Publikationsdatum:
2015-07-25
Beschreibung:
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〉
Schlagwort(e):
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
Digitale ISSN:
1095-9203
Thema:
Biologie
,
Chemie und Pharmazie
,
Informatik
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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