학술논문
Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency.
Document Type
Academic Journal
Author
Johnson MB; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; Ogishi M; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.; Domingo-Vila C; Department of Immunobiology, School of Immunology and Microbial Sciences, Kings College London, London, UK.; De Franco E; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; Wakeling MN; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; Imane Z; Faculty of Medicine and Pharmacy, Mohammed 5 University of Rabat , Rabat, Morocco.; Resnick B; National Institute for Health and Care Research Exeter Clinical Research Facility, Royal Devon University Healthcare NHS Foundation Trust , Exeter, UK.; Williams E; Department of Immunobiology, School of Immunology and Microbial Sciences, Kings College London, London, UK.; Galão RP; Department of Infectious Diseases, School of Immunobiology and Microbial Sciences, Kings College London, London, UK.; Caswell R; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; Russ-Silsby J; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; Seeleuthner Y; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 , Paris, France.; Imagine Institute, Paris Cité University , Paris, France.; Rinchai D; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.; Fagniez I; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.; Benson B; Center for Systems Immunology, Benaroya Research Institute , Seattle, WA, USA.; Dufort MJ; Center for Systems Immunology, Benaroya Research Institute , Seattle, WA, USA.; Speake C; Center for Interventional Immunology, Benaroya Research Institute , Seattle, WA, USA.; Smithmyer ME; Center for Interventional Immunology, Benaroya Research Institute , Seattle, WA, USA.; Hudson M; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; National Institute for Health and Care Research Exeter Clinical Research Facility, Royal Devon University Healthcare NHS Foundation Trust , Exeter, UK.; Dobbs R; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; National Institute for Health and Care Research Exeter Clinical Research Facility, Royal Devon University Healthcare NHS Foundation Trust , Exeter, UK.; Quandt Z; Endocrine Division, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.; Diabetes Center, University of California San Francisco , San Francisco, CA, USA.; Hattersley AT; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.; Zhang P; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.; Boisson-Dupuis S; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 , Paris, France.; Imagine Institute, Paris Cité University , Paris, France.; Anderson MS; Endocrine Division, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.; Diabetes Center, University of California San Francisco , San Francisco, CA, USA.; Casanova JL; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 , Paris, France.; Imagine Institute, Paris Cité University , Paris, France.; Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.; Howard Hughes Medical Institute , New York, NY, USA.; Tree TI; Department of Immunobiology, School of Immunology and Microbial Sciences, Kings College London, London, UK.; Oram RA; Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter , Exeter, UK.
Source
Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 2985109R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1540-9538 (Electronic) Linking ISSN: 00221007 NLM ISO Abbreviation: J Exp Med Subsets: MEDLINE
Subject
Language
English
Abstract
We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients' primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.
Competing Interests: Disclosures: C. Speake reported personal fees from Vertex Pharmaceuticals and GentiBio outside the submitted work. M.S. Anderson reported other from Merck, Inc. outside the submitted work. R.A. Oram reported grants from Randox, and personal fees from Sanofi, Provention Bio, and Janssen outside the submitted work; and that Randox are licensing knowhow relating to T1D polygenic scores from the University of Exeter. No other disclosures were reported.
(© 2024 Johnson et al.)
Competing Interests: Disclosures: C. Speake reported personal fees from Vertex Pharmaceuticals and GentiBio outside the submitted work. M.S. Anderson reported other from Merck, Inc. outside the submitted work. R.A. Oram reported grants from Randox, and personal fees from Sanofi, Provention Bio, and Janssen outside the submitted work; and that Randox are licensing knowhow relating to T1D polygenic scores from the University of Exeter. No other disclosures were reported.
(© 2024 Johnson et al.)