Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Hye Sun Kuehn; Weiming Ouyang; Bernice Lo; Elissa K Deenick; Julie E Niemela; Danielle T Avery; Jean-Nicolas Schickel; Dat Q Tran; Jennifer Stoddard; Yu Zhang; David M Frucht; Bogdan Dumitriu; Phillip Scheinberg; Les R Folio; Cathleen A Frein; Susan Price; Christopher Koh; Theo Heller; Christine M Seroogy; Anna Huttenlocher; V Koneti Rao; Helen C Su; David Kleiner; Luigi D Notarangelo; Yajesh Rampertaap; Kenneth N Olivier; Joshua McElwee; Jason Hughes; Stefania Pittaluga; Joao B Oliveira; Eric Meffre; Thomas A Fleisher; Steven M Holland; Michael J Lenardo; Stuart G Tangye; Gulbu Uzel

doi:10.1126/science.1255904

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Science. 2014 Sep 26;345(6204):1623-1627. doi: 10.1126/science.1255904. Epub 2014 Sep 11.

Authors

Hye Sun Kuehn^#¹, Weiming Ouyang^#², Bernice Lo^#^{3

4}, Elissa K Deenick^{5

6}, Julie E Niemela¹, Danielle T Avery⁵, Jean-Nicolas Schickel⁷, Dat Q Tran⁸, Jennifer Stoddard¹, Yu Zhang^{4

9}, David M Frucht², Bogdan Dumitriu¹⁰, Phillip Scheinberg¹⁰, Les R Folio¹¹, Cathleen A Frein¹², Susan Price^{3

4}, Christopher Koh¹³, Theo Heller¹³, Christine M Seroogy¹⁴, Anna Huttenlocher^{14

15}, V Koneti Rao^{3

4}, Helen C Su^{4

9}, David Kleiner¹⁶, Luigi D Notarangelo¹⁷, Yajesh Rampertaap¹⁸, Kenneth N Olivier¹⁸, Joshua McElwee¹⁹, Jason Hughes¹⁹, Stefania Pittaluga¹⁶, Joao B Oliveira²⁰, Eric Meffre⁷, Thomas A Fleisher¹, Steven M Holland^{4

18}, Michael J Lenardo^{3

4}, Stuart G Tangye^{5

6}, Gulbu Uzel¹⁸

Affiliations

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

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
B-Lymphocytes / immunology
CTLA-4 Antigen / genetics*
Female
Forkhead Transcription Factors / immunology
Germ-Line Mutation*
Haploinsufficiency*
Humans
Immune System Diseases / genetics*
Immunity / genetics*
Male
Mice
Mice, Mutant Strains
Pedigree
T-Lymphocytes, Regulatory / immunology
Young Adult

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

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