Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections
| Autor: | Emmanuelle Jouanguy, Annick Lim, James G. Krueger, Gérard Orth, Stuart G. Tangye, Claire Fieschi, Monika Schmidt, Vincent Pedergnana, Avinash Abhyankar, Capucine Picard, Anja Troeger, Ingrid Mueller-Fleckenstein, Amandine Crequer, Laure Gineau, Jean-Laurent Casanova, Etienne Patin, David A. Williams, Laurent Abel, Alain Taïeb, Cindy S. Ma |
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| Přispěvatelé: | St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Université Paris Descartes - Paris 5 (UPD5), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Dana-Farber Cancer Institute [Boston], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of New South Wales [Sydney] (UNSW), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale, Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris] (IP), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Herrada, Anthony |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
rho GTP-Binding Proteins
MESH: Signal Transduction Integrins MESH: Sequence Analysis DNA T-Lymphocytes [SDV]Life Sciences [q-bio] MESH: Base Sequence medicine.disease_cause MESH: Mice Knockout MESH: Genotype Consanguinity Mice MESH: Animals MESH: Codon Nonsense Mice Knockout Mutation MESH: Polymorphism Single Nucleotide Genetic disorder MESH: Integrins MESH: Receptors Antigen T-Cell General Medicine MESH: Transcription Factors MESH: Epidermodysplasia Verruciformis MESH: Case-Control Studies Pedigree [SDV] Life Sciences [q-bio] Haematopoiesis medicine.anatomical_structure Codon Nonsense Disease Susceptibility Stem cell Signal Transduction Research Article Adult MESH: Lymphocyte Count Genotype MESH: Pedigree T cell Receptors Antigen T-Cell MESH: Disease Susceptibility Biology MESH: Betapapillomavirus Polymorphism Single Nucleotide Antigen medicine Animals Betapapillomavirus Humans Lymphocyte Count MESH: Mice MESH: Consanguinity MESH: Humans Base Sequence MESH: Adult Sequence Analysis DNA Epidermodysplasia verruciformis medicine.disease MESH: rho GTP-Binding Proteins T cell deficiency MESH: T-Lymphocytes Case-Control Studies Epidermodysplasia Verruciformis Immunology MESH: Genome-Wide Association Study Genome-Wide Association Study Transcription Factors |
| Zdroj: | Journal of Clinical Investigation Journal of Clinical Investigation, 2012, 122 (9), pp.3239-3247. ⟨10.1172/JCI62949⟩ |
| ISSN: | 0021-9738 |
| Popis: | International audience; Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh-/- hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections. |
| Databáze: | OpenAIRE |
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