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  • 1
    Publication Date: 2011-07-29
    Description: The magnesium ion, Mg(2+), is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a part in intracellular signalling (as Ca(2+) does) is unknown. Here we identify mutations in the magnesium transporter gene, MAGT1, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. We demonstrate that a rapid transient Mg(2+) influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg(2+) influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase Cgamma1 and a markedly impaired Ca(2+) influx in T cells but not B cells. These observations reveal a role for Mg(2+) as an intracellular second messenger coupling cell-surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159560/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159560/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Feng-Yen -- Chaigne-Delalande, Benjamin -- Kanellopoulou, Chrysi -- Davis, Jeremiah C -- Matthews, Helen F -- Douek, Daniel C -- Cohen, Jeffrey I -- Uzel, Gulbu -- Su, Helen C -- Lenardo, Michael J -- ZIA AI000769-14/Intramural NIH HHS/ -- ZIA AI000769-15/Intramural NIH HHS/ -- England -- Nature. 2011 Jul 27;475(7357):471-6. doi: 10.1038/nature10246.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21796205" target="_blank"〉PubMed〈/a〉
    Keywords: Calcium/immunology ; Cation Transport Proteins/genetics ; Female ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Magnesium/*immunology ; Male ; Phospholipase C gamma/genetics/metabolism ; Second Messenger Systems/*immunology ; T-Lymphocytes/*immunology ; T-Lymphocytopenia, Idiopathic CD4-Positive/genetics/*immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-07-13
    Description: The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg(2+)) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg(2+) causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8(+) T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg(2+) and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg(2+) in eukaryotic cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894782/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894782/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chaigne-Delalande, Benjamin -- Li, Feng-Yen -- O'Connor, Geraldine M -- Lukacs, Marshall J -- Jiang, Ping -- Zheng, Lixin -- Shatzer, Amber -- Biancalana, Matthew -- Pittaluga, Stefania -- Matthews, Helen F -- Jancel, Timothy J -- Bleesing, Jack J -- Marsh, Rebecca A -- Kuijpers, Taco W -- Nichols, Kim E -- Lucas, Carrie L -- Nagpal, Sunil -- Mehmet, Huseyin -- Su, Helen C -- Cohen, Jeffrey I -- Uzel, Gulbu -- Lenardo, Michael J -- T32 GM007618/GM/NIGMS NIH HHS/ -- ZIA AI001187-01/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 Jul 12;341(6142):186-91. doi: 10.1126/science.1240094.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Development of the Immune System Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23846901" target="_blank"〉PubMed〈/a〉
    Keywords: CD8-Positive T-Lymphocytes/*immunology ; Cation Transport Proteins/genetics/metabolism ; *Cytotoxicity, Immunologic ; Epstein-Barr Virus Infections/*immunology ; Humans ; Killer Cells, Natural/*immunology ; Magnesium/*immunology ; Magnesium Deficiency/*immunology ; NK Cell Lectin-Like Receptor Subfamily K/genetics/*metabolism ; X-Linked Combined Immunodeficiency Diseases/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-09-13
    Description: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371526/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371526/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kuehn, Hye Sun -- Ouyang, Weiming -- Lo, Bernice -- Deenick, Elissa K -- Niemela, Julie E -- Avery, Danielle T -- Schickel, Jean-Nicolas -- Tran, Dat Q -- Stoddard, Jennifer -- Zhang, Yu -- Frucht, David M -- Dumitriu, Bogdan -- Scheinberg, Phillip -- Folio, Les R -- Frein, Cathleen A -- Price, Susan -- Koh, Christopher -- Heller, Theo -- Seroogy, Christine M -- Huttenlocher, Anna -- Rao, V Koneti -- Su, Helen C -- Kleiner, David -- Notarangelo, Luigi D -- Rampertaap, Yajesh -- Olivier, Kenneth N -- McElwee, Joshua -- Hughes, Jason -- Pittaluga, Stefania -- Oliveira, Joao B -- Meffre, Eric -- Fleisher, Thomas A -- Holland, Steven M -- Lenardo, Michael J -- Tangye, Stuart G -- Uzel, Gulbu -- 5R01HL113304-01/HL/NHLBI NIH HHS/ -- AI061093/AI/NIAID NIH HHS/ -- AI071087/AI/NIAID NIH HHS/ -- AI095848/AI/NIAID NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- P01 AI061093/AI/NIAID NIH HHS/ -- R01 AI071087/AI/NIAID NIH HHS/ -- R01 HL113304/HL/NHLBI NIH HHS/ -- R21 AI095848/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1623-7. doi: 10.1126/science.1255904. Epub 2014 Sep 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov. ; Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov. ; Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov. ; Immunology and Immunodeficiency Group, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia. ; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. ; Immunology and Immunodeficiency Group, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. ; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA. ; Department of Pediatrics, University of Texas Medical School, Houston, TX 77030, USA. ; NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. ; Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA. ; Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA. ; Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. ; Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. ; Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. ; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA. ; Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA. ; Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA. Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA. ; Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA. ; Division of Immunology and Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA 10217, USA. ; Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. ; Merck Research Laboratories, Merck & Co., Boston, MA 02130, USA. ; Instituto de Medicina Integral Prof. Fernando Figueira-IMIP, 50070 Recife-PE, Brazil. ; NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. ; Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25213377" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; B-Lymphocytes/immunology ; CTLA-4 Antigen/*genetics ; Female ; Forkhead Transcription Factors/immunology ; *Germ-Line Mutation ; *Haploinsufficiency ; Humans ; Immune System Diseases/*genetics ; Immunity/*genetics ; Male ; Mice ; Mice, Mutant Strains ; Pedigree ; T-Lymphocytes, Regulatory/immunology ; Young Adult
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-07-25
    Description: Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lo, Bernice -- Zhang, Kejian -- Lu, Wei -- Zheng, Lixin -- Zhang, Qian -- Kanellopoulou, Chrysi -- Zhang, Yu -- Liu, Zhiduo -- Fritz, Jill M -- Marsh, Rebecca -- Husami, Ammar -- Kissell, Diane -- Nortman, Shannon -- Chaturvedi, Vijaya -- Haines, Hilary -- Young, Lisa R -- Mo, Jun -- Filipovich, Alexandra H -- Bleesing, Jack J -- Mustillo, Peter -- Stephens, Michael -- Rueda, Cesar M -- Chougnet, Claire A -- Hoebe, Kasper -- McElwee, Joshua -- Hughes, Jason D -- Karakoc-Aydiner, Elif -- Matthews, Helen F -- Price, Susan -- Su, Helen C -- Rao, V Koneti -- Lenardo, Michael J -- Jordan, Michael B -- 1RC2 HG005608/HG/NHGRI NIH HHS/ -- 1ZIAAI000769-14/PHS HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 24;349(6246):436-40. doi: 10.1126/science.aaa1663.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Development of the Immune System Section and Clinical and Molecular Genomics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. michael.jordan@cchmc.org. ; Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. michael.jordan@cchmc.org. ; Molecular Development of the Immune System Section and Clinical and Molecular Genomics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Human Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. ; Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. ; Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, AL, USA. ; Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, and Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. ; Departments of Pathology and Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA, USA. ; Section of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA. ; Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA. ; Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA. ; Merck Research Laboratories, Merck & Co, Boston, MA, USA. ; Molecular Development of the Immune System Section and Clinical and Molecular Genomics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. Human Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, AL, USA. Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, and Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. Departments of Pathology and Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA, USA. Section of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA. Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA. Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA. Merck Research Laboratories, Merck & Co, Boston, MA, USA. Marmara University, Division of Pediatric Allergy and Immunology, Istanbul, Turkey. ; Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA. michael.jordan@cchmc.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26206937" target="_blank"〉PubMed〈/a〉
    Keywords: Abatacept ; Adaptor Proteins, Signal Transducing/genetics/*metabolism ; Adolescent ; Autoimmune Diseases/*drug therapy/metabolism ; CTLA-4 Antigen/*deficiency/genetics ; Child ; Chloroquine/pharmacology ; Common Variable Immunodeficiency/*drug therapy/metabolism ; Endosomes/metabolism ; Female ; Forkhead Transcription Factors/analysis ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Immunoconjugates/*therapeutic use ; Lung Diseases, Interstitial/drug therapy/metabolism ; Lymphocyte Activation ; Lysosomes/metabolism ; Male ; Proteolysis ; T-Lymphocytes/drug effects/immunology ; Young Adult
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 9 (1991), S. 373-398 
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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