title: AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.
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.
authors.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.
authors.forename: Bernice
authors.initials: B
authors.lastname: Lo
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. michael.jordan@cchmc.org.
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.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.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.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.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.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.
authors.forename: Chrysi
authors.initials: C
authors.lastname: Kanellopoulou
authors.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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zhiduo
authors.initials: Z
authors.lastname: Liu
authors.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.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Fritz
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marsh
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Ammar
authors.initials: A
authors.lastname: Husami
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Kissell
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Nortman
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Chaturvedi
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, AL, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Haines
authors.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.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.affiliation: Departments of Pathology and Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Mo
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Filipovich
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Bleesing
authors.affiliation: Section of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Mustillo
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Stephens
authors.affiliation: Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Cesar M
authors.initials: CM
authors.lastname: Rueda
authors.affiliation: Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.affiliation: Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
authors.affiliation: Merck Research Laboratories, Merck & Co, Boston, MA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: McElwee
authors.affiliation: Merck Research Laboratories, Merck & Co, Boston, MA, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Hughes
authors.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.
authors.forename: Elif
authors.initials: E
authors.lastname: Karakoc-Aydiner
authors.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.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.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.
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.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.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.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.
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.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.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jordan
mesh_terms: D000069594:Abatacept; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000172:deficiency* / Q000235:genetics; D002648:Child; D002738:Chloroquine / Q000494:pharmacology; D017074:Common Variable Immunodeficiency / Q000188:drug therapy* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D017563:Lung Diseases, Interstitial / Q000188:drug therapy / Q000378:metabolism; D008213:Lymphocyte Activation; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D059748:Proteolysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018796:Immunoconjugates; D000069594:Abatacept; D002738:Chloroquine; C428703:LRBA protein, human