An essential role for the Zn 2+ transporter ZIP7 in B cell development.

Autor: Anzilotti C; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Swan DJ; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK., Boisson B; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163 Necker Hospital for Sick Children, Paris, France.; Paris Descartes University, Imagine Institute, Paris, France., Deobagkar-Lele M; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Oliveira C; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Chabosseau P; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College, London, UK., Engelhardt KR; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK., Xu X; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Chen R; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK., Alvarez L; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Berlinguer-Palmini R; Bioimaging Unit, Newcastle University Medical School, Newcastle upon Tyne, UK., Bull KR; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Cawthorne E; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Cribbs AP; MRC WIMM Centre for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Crockford TL; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Dang TS; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK., Fearn A; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Fenech EJ; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK., de Jong SJ; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA., Lagerholm BC; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Ma CS; Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Darlinghurst, New South Wales, Australia., Sims D; MRC WIMM Centre for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., van den Berg B; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Xu Y; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK., Cant AJ; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Kleiner G; Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA., Leahy TR; Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland., de la Morena MT; Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, USA., Puck JM; Department of Pediatrics, Division of Allergy, Immunology, and Blood and Bone Marrow Transplantation, University of California, San Francisco, CA, USA.; UCSF Benioff Children's Hospital, San Francisco, CA, USA., Shapiro RS; Midwest Immunology Clinic, Plymouth, MN, USA., van der Burg M; Department of Immunology, Erasmus University Medical Centre, Rotterdam, the Netherlands., Chapman JR; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Christianson JC; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK., Davies B; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., McGrath JA; St John's Institute of Dermatology, King's College London, London, UK., Przyborski S; Department of Biosciences, Durham University, Durham, UK., Santibanez Koref M; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK., Tangye SG; Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Darlinghurst, New South Wales, Australia., Werner A; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Rutter GA; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College, London, UK., Padilla-Parra S; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.; Dynamic Structural Virology Group, Biocruces Health Research Institute, Barakaldo, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain., Casanova JL; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163 Necker Hospital for Sick Children, Paris, France.; Paris Descartes University, Imagine Institute, Paris, France.; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.; Howard Hughes Medical Institute, New York, NY, USA., Cornall RJ; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. richard.cornall@ndm.ox.ac.uk., Conley ME; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. conley.maryellen@gmail.com., Hambleton S; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. sophie.hambleton@newcastle.ac.uk.; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. sophie.hambleton@newcastle.ac.uk.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2019 Mar; Vol. 20 (3), pp. 350-361. Date of Electronic Publication: 2019 Feb 04.
DOI: 10.1038/s41590-018-0295-8
Abstrakt: Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn 2+ in modulating B cell receptor signal strength and positive selection.
Databáze: MEDLINE