Clinical and functional spectrum of RAC2-related immunodeficiency.

Autor: Donkó Á; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Sharapova SO; Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus., Kabat J; Research Technologies Branch, Biological Imaging Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Ganesan S; Research Technologies Branch, Biological Imaging Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Hauck FH; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Bergerson JRE; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Marois L; Department of Medicine, Centre Hospitalier Universitaire de Montréal and Institut de Recherches Cliniques de Montréal, Université de Montréal, Montreal, QC, Canada.; Department of Medecine, Centre Hospitalier Universitaire de Québec, Université de Laval, Québec, QC, Canada., Abbott J; University of Colorado School of Medicine, Department of Pediatrics, Section of Allergy and Immunology, Children's Hospital of Colorado, Aurora, CO., Moshous D; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris Centre Université de Paris, Paris, France.; Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, INSERM UMR 1163, Paris, France., Williams KW; Department of Pediatrics, Medical University of South Carolina, Charleston, SC., Campbell N; Hôpital Enfant Jésus, CHU de Québec, Québec, QC, Canada., Martin PL; Division of Transplant and Cellular Therapy, Duke University Medical School, Durham, NC., Lagresle-Peyrou C; Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France., Trojan T; Allergy Partners of Oklahama, Stillwater, OK., Kuzmenko NB; D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Deordieva EA; D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Raykina EV; D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Abers MS; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Abolhassani H; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.; Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran., Barlogis V; Pediatric Hematology Unit, La Timone University Hospital, Marseille, France., Milla C; Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA., Hall G; Department of Pediatrics, Division of Pediatric Allergy and Immunology, Duke University Medical Center, Durham, NC., Mousallem T; Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC., Church J; Pediatric Allergy/Immunology, Children's Hospital Los Angeles, Los Angeles, CA.; Clinical Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA., Kapoor N; Division of Hematology, Oncology and Blood and Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA., Cros G; Department of Medicine, Université de Montreal, Montreal, QC, Canada.; Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada., Chapdelaine H; Department of Medicine, Université de Montreal, Montreal, QC, Canada.; Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada., Franco-Jarava C; Department of Immunology, Hospital Universitari Vall d'Hebron, Barcelona, Spain., Lopez-Lerma I; Department of Immunology, Hospital Universitari Vall d'Hebron, Barcelona, Spain., Miano M; Haematology Unit, Scientific Institute for Research, Hospitalization and Healthcare Istituto Giannina Gaslini, Genoa, Italy., Leiding JW; Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD.; Institute for Clinical and Translational Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL., Klein C; Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University Munich, Munich, Germany., Stasia MJ; Centre Hospitalier Universitaire Grenoble Alpes, Pôle de Biologie, Centre Diagnostic et Recherche sur la Granulomatose Septique Chronique, Grenoble, France.; Université Grenoble Alpes, Centre National de le Recherche Scientifique, CEA, UMR5075, Institut de Biologie Structurale, Grenoble, France., Fischer A; Université Paris Cité, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France., Hsiao KC; Department of Immunology, Starship Child Health, Te Whatu Ora, Auckland, New Zealand.; Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand., Martelius T; Inflammation Center/Infectious Diseases, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland., Seppänen MRJ; Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.; ERN-RITA Core Center Member, RITAFIN, Helsinki, Finland.; Rare Disease Center and Pediatric Research Center, Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.; Translational Immunology Research Program, University of Helsinki, Helsinki, Finland., Barmettler S; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA., Walter J; University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL., Masmas TN; Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, The Child and Adolescent Department, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Mukhina AA; D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Falcone EL; Center for Inflammation, Immunity and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada.; Department of Medicine, Université de Montréal, Montreal, QC, Canada.; Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada., Kracker S; Université Paris Cité, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France., Shcherbina A; D. Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Holland SM; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Leto TL; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Hsu AP; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Jazyk: angličtina
Zdroj: Blood [Blood] 2024 Apr 11; Vol. 143 (15), pp. 1476-1487.
DOI: 10.1182/blood.2023022098
Abstrakt: Abstract: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.
Databáze: MEDLINE