Format

Send to:

Choose Destination
See comment in PubMed Commons below
Science. 2014 Sep 26;345(6204):1623-7. doi: 10.1126/science.1255904. Epub 2014 Sep 11.

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.

Author information

  • 1Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov.
  • 2Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov.
  • 3Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov.
  • 4Immunology and Immunodeficiency Group, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia.
  • 5Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
  • 6Immunology and Immunodeficiency Group, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
  • 7Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
  • 8Department of Pediatrics, University of Texas Medical School, Houston, TX 77030, USA.
  • 9NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
  • 10Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA.
  • 11Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
  • 12Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
  • 13Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 14Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
  • 15Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
  • 16Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA.
  • 17Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA. Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA.
  • 18Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
  • 19Division of Immunology and Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA 10217, USA.
  • 20Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
  • 21Merck Research Laboratories, Merck & Co., Boston, MA 02130, USA.
  • 22Instituto de Medicina Integral Prof. Fernando Figueira-IMIP, 50070 Recife-PE, Brazil.
  • 23NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
  • 24Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. tfleishe@cc.nih.gov lenardo@nih.gov guzel@niaid.nih.gov.

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.

Copyright © 2014, American Association for the Advancement of Science.

PMID:
25213377
[PubMed - indexed for MEDLINE]
PMCID:
PMC4371526
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk