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PMID: 26206937 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.

Science (New York, N.Y.) ·Vol. 349 ·No. 6246 ·2015-07-24 ·Pages 436-40

Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R, Husami A, Kissell D, Nortman S, Chaturvedi V, Haines H, Young LR, Mo J, Filipovich AH, Bleesing JJ, Mustillo P, Stephens M, Rueda CM, Chougnet CA, Hoebe K, McElwee J, Hughes JD, Karakoc-Aydiner E, Matthews HF, Price S, Su HC, Rao VK, Lenardo MJ, Jordan MB

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.

MeSH Terms
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
Chemicals
Adaptor Proteins, Signal Transducing CTLA-4 Antigen FOXP3 protein, human Forkhead Transcription Factors Immunoconjugates Abatacept Chloroquine LRBA protein, human
Authors & Affiliations
33 authors, click to expand affiliations / ORCID
Lo Bernice
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.
Zhang Kejian
Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. michael.jordan@cchmc.org.
Lu Wei
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.
Zheng Lixin
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.
Zhang Qian
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.
Kanellopoulou Chrysi
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.
Zhang Yu
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.
Liu Zhiduo
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Fritz Jill M
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.
Marsh Rebecca
Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Husami Ammar
Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Kissell Diane
Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Nortman Shannon
Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Chaturvedi Vijaya
Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Haines Hilary
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, AL, USA.
Young Lisa R
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.
Mo Jun
Departments of Pathology and Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA, USA.
Filipovich Alexandra H
Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Bleesing Jack J
Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Mustillo Peter
Section of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA.
Stephens Michael
Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
Rueda Cesar M
Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.
Chougnet Claire A
Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.
Hoebe Kasper
Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center/ University of Cincinnati, Cincinnati, OH, USA.
McElwee Joshua
Merck Research Laboratories, Merck & Co, Boston, MA, USA.
Hughes Jason D
Merck Research Laboratories, Merck & Co, Boston, MA, USA.
Karakoc-Aydiner Elif
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.
Matthews Helen F
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.
Price Susan
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.
Su Helen C
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.
Rao V Koneti
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.
Lenardo Michael J
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.
Jordan Michael B
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.
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
Published
2015-07-24
Pages
436-40
Language
English
Region
United States
NLM ID
0404511
Subset
IM
Grants
NHGRI NIH HHS · 1RC2 HG005608 · United States
PHS HHS · 1ZIAAI000769-14 · United States
Intramural NIH HHS · United States
Corrections
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