% incidence of diffuse large B-cell non-Hodgkin lymphomas (22.2% in males and 29.6% in females) within 600 days after birth. Expression levels of aspartate aminotransferase and alanine aminotransferase, as well as 32 different cytokines, chemokines and growth factors, were examined. The incidence of B-cell lymphoma was significantly correlated with only the level of soluble interleukin-2 receptor α subunit (sIL-2Rα) in RzCD19Cre mouse serum. All RzCD19Cre mice with substantially elevated serum sIL-2Rα levels (> 1000 pg/mL) developed B-cell lymphomas. Moreover, compared with tissues from control animals, the B-cell lymphoma tissues of RzCD19Cre mice expressed significantly higher levels of IL-2Rα. We show that the expression of HCV in B cells promotes non-Hodgkin-type diffuse B-cell lymphoma, and therefore, the RzCD19Cre mouse is a powerful model to study the mechanisms related to the development of HCV-associated B-cell lymphoma.
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Antiapoptotic effect of interleukin-2 (IL-2) in B-CLL cells with low and high affinity IL-2 receptors. Ann Hematol 2010; 89:1125-32. [PMID: 20544350 DOI: 10.1007/s00277-010-0994-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Accepted: 05/11/2010] [Indexed: 10/19/2022]
Abstract
Although B chronic lymphocytic leukemia (B-CLL) cells express the alpha chain of the interleukin-2 (IL-2) receptor CD25, little is known about the effect of IL-2 on apoptosis in B-CLL cells. We have shown previously that stimulation of B-CLL cells with a CpG-oligonucleotide induces IL-2 high affinity receptors. In our current work, we analyzed the effect of IL-2 on apoptosis in resting B-CLL cells and in our model of activated B-CLL cells (CD25 high cells). IL-2 had modest antiapoptotic activity in resting B-CLL cells. In contrast, IL-2 was much more potent to prevent apoptosis in activated cells. Prevention of cell death was also associated with the maintenance of the mitochondrial membrane potential. While only limited regulation of apoptosis controlling proteins was observed in resting B-CLL cells, IL-2 had strong effects on MCL-1, Bcl-xl, and survivin expression and inhibited Bax cleavage in CD25 high cells. Interestingly, expression of Bcl-2 was reduced. Addition of IL-2 to activated B-CLL cells caused rapid phosphorylation of Akt, while IL-2 failed to significantly phosphorylate Akt in resting B-CLL cells. Pharmacological inhibition of Akt by LY294002 restored sensitivity of activated B-CLL cells to fludarabine. IL-2 might be an important survival factor in activated B-CLL cells and might contribute to disease progression by upregulation of several critical antiapoptotic proteins.
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Cao Y, Gordic M, Kobold S, Lajmi N, Meyer S, Bartels K, Hildebrandt Y, Luetkens T, Ihloff AS, Kröger N, Bokemeyer C, Atanackovic D. An optimized assay for the enumeration of antigen-specific memory B cells in different compartments of the human body. J Immunol Methods 2010; 358:56-65. [PMID: 20302874 DOI: 10.1016/j.jim.2010.03.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Revised: 03/09/2010] [Accepted: 03/11/2010] [Indexed: 12/18/2022]
Abstract
OBJECT In the framework of our current study we set out to develop an optimized assay for the quantification of antigen-specific B cells in different compartments of the human body. METHODS Mononuclear cells (MNC) derived from the peripheral blood, bone marrow (BM), or human tonsils were incubated with different combinations of stimuli. The stimulated cells and culture supernatants were then applied to IgG-ELISPOT and ELISA read-out assays and tetanus toxoid (TT)-specific B cell responses were quantified. RESULTS We found that a combination of CD40L, CpG, and IL21 was optimal for the induction of TT-specific IgG-producing cells from memory B cell (mBc) precursors. This cocktail of stimuli led to a proliferation-dependent induction of CD19(intermediate)CD38(high)CD138(high)IgD(negative) terminally differentiated plasma cells. Applying our optimized methodology we were also able to quantify mBc specific for cytomegalovirus and influenza virus A. Most importantly, the same method proved useful for the comparison of mBc frequencies between different compartments of the body and, accordingly, we were able to demonstrate that TT-specific mBc preferably reside within tonsillar tissue. CONCLUSION Here, we optimized an assay for the quantification of antigen-specific B cells in different human tissues demonstrating, for example, that TT-specific mBc preferably reside in human tonsils but not in the BM or the peripheral blood. We suggest that our approach can be used for the enumeration of mBc specific for a wide variety of Ag (microbial, tumor-related, auto-antigens), which will lead to significant improvements regarding our knowledge about the biology of humoral immunity.
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Affiliation(s)
- Yanran Cao
- Department of Internal Medicine II (Oncology, Haematology, Stem Cell Transplantation), University Cancer Centre Hamburg (Hubertus Wald Tumorzentrum), Hamburg, Germany.
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Plander M, Seegers S, Ugocsai P, Diermeier-Daucher S, Iványi J, Schmitz G, Hofstädter F, Schwarz S, Orsó E, Knüchel R, Brockhoff G. Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudofollicles. Leukemia 2009; 23:2118-28. [DOI: 10.1038/leu.2009.145] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells. Blood 2008; 112:711-20. [PMID: 18497318 DOI: 10.1182/blood-2007-04-084756] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder characterized by the surface expression of CD20, CD5 antigens, as well as the receptor CD40. Activation of CD40 by its ligand (CD40L) induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines, such as IL-6, IL-10, TNF-alpha, IL-8, and GM-CSF, which are involved in tumor cell survival, migration, and interaction with cells in the tumor microenvironment. Here we demonstrate that in primary B-CLL tumor cells, the novel antagonist anti-CD40 monoclonal antibody, HCD122, inhibits CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines. Furthermore, HCD122 is also a potent mediator of antibody-dependent cellular cytotoxicity (ADCC), lysing B-CLL cells more efficiently than rituximab in vitro, despite a significantly higher number of cell surface CD20 binding sites compared with CD40. Unlike rituximab, however, HCD122 (formerly CHIR-12.12) does not internalize upon binding to the cells. Our data suggest that HCD122 may inhibit B-CLL growth by blocking CD40 signaling and by ADCC-mediated cell lysis.
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Bryant VL, Ma CS, Avery DT, Li Y, Good KL, Corcoran LM, de Waal Malefyt R, Tangye SG. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. THE JOURNAL OF IMMUNOLOGY 2008; 179:8180-90. [PMID: 18056361 DOI: 10.4049/jimmunol.179.12.8180] [Citation(s) in RCA: 400] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Differentiation of B cells into Ig-secreting cells (ISC) is critical for the generation of protective humoral immune responses. Because of the important role played by secreted Ig in host protection against infection, it is necessary to identify molecules that control B cell differentiation. Recently, IL-21 was reported to generate ISC from activated human B cells. In this study, we examined the effects of IL-21 on the differentiation of all human mature B cell subsets--neonatal, transitional, naive, germinal center, IgM-memory, and isotype-switched memory cells--into ISC and compared its efficacy to that of IL-10, a well-known mediator of human B cell differentiation. IL-21 rapidly induced the generation of ISC and the secretion of vast quantities IgM, IgG and IgA from all of these B cell subsets. Its effect exceeded that of IL-10 by up to 100-fold, highlighting the potency of IL-21 as a B cell differentiation factor. Strikingly, IL-4 suppressed the stimulatory effects of IL-21 on naive B cells by reducing the expression of B-lymphocyte induced maturation protein-1 (Blimp-1). In contrast, memory B cells were resistant to the inhibitory effects of IL-4. Finally, the ability of human tonsillar CD4+CXCR5+CCR7- T follicular helper (TFH) cells, known to be a rich source of IL-21, to induce the differentiation of autologous B cells into ISC was mediated by the production of IL-21. These findings suggest that IL-21 produced by TFH cells during the primary as well as the subsequent responses to T cell-dependent Ag makes a major contribution to eliciting and maintaining long-lived humoral immunity.
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Affiliation(s)
- Vanessa L Bryant
- Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
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Mueller CG, Boix C, Kwan WH, Daussy C, Fournier E, Fridman WH, Molina TJ. Critical role of monocytes to support normal B cell and diffuse large B cell lymphoma survival and proliferation. J Leukoc Biol 2007; 82:567-75. [PMID: 17575267 DOI: 10.1189/jlb.0706481] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Large B cell lymphomas can comprise numerous CD14+ cells in the tumor stroma, which raises the question of whether monocytes can support B cell survival and proliferation. We show that the coculture of monocytes with B cells from peripheral blood or from diffuse large B cell lymphoma enabled prolonged B cell survival. Under these conditions, diffuse large lymphoma B cells proliferated, and addition of B cell-activating factor of the TNF family (BAFF) and IL-2 enhanced cell division. Monocytes and dendritic cells (DC) had similar antiapoptotic activity on healthy B cells but displayed differences with respect to B cell proliferation. Monocytes and cord blood-derived CD14+ cells promoted B cell proliferation in the presence of an anti-CD40 stimulus, whereas DC supported B cell proliferation when activated through the BCR. DC and CD14+ cells were able to induce plasmocyte differentiation. When B cells were activated via the BCR or CD40, they released the leukocyte attractant CCL5, and this chemokine is one of the main chemokines expressed in diffuse large B cell lymphoma. The data support the notion that large B cell lymphoma recruit monocytes via CCL5 to support B cell survival and proliferation.
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Affiliation(s)
- Chris G Mueller
- INSERM, U872, Centre de Recherches Biomédicales des Cordeliers Université Pierre et Marie Curie (Paris VI) et René Descartes (Paris V), UMR S 872, Paris, France.
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Perez-Chacon G, Vargas JA, Jorda J, Morado M, Rosado S, Martin-Donaire T, Losada-Fernandez I, Rebolleda N, Perez-Aciego P. CD5 provides viability signals to B cells from a subset of B-CLL patients by a mechanism that involves PKC. Leuk Res 2007; 31:183-93. [PMID: 16725198 DOI: 10.1016/j.leukres.2006.03.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2006] [Revised: 03/22/2006] [Accepted: 03/27/2006] [Indexed: 11/17/2022]
Abstract
B-chronic lymphocytic leukaemia (B-CLL) is a heterogeneous disease characterized by an accumulation of B lymphocytes expressing CD5. To date, the biological significance of this molecule in B-CLL B cells remains to be elucidated. In this study, we have analysed the functional consequences of the binding of an anti-CD5 antibody on B-CLL B cells. To this purpose, we have measured the percentage of viability of B-CLL B cells in the presence or in the absence of anti-CD5 antibodies and also examined some of the biochemical events downstream the CD5-signalling. We demonstrate that anti-CD5 induces phosphorylation of protein tyrosine kinases and protein kinase C (PKC), while no activation of Akt/PKB and MAPKs is detected. This signalling cascade results in viability in a group of patients in which we observe an increase of Mcl-1 levels, whereas the levels of bcl-2, bcl-x(L) and XIAP do not change. We also report that this pathway leads to IL-10 production, an immunoregulatory cytokine that might act as an autocrine growth factor for leukaemic B cells. Inhibition of PKC prevents the induction of Mcl-1 and IL-10, suggesting that the activation of PKC plays an important role in the CD5-mediated survival signals in B cells from a subset of B-CLL patients.
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Makar VR, Logani MK, Bhanushali A, Alekseev SI, Ziskin MC. Effect of cyclophosphamide and 61.22 GHz millimeter waves on T-cell, B-cell, and macrophage functions. Bioelectromagnetics 2006; 27:458-66. [PMID: 16622862 DOI: 10.1002/bem.20230] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The present study was undertaken to investigate whether millimeter waves (MMWs) at 61.22 GHz can modulate the effect of cyclophosphamide (CPA), an anti-cancer drug, on the immune functions of mice. During the exposure each mouse's nose was placed in front of the center of the antenna aperture (1.5 x 1.5 cm) of MMW generator. The device produced 61.22 +/- 0.2 GHz wave radiation. Spatial peak Specific Absorption Rate (SAR) at the skin surface and spatial peak incident power density were measured as 885 +/- 100 W/kg and 31 +/- 5 mW/cm(2), respectively. Duration of the exposure was 30 min each day for 3 consecutive days. The maximum temperature elevation at the tip of the nose, measured at the end of 30 min, was 1 degrees C. CPA injection (100 mg/kg) was given intraperitoneally on the second day of exposure to MMWs. The animals were sacrificed 2, 5, and 7 days after CPA administration. MMW exposure caused upregulation in tumor necrosis factor-alpha (TNF-alpha) production in peritoneal macrophages suppressed by CPA administration. MMWs also caused a significant increase in interferon-gamma (IFN-gamma) production by splenocytes and enhanced proliferative activity of T-cells. Conversely, no changes were observed in interleukin-10 (IL-10) level and B-cell proliferation. These results suggest that MMWs accelerate the recovery process selectively through a T-cell-mediated immune response.
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Affiliation(s)
- V R Makar
- Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA
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34
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Gandolfo LD, Ameglio F, Biolcati G, Pimpinelli F, Trento E, Galante M, Nardi A, Topi G. Anti-HCV-core specific IgM in porphyria cutanea tarda. J Eur Acad Dermatol Venereol 2006. [DOI: 10.1111/j.1468-3083.1996.tb00175.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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35
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Solanilla A, Pasquet JM, Viallard JF, Contin C, Grosset C, Déchanet-Merville J, Dupouy M, Landry M, Belloc F, Nurden P, Blanco P, Moreau JF, Pellegrin JL, Nurden AT, Ripoche J. Platelet-associated CD154 in immune thrombocytopenic purpura. Blood 2005; 105:215-8. [PMID: 15191945 DOI: 10.1182/blood-2003-07-2367] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
CD40-ligand (CD154) is expressed on activated CD4+ T lymphocytes and is essential for the T cell–dependent activation of B lymphocytes. CD154 is also expressed at the activated platelet surface. In this study, we show that platelet-associated CD154 is increased in immune thrombocytopenic purpura (ITP), a disease characterized by an autoimmune response against proteins of the platelet membrane. CD154 and its messenger RNA were also present in increased amounts in the megakaryocytes of patients with ITP. We found that platelet-associated CD154 is competent to induce the CD40-dependent proliferation of B lymphocytes, and we observed an in vitro CD154-dependent production of antibodies to the GPIIb/IIIa complex (integrin αIIbβ3) when platelets and peripheral blood B lymphocytes from ITP patients with circulating anti-GPIIb/IIIa antibody were cultured together. Therefore, platelet-associated CD154 expression is increased in ITP and is able to drive the activation of autoreactive B lymphocytes in this disease.
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Affiliation(s)
- Anne Solanilla
- CNRS FRE 2617 and UMR 5540, Université de Bordeaux 2, France
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36
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Mocellin S, Marincola F, Rossi CR, Nitti D, Lise M. The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle. Cytokine Growth Factor Rev 2004; 15:61-76. [PMID: 14746814 DOI: 10.1016/j.cytogfr.2003.11.001] [Citation(s) in RCA: 181] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Interleukin-10 (IL-10) is a pleiotropic cytokine that modulates the function of several adaptive immunity-related cells. Although generally considered an immunosuppressive molecule, IL-10 possesses immunostimulatory properties in several in vitro and in vivo models. These very different outcomes are believed to depend upon experimental conditions, the dominant immune effector mediating a given immune response, the timing of IL-10 production/administration, and IL-10 dose and/or location of expression. In the present work, we review the current knowledge regarding IL-10 activity on adaptive immunity related cells, emphasize new insights on IL-10 molecular/cellular targets, and summarize the available data on the relationship between IL-10 and some pathological conditions (e.g. infectious diseases, autoimmunity, allergy, cancer and transplantation) involving adaptive immunity.
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Affiliation(s)
- Simone Mocellin
- Department of Oncological and Surgical Sciences, University of Padova, Clinica Chirurgica II, Via Giustiniani, 2, 35128 Padova, Italy.
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37
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Hirano T, Yonekubo I, Shimo K, Mizuguchi J. CD27 synergizes with CD40 to induce IgM, IgG, and IgA antibody responses of peripheral blood B cells in the presence of IL-2 and IL-10. Immunol Lett 2003; 89:251-7. [PMID: 14556986 DOI: 10.1016/s0165-2478(03)00156-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
CD40, a member of the tumor necrosis factor receptor (TNFR) family, promotes IgM, IgG, and IgA antibody (Ab) synthesis in combination with a variety of cytokines. Another TNFR family member, CD27, causes B cells to differentiate into antibody-forming cells, with marginal effects on proliferation. In the present study, we examined whether anti-CD27 monoclonal antibody (mAb) modulates the antibody production induced by anti-CD40 mAb immobilized on L cells expressing FcgammaRII (CDw32) in the presence of IL-2 and/or IL-10. The anti-CD40 mAb substantially enhanced IgM, IgG, and IgA production in combination with IL-2 and IL-10, whereas anti-CD27 mAb augmented it only marginally, as assessed by enzyme-linked immunosorbent assay. The addition of anti-CD27 mAb enhanced the anti-CD40-mediated IgM, IgG, and IgA antibody production only when both IL-2 and IL-10 were present in the culture. The CD27-positive B cell compartment generated synergistic antibody responses in response to four different stimulants, anti-CD27/anti-CD40 mAb and cytokines IL-2/IL-10, whereas the CD27-negative B cell compartment failed to do so. Kinetic analysis showed that anti-CD40 might function in the early phase of B cell activation, while anti-CD27 mAb functioned in the late stage. The addition of CD27(-) to CD27(+) B cells in various ratios did not have any effect on the antibody production, suggesting that CD27(+) to CD27(-) B cell interaction does not occur in this system. Our findings suggest that a member of the TNFR family, CD27, cooperates with CD40 to induce efficient antibody production in combination with cytokines IL-2 and IL-10.
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Affiliation(s)
- Testuo Hirano
- Department of Immunology and Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, 160-8402, Tokyo, Japan
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38
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Contin C, Pitard V, Delmas Y, Pelletier N, Defrance T, Moreau JF, Merville P, Déchanet-Merville J. Potential role of soluble CD40 in the humoral immune response impairment of uraemic patients. Immunology 2003; 110:131-40. [PMID: 12941150 PMCID: PMC1783029 DOI: 10.1046/j.1365-2567.2003.01716.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
CD40/CD154 interaction is essential for both humoral and cellular immune response. We investigated whether this interaction could be altered in patients with kidney failure who are known to present an impaired immune response. To that aim, we measured the levels of the soluble form of CD40 (sCD40), which is known to interfere with CD40/CD154 interaction, in 43 chronic renal failure patients, 162 hemodialysed patients, and 83 healthy donors. Uraemic and haemodialysed patients presented a three- and fivefold increase, respectively, of the antagonist soluble form of CD40 in their serum, when compared to healthy subjects. Serum sCD40 levels correlated with those of creatinine in uraemic non-haemodialysed patients. While sCD40 is widely excreted in urine of healthy individuals, it is not eliminated by dialysis sessions on classic membranes. The return to a normal kidney function in nine haemodialysed patients who received renal transplantation, leads to a rapid decrease of serum sCD40 levels. This natural sCD40 exhibited multimeric forms and was able to inhibit immunoglobulin production by CD154-activated B lymphocytes in vitro. Furthermore, the positive correlation we observed between the serum levels of sCD40 and the deficient response to hepatitis B vaccination in uraemic patients suggests that sCD40 also compromises the humoral response in vivo.
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Affiliation(s)
- Cécile Contin
- UMR-CNRS 5540, Université Bordeaux 2, Bordeaux, France
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39
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Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 2003; 19:225-34. [PMID: 12932356 DOI: 10.1016/s1074-7613(03)00208-5] [Citation(s) in RCA: 808] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dendritic cells (DCs) initiate and control immune responses. Plasmacytoid DCs (pDCs) represent a unique DC subset able to promptly release large amounts of type I interferon (IFN-alphabeta) upon viral encounter. Here we report that depletion of pDCs from human blood mononuclear cells abrogates the secretion of specific and polyclonal IgGs in response to influenza virus. Furthermore, purified pDCs triggered with virus induce CD40-activated B cells to differentiate into plasma cells. Two pDC cytokines act sequentially, with IFN-alphabeta generating non-Ig-secreting plasma blasts and IL-6 inducing their differentiation into Ig-secreting plasma cells. These plasma cells display the high levels of CD38 found on tissue plasma cells. Thus, pDCs are critical for the generation of plasma cells and antibody responses.
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Affiliation(s)
- Gaetan Jego
- Baylor Institute for Immunology Research, 3434 Live Oak Street, Dallas, Texas 75204, USA
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40
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Tangye SG, Avery DT, Deenick EK, Hodgkin PD. Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 170:686-94. [PMID: 12517929 DOI: 10.4049/jimmunol.170.2.686] [Citation(s) in RCA: 225] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Humoral immune responses elicited after secondary exposure to immunizing Ag are characterized by robust and elevated reactivity of memory B cells that exceed those of naive B cells during the primary response. The mechanism underlying this difference in responsiveness of naive vs memory B cells remains unclear. We have quantitated the response of naive and memory human B cells after in vitro stimulation with T cell-derived stimuli. In response to stimulation with CD40 ligand alone or with IL-10, both IgM-expressing and Ig isotype-switched memory B cells entered their first division 20-30 h earlier than did naive B cells. In contrast, the time spent traversing subsequent divisions was similar. Consistent with previous studies, only memory cells differentiated to CD38(+) blasts in a manner that increased with consecutive division number. These differentiated CD38(+) B cells divided faster than did CD38(-) memory B cell blasts. Proliferation of CD40 ligand-stimulated naive B cells as well as both CD38(+) and CD38(-) cells present in cultures of memory B cells was increased by IL-10. In contrast, IL-2 enhanced proliferation of CD38(-) and CD38(+) memory B cell blasts, but not naive cells. Thus, memory B cells possess an intrinsic advantage over naive B cells in both the time to initiate a response and in the division-based rate of effector cell development. These differences help explain the accelerated Ab response exhibited by memory B cells after secondary challenge by an invading pathogen, a hallmark of immunological memory.
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Affiliation(s)
- Stuart G Tangye
- Immune Regulation Group, Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia.
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41
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Decker T, Hipp S, Ringshausen I, Bogner C, Oelsner M, Schneller F, Peschel C. Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood 2003; 101:278-85. [PMID: 12393642 DOI: 10.1182/blood-2002-01-0189] [Citation(s) in RCA: 134] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
In B-cell chronic lymphocytic leukemia (B-CLL), malignant cells seem to be arrested in the G(0)/early G(1) phase of the cell cycle, and defective apoptosis might be involved in disease progression. However, increasing evidence exists that B-CLL is more than a disease consisting of slowly accumulating resting B cells: a proliferating pool of cells has been described in lymph nodes and bone marrow and might feed the accumulating pool in the blood. Rapamycin has been reported to inhibit cell cycle progression in a variety of cell types, including human B cells, and has shown activity against a broad range of human tumor cell lines. Therefore, we investigated the ability of rapamycin to block cell cycle progression in proliferating B-CLL cells. We have recently demonstrated that stimulation with CpG-oligonucleotides and interleukin-2 provides a valuable model for studying cell cycle regulation in malignant B cells. In our present study, we demonstrated that rapamycin induced cell cycle arrest in proliferating B-CLL cells and inhibited phosphorylation of p70s6 kinase (p70(s6k)). In contrast to previous reports on nonmalignant B cells, the expression of the cell cycle inhibitor p27 was not changed in rapamycin-treated leukemic cells. Treatment with rapamycin prevented retinoblastoma protein (RB) phosphorylation in B-CLL cells without affecting the expression of cyclin D2, but cyclin D3 was no longer detectable in rapamycin-treated B-CLL cells. In addition, rapamycin treatment inhibited cyclin-dependent kinase 2 activity by preventing up-regulation of cyclin E and cyclin A. Interestingly, survivin, which is expressed in the proliferation centers of B-CLL patients in vivo, is not up-regulated in rapamycin-treated cells. Therefore, rapamycin interferes with the expression of many critical molecules for cell cycle regulation in cycling B-CLL cells. We conclude from our study that rapamycin might be an attractive substance for therapy for B-CLL patients by inducing a G(1) arrest in proliferating tumor cells.
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MESH Headings
- Aged
- Aged, 80 and over
- Antibiotics, Antineoplastic/pharmacology
- B-Lymphocytes/drug effects
- B-Lymphocytes/pathology
- Cell Culture Techniques
- Cell Cycle/drug effects
- Cyclin A/drug effects
- Cyclin A/metabolism
- Cyclin D3
- Cyclin E/drug effects
- Cyclin E/metabolism
- Cyclins/drug effects
- Cyclins/metabolism
- G1 Phase/drug effects
- Humans
- Inhibitor of Apoptosis Proteins
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Male
- Microtubule-Associated Proteins/drug effects
- Microtubule-Associated Proteins/metabolism
- Middle Aged
- Neoplasm Proteins
- Sirolimus/pharmacology
- Survivin
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Affiliation(s)
- Thomas Decker
- 3rd Department of Medicine, Technical University of Munich, Germany.
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42
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Cerutti A, Zan H, Kim EC, Shah S, Schattner EJ, Schaffer A, Casali P. Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 169:6594-603. [PMID: 12444172 PMCID: PMC4625981 DOI: 10.4049/jimmunol.169.11.6594] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic lymphocytic leukemia (CLL) results from the expansion of malignant CD5(+) B cells that usually express IgD and IgM. These leukemic cells can give rise in vivo to clonally related IgG(+) or IgA(+) elements. The requirements and modalities of this process remain elusive. Here we show that leukemic B cells from 14 of 20 CLLs contain the hallmarks of ongoing Ig class switch DNA recombination (CSR), including extrachromosomal switch circular DNAs and circle transcripts generated by direct S micro -->Sgamma, S micro -->Salpha, and S micro -->Sepsilon as well as sequential Sgamma-->Salpha and Sgamma-->Sepsilon CSR. Similar CLL B cells express transcripts for activation-induced cytidine deaminase, a critical component of the CSR machinery, and contain germline I(H)-C(H) and mature V(H)DJ(H)-C(H) transcripts encoded by multiple Cgamma, Calpha, and Cepsilon genes. Ongoing CSR occurs in only a fraction of the CLL clone, as only small proportions of CD5(+)CD19(+) cells express surface IgG or IgA and lack IgM and IgD. In vivo class-switching CLL B cells down-regulate switch circles and circle transcripts in vitro unless exposed to exogenous CD40 ligand and IL-4. In addition, CLL B cells that do not class switch in vivo activate the CSR machinery and secrete IgG, IgA, or IgE upon in vitro exposure to CD40 ligand and IL-4. These findings indicate that in CLL at least some members of the malignant clone actively differentiate in vivo along a pathway that induces CSR. They also suggest that this process is elicited by external stimuli, including CD40 ligand and IL-4, provided by bystander immune cells.
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MESH Headings
- B-Lymphocytes/drug effects
- B-Lymphocytes/enzymology
- B-Lymphocytes/immunology
- Base Sequence
- CD40 Ligand/pharmacology
- Cytidine Deaminase/metabolism
- DNA, Circular/genetics
- DNA, Neoplasm/genetics
- Down-Regulation
- Humans
- Immunoglobulin A/biosynthesis
- Immunoglobulin A/genetics
- Immunoglobulin G/biosynthesis
- Immunoglobulin G/genetics
- Immunoglobulin Switch Region
- In Vitro Techniques
- Interleukin-4/pharmacology
- Leukemia, Lymphocytic, Chronic, B-Cell/enzymology
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Molecular Sequence Data
- Phenotype
- Recombinant Proteins/pharmacology
- Recombination, Genetic
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Affiliation(s)
- Andrea Cerutti
- Division of Molecular Immunology, Department of Pathology, Weill Medical College of Cornell University, New York, New York 10021, USA.
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43
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44
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Hirohata S, Yanagida T, Tomita T, Yoshikawa H, Ochi T. Bone marrow CD34+ progenitor cells stimulated with stem cell factor and GM‐CSF have the capacity to activate IgD− B cells through direct cellular interaction. J Leukoc Biol 2002. [DOI: 10.1189/jlb.71.6.987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Shunsei Hirohata
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan; and
| | - Tamiko Yanagida
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan; and
| | - Tetsuya Tomita
- Department of Orthopedic Surgery, Osaka University Medical School, Japan
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Osaka University Medical School, Japan
| | - Takahiro Ochi
- Department of Orthopedic Surgery, Osaka University Medical School, Japan
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45
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Ruan Y, Okamoto Y, Matsuzaki Z, Endo S, Matsuoka T, Kohno T, Chazono H, Eiko I, Tsubota K, Saito I. Suppressive effect of locally produced interleukin-10 on respiratory syncytial virus infection. Immunology 2001; 104:355-60. [PMID: 11722651 PMCID: PMC1783310 DOI: 10.1046/j.1365-2567.2001.01318.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Interleukin (IL)-10 is known to be a multifunctional cytokine. This study was designed to evaluate the role of IL-10 during respiratory syncytial virus (RSV) infection using a C57BL/6 transgenic (TG) mouse model in which the expression of murine IL-10 cDNA was regulated by a human salivary amylase promoter (IL-10 TG mice). These mice expressed a large amount of IL-10 in the nasal mucosa and in salivary glands. Viral replication in the respiratory tract after intranasal infection with RSV was suppressed significantly in IL-10 TG mice compared to non-transgenic controls. This suppression was IL-10 specific, because it was prevented by treating mice with neutralizing anti-IL-10 antibodies. We also found that IL-10-stimulated T cells displayed cytotoxic activity against infected murine nasal epithelial cells. Previous data indicated that IL-10 induces Fas ligand (L) expression on mouse T cells. Taken together, these data suggest that Fas/Fas L mediated cytotoxicity is involved in the suppression of RSV replication observed in IL-10 TG mice after intranasal infection.
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Affiliation(s)
- Y Ruan
- Department of Otolaryngology, Yamanashi Medical University, Yamanshi, Japan
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46
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Su YC, Wu WM, Wu MF, Chiang BL. A model of chronic lymphocytic leukemia with Ritcher's transformation in severe combined immunodeficiency mice. Exp Hematol 2001; 29:1218-25. [PMID: 11602324 DOI: 10.1016/s0301-472x(01)00690-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The major aim of the study was to establish a murine model of chronic lymphocytic leukemia with B-1 cells derived from a New Zealand white mouse. MATERIAL AND METHODS Malignant B-1 cells (named CLL-RT cells) derived from a New Zealand white mouse were injected into the peritoneal cavity of severe combined immunodeficiency mice. Upon follow-up of recipient mice, the lymphomas showed characteristics similar to chronic lymphocytic leukemia (CLL) with Ritcher's transformation. RESULTS Blood samples from the recipient mice showed that CLL-RT cells increased rapidly in peripheral blood after 5 weeks. Serum interleukin-10 also increased significantly in recipient mice, as in human chronic lymphocytic leukemia patients. These CLL-RT cells showed a high nucleus-to-cytoplasm ratio. These cells could metastasize via circulation in the recipients and form diffuse lymphomas in various tissues. These aggressive and diffuse lymphomas were similar to Ritcher's transformation of human CLL. The cell surface antigens of the spleen and peritoneal resident cells were analyzed by flow cytometry. The CLL-RT cells constantly expressed surface immunoglobulins M and G, and CD5, CD19, B220, and CD40 molecules. They did not express any CD11b, CD3, MAC-3, CD23, NK1.1, or H-2K(d) molecules. CONCLUSIONS The characteristics of our animal model are very similar to human CLL. This animal system could be an ideal model for the human disease. We believe the animal model would be valuable in therapeutic studies and aid in the identification of the specific genetic alleles associated with the disease.
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MESH Headings
- Animals
- Cell Transformation, Neoplastic
- Disease Models, Animal
- Female
- Humans
- Immunohistochemistry
- Interleukin-10/analysis
- Leukemia, Lymphocytic, Chronic, B-Cell/blood
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/physiopathology
- Leukocyte Count
- Lymphocytes/immunology
- Lymphocytes/pathology
- Mice
- Mice, SCID
- Neoplasm Transplantation
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Affiliation(s)
- Y C Su
- Laboratory Animal Center, National Taiwan University, Taipei, Republic of China
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47
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Abstract
Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.
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MESH Headings
- Animals
- Autoimmune Diseases/genetics
- Autoimmune Diseases/immunology
- Clinical Trials as Topic
- Clinical Trials, Phase II as Topic
- Dendritic Cells/immunology
- Diabetes Mellitus, Type 1/immunology
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Gene Expression Regulation
- Herpesviridae/physiology
- Humans
- Infections
- Inflammation
- Interleukin-10/genetics
- Interleukin-10/physiology
- Interleukin-10/therapeutic use
- Lupus Erythematosus, Systemic/genetics
- Lupus Erythematosus, Systemic/immunology
- Lymphocyte Subsets/immunology
- Mice
- Mice, Inbred NOD
- Mice, Inbred NZB
- Mice, Knockout
- Neoplasms/immunology
- Neutrophils/immunology
- Primates
- Protein-Tyrosine Kinases/physiology
- Receptors, Interleukin/genetics
- Receptors, Interleukin/physiology
- Receptors, Interleukin-10
- Signal Transduction
- Transcription Factors/physiology
- Transcription, Genetic
- Viral Proteins/physiology
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Affiliation(s)
- K W Moore
- Department of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304, USA.
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48
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Abstract
Interleukin (IL-)2 and its receptor (IL-2R) constitute one of the most extensively studied cytokine receptor systems. IL-2 is produced primarily by activated T cells and is involved in early T cell activation as well as in maintaining homeostatic immune responses that prevent autoimmunity. This review focuses on molecular signaling pathways triggered by the IL-2/IL-2R complex, with an emphasis on how the IL-2R physically translates its interaction with IL-2 into a coherent biological outcome. The IL-2R is composed of three subunits, IL-2Ralpha, IL-2Rbeta and gammac. Although IL-2Ralpha is an important affinity modulator that is essential for proper responses in vivo, it does not contribute to signaling due a short cytoplasmic tail. In contrast, IL-2Rbeta and gammac together are necessary and sufficient for effective signal transduction, and they serve physically to connect the receptor complex to cytoplasmic signaling intermediates. Despite an absolute requirement for gammac in signaling, the majority of known pathways physically link to the receptor via IL-2Rbeta, generally through phosphorylated cytoplasmic tyrosine residues. This review highlights work performed both in cultured cells and in vivo that defines the functional contributions of specific receptor subdomains-and, by inference, the specific signaling pathways that they activate-to IL-2-dependent biological activities.
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Affiliation(s)
- S L Gaffen
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY14214, USA.
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49
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Abstract
Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.
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Affiliation(s)
- Kevin W. Moore
- Departments of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Pharmacology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Immunology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304;,
| | - Rene de Waal Malefyt
- Departments of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Pharmacology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Immunology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304;,
| | - Robert L. Coffman
- Departments of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Pharmacology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Immunology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304;,
| | - Anne O'Garra
- Departments of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Pharmacology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304
- Departments of Immunology, DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304;,
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50
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Jego G, Bataille R, Pellat-Deceunynck C. Interleukin-6 is a growth factor for nonmalignant human plasmablasts. Blood 2001; 97:1817-22. [PMID: 11238125 DOI: 10.1182/blood.v97.6.1817] [Citation(s) in RCA: 142] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Interleukin-6 (IL-6), although often regarded as a B-cell differentiation factor, was recently described as the essential survival factor for human plasmablasts in vivo in reactive plasmacytosis. The present study reinvestigated the roles of IL-6 and IL-2 in the generation of plasma cells from human memory B cells in vitro. The cells involved in this differentiation process were identified as preplasmablasts (CD20+/-CD38+/-CD138-), plasmablasts (CD20-CD38++CD138-), and early plasma cells (CD20-CD38+++CD138+++). IL-2 or IL-10 induced a strong generation of plasmablasts and early plasma cells (PCs). Compared to IL-2 or IL-10, IL-6 alone was inefficient at PC generation. However, when combined with IL-2 or IL-10, IL-6 enhanced generation of early PCs. Moreover, anti-IL-6 monoclonal antibody markedly reduced IL-2-induced generation of early plasma cells, but not of plasmablasts. These roles of IL-2 and IL-6 were consistent with the difference in the expression of their respective receptors (R). CD25 (IL-2Ralpha) was increased 72 +/- 10-fold on activated B cells, but decreased and then disappeared on plasmablasts. Conversely, CD126 (IL-6Ralpha) was barely expressed on activated B cells, but increased 18 +/- 2-fold on preplasmablasts. Finally, IL-6 enhanced the proliferation (2-fold increase) of IL-2-generated plasmablasts. In conclusion, the data indicate that IL-6 is a growth factor for nonmalignant human plasmablasts.
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Affiliation(s)
- G Jego
- Institut National de la Santé et de la Recherche Médicale U463 and Laboratoire d'Hématologie, Institut de Biologie, Nantes, France
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