AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.
Identifieur interne : 000241 ( PubMed/Corpus ); précédent : 000240; suivant : 000242AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.
Auteurs : Bernice Lo ; Kejian Zhang ; Wei Lu ; Lixin Zheng ; Qian Zhang ; Chrysi Kanellopoulou ; Yu Zhang ; Zhiduo Liu ; Jill M. Fritz ; Rebecca Marsh ; Ammar Husami ; Diane Kissell ; Shannon Nortman ; Vijaya Chaturvedi ; Hilary Haines ; Lisa R. Young ; Jun Mo ; Alexandra H. Filipovich ; Jack J. Bleesing ; Peter Mustillo ; Michael Stephens ; Cesar M. Rueda ; Claire A. Chougnet ; Kasper Hoebe ; Joshua Mcelwee ; Jason D. Hughes ; Elif Karakoc-Aydiner ; Helen F. Matthews ; Susan Price ; Helen C. Su ; V Koneti Rao ; Michael J. Lenardo ; Michael B. JordanSource :
- Science (New York, N.Y.) [ 1095-9203 ] ; 2015.
English descriptors
- KwdEn :
- Abatacept, Adaptor Proteins, Signal Transducing (genetics), Adaptor Proteins, Signal Transducing (metabolism), Adolescent, Autoimmune Diseases (drug therapy), Autoimmune Diseases (metabolism), CTLA-4 Antigen (deficiency), CTLA-4 Antigen (genetics), Child, Chloroquine (pharmacology), Common Variable Immunodeficiency (drug therapy), Common Variable Immunodeficiency (metabolism), Endosomes (metabolism), Female, Forkhead Transcription Factors (analysis), Gene Knockdown Techniques, HEK293 Cells, Humans, Immunoconjugates (therapeutic use), Lung Diseases, Interstitial (drug therapy), Lung Diseases, Interstitial (metabolism), Lymphocyte Activation, Lysosomes (metabolism), Male, Proteolysis, T-Lymphocytes (drug effects), T-Lymphocytes (immunology), Young Adult.
- MESH :
- chemical , analysis : Forkhead Transcription Factors.
- chemical , deficiency : CTLA-4 Antigen.
- chemical , genetics : Adaptor Proteins, Signal Transducing, CTLA-4 Antigen.
- chemical , metabolism : Adaptor Proteins, Signal Transducing.
- chemical , pharmacology : Chloroquine.
- chemical , therapeutic use : Immunoconjugates.
- chemical : Abatacept.
- drug effects : T-Lymphocytes.
- drug therapy : Autoimmune Diseases, Common Variable Immunodeficiency, Lung Diseases, Interstitial.
- immunology : T-Lymphocytes.
- metabolism : Autoimmune Diseases, Common Variable Immunodeficiency, Endosomes, Lung Diseases, Interstitial, Lysosomes.
- Adolescent, Child, Female, Gene Knockdown Techniques, HEK293 Cells, Humans, Lymphocyte Activation, Male, Proteolysis, Young Adult.
Abstract
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.
DOI: 10.1126/science.aaa1663
PubMed: 26206937
Links to Exploration step
pubmed:26206937Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.</title><author><name sortKey="Lo, Bernice" sort="Lo, Bernice" uniqKey="Lo B" first="Bernice" last="Lo">Bernice Lo</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Kejian" sort="Zhang, Kejian" uniqKey="Zhang K" first="Kejian" last="Zhang">Kejian Zhang</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. michael.jordan@cchmc.org.</nlm:affiliation></affiliation></author><author><name sortKey="Lu, Wei" sort="Lu, Wei" uniqKey="Lu W" first="Wei" last="Lu">Wei Lu</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zheng, Lixin" sort="Zheng, Lixin" uniqKey="Zheng L" first="Lixin" last="Zheng">Lixin Zheng</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Qian" sort="Zhang, Qian" uniqKey="Zhang Q" first="Qian" last="Zhang">Qian Zhang</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Kanellopoulou, Chrysi" sort="Kanellopoulou, Chrysi" uniqKey="Kanellopoulou C" first="Chrysi" last="Kanellopoulou">Chrysi Kanellopoulou</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Yu" sort="Zhang, Yu" uniqKey="Zhang Y" first="Yu" last="Zhang">Yu Zhang</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Zhiduo" sort="Liu, Zhiduo" uniqKey="Liu Z" first="Zhiduo" last="Liu">Zhiduo Liu</name><affiliation><nlm:affiliation>Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Fritz, Jill M" sort="Fritz, Jill M" uniqKey="Fritz J" first="Jill M" last="Fritz">Jill M. Fritz</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Marsh, Rebecca" sort="Marsh, Rebecca" uniqKey="Marsh R" first="Rebecca" last="Marsh">Rebecca Marsh</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Husami, Ammar" sort="Husami, Ammar" uniqKey="Husami A" first="Ammar" last="Husami">Ammar Husami</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kissell, Diane" sort="Kissell, Diane" uniqKey="Kissell D" first="Diane" last="Kissell">Diane Kissell</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Nortman, Shannon" sort="Nortman, Shannon" uniqKey="Nortman S" first="Shannon" last="Nortman">Shannon Nortman</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chaturvedi, Vijaya" sort="Chaturvedi, Vijaya" uniqKey="Chaturvedi V" first="Vijaya" last="Chaturvedi">Vijaya Chaturvedi</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Haines, Hilary" sort="Haines, Hilary" uniqKey="Haines H" first="Hilary" last="Haines">Hilary Haines</name><affiliation><nlm:affiliation>Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, AL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Young, Lisa R" sort="Young, Lisa R" uniqKey="Young L" first="Lisa R" last="Young">Lisa R. Young</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Mo, Jun" sort="Mo, Jun" uniqKey="Mo J" first="Jun" last="Mo">Jun Mo</name><affiliation><nlm:affiliation>Departments of Pathology and Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Filipovich, Alexandra H" sort="Filipovich, Alexandra H" uniqKey="Filipovich A" first="Alexandra H" last="Filipovich">Alexandra H. Filipovich</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Bleesing, Jack J" sort="Bleesing, Jack J" uniqKey="Bleesing J" first="Jack J" last="Bleesing">Jack J. Bleesing</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mustillo, Peter" sort="Mustillo, Peter" uniqKey="Mustillo P" first="Peter" last="Mustillo">Peter Mustillo</name><affiliation><nlm:affiliation>Section of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Stephens, Michael" sort="Stephens, Michael" uniqKey="Stephens M" first="Michael" last="Stephens">Michael Stephens</name><affiliation><nlm:affiliation>Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rueda, Cesar M" sort="Rueda, Cesar M" uniqKey="Rueda C" first="Cesar M" last="Rueda">Cesar M. Rueda</name><affiliation><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chougnet, Claire A" sort="Chougnet, Claire A" uniqKey="Chougnet C" first="Claire A" last="Chougnet">Claire A. Chougnet</name><affiliation><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hoebe, Kasper" sort="Hoebe, Kasper" uniqKey="Hoebe K" first="Kasper" last="Hoebe">Kasper Hoebe</name><affiliation><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mcelwee, Joshua" sort="Mcelwee, Joshua" uniqKey="Mcelwee J" first="Joshua" last="Mcelwee">Joshua Mcelwee</name><affiliation><nlm:affiliation>Merck Research Laboratories, Merck & Co, Boston, MA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hughes, Jason D" sort="Hughes, Jason D" uniqKey="Hughes J" first="Jason D" last="Hughes">Jason D. Hughes</name><affiliation><nlm:affiliation>Merck Research Laboratories, Merck & Co, Boston, MA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Karakoc Aydiner, Elif" sort="Karakoc Aydiner, Elif" uniqKey="Karakoc Aydiner E" first="Elif" last="Karakoc-Aydiner">Elif Karakoc-Aydiner</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Matthews, Helen F" sort="Matthews, Helen F" uniqKey="Matthews H" first="Helen F" last="Matthews">Helen F. Matthews</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Price, Susan" sort="Price, Susan" uniqKey="Price S" first="Susan" last="Price">Susan Price</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Su, Helen C" sort="Su, Helen C" uniqKey="Su H" first="Helen C" last="Su">Helen C. Su</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Rao, V Koneti" sort="Rao, V Koneti" uniqKey="Rao V" first="V Koneti" last="Rao">V Koneti Rao</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Lenardo, Michael J" sort="Lenardo, Michael J" uniqKey="Lenardo M" first="Michael J" last="Lenardo">Michael J. Lenardo</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Jordan, Michael B" sort="Jordan, Michael B" uniqKey="Jordan M" first="Michael B" last="Jordan">Michael B. Jordan</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26206937</idno><idno type="pmid">26206937</idno><idno type="doi">10.1126/science.aaa1663</idno><idno type="wicri:Area/PubMed/Corpus">000241</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000241</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.</title><author><name sortKey="Lo, Bernice" sort="Lo, Bernice" uniqKey="Lo B" first="Bernice" last="Lo">Bernice Lo</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Kejian" sort="Zhang, Kejian" uniqKey="Zhang K" first="Kejian" last="Zhang">Kejian Zhang</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. michael.jordan@cchmc.org.</nlm:affiliation></affiliation></author><author><name sortKey="Lu, Wei" sort="Lu, Wei" uniqKey="Lu W" first="Wei" last="Lu">Wei Lu</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zheng, Lixin" sort="Zheng, Lixin" uniqKey="Zheng L" first="Lixin" last="Zheng">Lixin Zheng</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Qian" sort="Zhang, Qian" uniqKey="Zhang Q" first="Qian" last="Zhang">Qian Zhang</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Kanellopoulou, Chrysi" sort="Kanellopoulou, Chrysi" uniqKey="Kanellopoulou C" first="Chrysi" last="Kanellopoulou">Chrysi Kanellopoulou</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Yu" sort="Zhang, Yu" uniqKey="Zhang Y" first="Yu" last="Zhang">Yu Zhang</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Zhiduo" sort="Liu, Zhiduo" uniqKey="Liu Z" first="Zhiduo" last="Liu">Zhiduo Liu</name><affiliation><nlm:affiliation>Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Fritz, Jill M" sort="Fritz, Jill M" uniqKey="Fritz J" first="Jill M" last="Fritz">Jill M. Fritz</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Marsh, Rebecca" sort="Marsh, Rebecca" uniqKey="Marsh R" first="Rebecca" last="Marsh">Rebecca Marsh</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Husami, Ammar" sort="Husami, Ammar" uniqKey="Husami A" first="Ammar" last="Husami">Ammar Husami</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kissell, Diane" sort="Kissell, Diane" uniqKey="Kissell D" first="Diane" last="Kissell">Diane Kissell</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Nortman, Shannon" sort="Nortman, Shannon" uniqKey="Nortman S" first="Shannon" last="Nortman">Shannon Nortman</name><affiliation><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chaturvedi, Vijaya" sort="Chaturvedi, Vijaya" uniqKey="Chaturvedi V" first="Vijaya" last="Chaturvedi">Vijaya Chaturvedi</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Haines, Hilary" sort="Haines, Hilary" uniqKey="Haines H" first="Hilary" last="Haines">Hilary Haines</name><affiliation><nlm:affiliation>Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, AL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Young, Lisa R" sort="Young, Lisa R" uniqKey="Young L" first="Lisa R" last="Young">Lisa R. Young</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Mo, Jun" sort="Mo, Jun" uniqKey="Mo J" first="Jun" last="Mo">Jun Mo</name><affiliation><nlm:affiliation>Departments of Pathology and Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Filipovich, Alexandra H" sort="Filipovich, Alexandra H" uniqKey="Filipovich A" first="Alexandra H" last="Filipovich">Alexandra H. Filipovich</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Bleesing, Jack J" sort="Bleesing, Jack J" uniqKey="Bleesing J" first="Jack J" last="Bleesing">Jack J. Bleesing</name><affiliation><nlm:affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mustillo, Peter" sort="Mustillo, Peter" uniqKey="Mustillo P" first="Peter" last="Mustillo">Peter Mustillo</name><affiliation><nlm:affiliation>Section of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Stephens, Michael" sort="Stephens, Michael" uniqKey="Stephens M" first="Michael" last="Stephens">Michael Stephens</name><affiliation><nlm:affiliation>Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rueda, Cesar M" sort="Rueda, Cesar M" uniqKey="Rueda C" first="Cesar M" last="Rueda">Cesar M. Rueda</name><affiliation><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chougnet, Claire A" sort="Chougnet, Claire A" uniqKey="Chougnet C" first="Claire A" last="Chougnet">Claire A. Chougnet</name><affiliation><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hoebe, Kasper" sort="Hoebe, Kasper" uniqKey="Hoebe K" first="Kasper" last="Hoebe">Kasper Hoebe</name><affiliation><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mcelwee, Joshua" sort="Mcelwee, Joshua" uniqKey="Mcelwee J" first="Joshua" last="Mcelwee">Joshua Mcelwee</name><affiliation><nlm:affiliation>Merck Research Laboratories, Merck & Co, Boston, MA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hughes, Jason D" sort="Hughes, Jason D" uniqKey="Hughes J" first="Jason D" last="Hughes">Jason D. Hughes</name><affiliation><nlm:affiliation>Merck Research Laboratories, Merck & Co, Boston, MA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Karakoc Aydiner, Elif" sort="Karakoc Aydiner, Elif" uniqKey="Karakoc Aydiner E" first="Elif" last="Karakoc-Aydiner">Elif Karakoc-Aydiner</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Matthews, Helen F" sort="Matthews, Helen F" uniqKey="Matthews H" first="Helen F" last="Matthews">Helen F. Matthews</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Price, Susan" sort="Price, Susan" uniqKey="Price S" first="Susan" last="Price">Susan Price</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Su, Helen C" sort="Su, Helen C" uniqKey="Su H" first="Helen C" last="Su">Helen C. Su</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Rao, V Koneti" sort="Rao, V Koneti" uniqKey="Rao V" first="V Koneti" last="Rao">V Koneti Rao</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Lenardo, Michael J" sort="Lenardo, Michael J" uniqKey="Lenardo M" first="Michael J" last="Lenardo">Michael J. Lenardo</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Jordan, Michael B" sort="Jordan, Michael B" uniqKey="Jordan M" first="Michael B" last="Jordan">Michael B. Jordan</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Science (New York, N.Y.)</title><idno type="eISSN">1095-9203</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Abatacept</term><term>Adaptor Proteins, Signal Transducing (genetics)</term><term>Adaptor Proteins, Signal Transducing (metabolism)</term><term>Adolescent</term><term>Autoimmune Diseases (drug therapy)</term><term>Autoimmune Diseases (metabolism)</term><term>CTLA-4 Antigen (deficiency)</term><term>CTLA-4 Antigen (genetics)</term><term>Child</term><term>Chloroquine (pharmacology)</term><term>Common Variable Immunodeficiency (drug therapy)</term><term>Common Variable Immunodeficiency (metabolism)</term><term>Endosomes (metabolism)</term><term>Female</term><term>Forkhead Transcription Factors (analysis)</term><term>Gene Knockdown Techniques</term><term>HEK293 Cells</term><term>Humans</term><term>Immunoconjugates (therapeutic use)</term><term>Lung Diseases, Interstitial (drug therapy)</term><term>Lung Diseases, Interstitial (metabolism)</term><term>Lymphocyte Activation</term><term>Lysosomes (metabolism)</term><term>Male</term><term>Proteolysis</term><term>T-Lymphocytes (drug effects)</term><term>T-Lymphocytes (immunology)</term><term>Young Adult</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Forkhead Transcription Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>CTLA-4 Antigen</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term><term>CTLA-4 Antigen</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Chloroquine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Immunoconjugates</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Abatacept</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>T-Lymphocytes</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Autoimmune Diseases</term><term>Common Variable Immunodeficiency</term><term>Lung Diseases, Interstitial</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>T-Lymphocytes</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Autoimmune Diseases</term><term>Common Variable Immunodeficiency</term><term>Endosomes</term><term>Lung Diseases, Interstitial</term><term>Lysosomes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Child</term><term>Female</term><term>Gene Knockdown Techniques</term><term>HEK293 Cells</term><term>Humans</term><term>Lymphocyte Activation</term><term>Male</term><term>Proteolysis</term><term>Young Adult</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26206937</PMID><DateCompleted><Year>2015</Year><Month>08</Month><Day>17</Day></DateCompleted><DateRevised><Year>2016</Year><Month>08</Month><Day>12</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1095-9203</ISSN><JournalIssue CitedMedium="Internet"><Volume>349</Volume><Issue>6246</Issue><PubDate><Year>2015</Year><Month>Jul</Month><Day>24</Day></PubDate></JournalIssue><Title>Science (New York, N.Y.)</Title><ISOAbbreviation>Science</ISOAbbreviation></Journal><ArticleTitle>AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.</ArticleTitle><Pagination><MedlinePgn>436-40</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1126/science.aaa1663</ELocationID><Abstract><AbstractText>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. </AbstractText><CopyrightInformation>Copyright © 2015, American Association for the Advancement of Science.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lo</LastName><ForeName>Bernice</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Kejian</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. michael.jordan@cchmc.org.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lu</LastName><ForeName>Wei</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zheng</LastName><ForeName>Lixin</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Qian</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kanellopoulou</LastName><ForeName>Chrysi</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Yu</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Zhiduo</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fritz</LastName><ForeName>Jill M</ForeName><Initials>JM</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marsh</LastName><ForeName>Rebecca</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Husami</LastName><ForeName>Ammar</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kissell</LastName><ForeName>Diane</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nortman</LastName><ForeName>Shannon</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chaturvedi</LastName><ForeName>Vijaya</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haines</LastName><ForeName>Hilary</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, AL, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Young</LastName><ForeName>Lisa R</ForeName><Initials>LR</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mo</LastName><ForeName>Jun</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Departments of Pathology and Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Filipovich</LastName><ForeName>Alexandra H</ForeName><Initials>AH</Initials><AffiliationInfo><Affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bleesing</LastName><ForeName>Jack J</ForeName><Initials>JJ</Initials><AffiliationInfo><Affiliation>Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mustillo</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Section of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stephens</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rueda</LastName><ForeName>Cesar M</ForeName><Initials>CM</Initials><AffiliationInfo><Affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chougnet</LastName><ForeName>Claire A</ForeName><Initials>CA</Initials><AffiliationInfo><Affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hoebe</LastName><ForeName>Kasper</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McElwee</LastName><ForeName>Joshua</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Merck Research Laboratories, Merck & Co, Boston, MA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hughes</LastName><ForeName>Jason D</ForeName><Initials>JD</Initials><AffiliationInfo><Affiliation>Merck Research Laboratories, Merck & Co, Boston, MA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Karakoc-Aydiner</LastName><ForeName>Elif</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Matthews</LastName><ForeName>Helen F</ForeName><Initials>HF</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Price</LastName><ForeName>Susan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Helen C</ForeName><Initials>HC</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rao</LastName><ForeName>V Koneti</ForeName><Initials>VK</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lenardo</LastName><ForeName>Michael J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jordan</LastName><ForeName>Michael B</ForeName><Initials>MB</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>1RC2 HG005608</GrantID><Acronym>HG</Acronym><Agency>NHGRI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>1ZIAAI000769-14</GrantID><Agency>PHS HHS</Agency><Country>United States</Country></Grant><Grant><Agency>Intramural NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D052060">Research Support, N.I.H., Intramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Science</MedlineTA><NlmUniqueID>0404511</NlmUniqueID><ISSNLinking>0036-8075</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D048868">Adaptor Proteins, Signal Transducing</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D060908">CTLA-4 Antigen</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C418974">FOXP3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051858">Forkhead Transcription Factors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018796">Immunoconjugates</NameOfSubstance></Chemical><Chemical><RegistryNumber>7D0YB67S97</RegistryNumber><NameOfSubstance UI="D000069594">Abatacept</NameOfSubstance></Chemical><Chemical><RegistryNumber>886U3H6UFF</RegistryNumber><NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.-</RegistryNumber><NameOfSubstance UI="C428703">LRBA protein, human</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>Science. 2015 Jul 24;349(6246):377-8</RefSource><PMID Version="1">26206917</PMID></CommentsCorrections><CommentsCorrections RefType="CommentIn"><RefSource>Oral Dis. 2016 May;22(4):249-50</RefSource><PMID Version="1">26847262</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000069594" MajorTopicYN="N">Abatacept</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D048868" MajorTopicYN="N">Adaptor Proteins, Signal Transducing</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000293" MajorTopicYN="N">Adolescent</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001327" MajorTopicYN="N">Autoimmune Diseases</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D060908" MajorTopicYN="N">CTLA-4 Antigen</DescriptorName><QualifierName UI="Q000172" MajorTopicYN="Y">deficiency</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002648" MajorTopicYN="N">Child</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName><QualifierName UI="Q000494" 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Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018796" MajorTopicYN="N">Immunoconjugates</DescriptorName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017563" MajorTopicYN="N">Lung Diseases, Interstitial</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008213" MajorTopicYN="N">Lymphocyte Activation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008247" MajorTopicYN="N">Lysosomes</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D059748" MajorTopicYN="N">Proteolysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013601" MajorTopicYN="N">T-Lymphocytes</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055815" MajorTopicYN="N">Young Adult</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>7</Month><Day>25</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>7</Month><Day>25</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>8</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26206937</ArticleId><ArticleId IdType="pii">349/6246/436</ArticleId><ArticleId IdType="doi">10.1126/science.aaa1663</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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