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DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity.
Boussard, Charlotte; Delage, Laure; Gajardo, Tania; Kauskot, Alexandre; Batignes, Maxime; Goudin, Nicolas; Stolzenberg, Marie-Claude; Brunaud, Camille; Panikulam, Patricia; Riller, Quentin; Moya-Nilges, Maryse; Solarz, Jean; Repérant, Christelle; Durel, Béatrice; Bordet, Jean-Claude; Pellé, Olivier; Lebreton, Corinne; Magérus, Aude; Pirabakaran, Vithura; Vargas, Pablo; Dupichaud, Sébastien; Jeanpierre, Marie; Vinit, Angélique; Zarhrate, Mohammed; Masson, Cécile; Aladjidi, Nathalie; Arkwright, Peter D; Bader-Meunier, Brigitte; Baron Joly, Sandrine; Benadiba, Joy; Bernard, Elise; Berrebi, Dominique; Bodemer, Christine; Castelle, Martin; Charbit-Henrion, Fabienne; Chbihi, Marwa; Debray, Agathe; Drabent, Philippe; Fraitag, Sylvie; Hié, Miguel; Landman-Parker, Judith; Lhermitte, Ludovic; Moshous, Despina; Rohrlich, Pierre; Ruemmele, Frank; Welfringer-Morin, Anne; Tusseau, Maud; Belot, Alexandre; Cerf-Bensussan, Nadine; Roelens, Marie.
Afiliación
  • Boussard C; Université Paris Cité, Paris, France.
  • Delage L; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Gajardo T; Université Paris Cité, Paris, France.
  • Kauskot A; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Batignes M; Université Paris Cité, Paris, France.
  • Goudin N; Laboratory of Molecular Basis of Altered Immune Homeostasis, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Stolzenberg MC; INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Brunaud C; Université Paris Cité, Paris, France.
  • Panikulam P; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Institut Imagine, Atip-Avenir Team, INSERM UMR 1163, Paris, France.
  • Riller Q; Université Paris Cité, Paris, France.
  • Moya-Nilges M; Necker Bio-image Analysis Platform, Structure Fédérative de Recherche Necker, INSERM US24, CNRS UMS3633, Paris, France.
  • Solarz J; Université Paris Cité, Paris, France.
  • Repérant C; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Durel B; Université Paris Cité, Paris, France.
  • Bordet JC; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Pellé O; Université Paris Cité, Paris, France.
  • Lebreton C; Laboratory of Molecular Basis of Altered Immune Homeostasis, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Magérus A; Université Paris Cité, Paris, France.
  • Pirabakaran V; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Vargas P; Institut Pasteur, UTechS Ultrastructural BioImaging UBI, Paris, France.
  • Dupichaud S; INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Jeanpierre M; INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Vinit A; Université Paris Cité, Paris, France.
  • Zarhrate M; Cell Imaging Platform, Structure Fédérative de Recherche Necker, INSERM US24, CNRS UMS3633, Paris, France.
  • Masson C; Laboratoire d'Hémostase, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France.
  • Aladjidi N; Université Paris Cité, Paris, France.
  • Arkwright PD; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Bader-Meunier B; Flow Cytometry Core Facility, Structure Fédérative de Recherche Necker INSERM US24, CNRS UMS3633, Paris, France.
  • Baron Joly S; Université Paris Cité, Paris, France.
  • Benadiba J; Laboratory of Intestinal Immunity, Université Paris Cité, Imagine Institute, INSERM UMR-S_1163, Paris, France.
  • Bernard E; Université Paris Cité, Paris, France.
  • Berrebi D; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Bodemer C; Université Paris Cité, Paris, France.
  • Castelle M; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Charbit-Henrion F; Université Paris Cité, Paris, France.
  • Chbihi M; Institut Necker Enfants Malades, INSERM U1151/CNRS UMR 8253, Université de Paris, Paris, France.
  • Debray A; Institut Pasteur, UTechS Ultrastructural BioImaging UBI, Paris, France.
  • Drabent P; Université Paris Cité, Paris, France.
  • Fraitag S; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Hié M; Sorbonne Université, UMS037, PASS, Plateforme de cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
  • Landman-Parker J; Université Paris Cité, Paris, France.
  • Lhermitte L; Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Université Paris Cité, Paris, France.
  • Moshous D; Université Paris Cité, Paris, France.
  • Rohrlich P; Bioinformatics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Université Paris Cité, Paris, France.
  • Ruemmele F; Centre de Référence National des Cytopénies Auto-immunes de l'Enfant, Bordeaux, France.
  • Welfringer-Morin A; Pediatric Oncology Hematology Unit, University Hospital, Plurithématique CIC, Centre d'Investigation Clinique, 1401, INSERM, Bordeaux, France.
  • Tusseau M; Lydia Becker Institute of Immunology and Inflammation, University of Manchester & Department of Pediatric Allergy and Immunology, Royal Manchester Children's Hospital, Manchester, United Kingdom.
  • Belot A; Université Paris Cité, Paris, France.
  • Cerf-Bensussan N; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S_1163, Paris, France.
  • Roelens M; Pediatric Immunology, Hematology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
Blood ; 141(22): 2713-2726, 2023 06 01.
Article en En | MEDLINE | ID: mdl-36952639
ABSTRACT
Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a Rho-guanosine triphosphate hydrolases involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but, to the best of our knowledge, has never been described to date. We studied 8 male patients, from 7 unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B-lymphoblastoid cell lines from patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. Knock down of DOCK11 recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T-cell (Treg) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found reduced T-cell proliferation and impaired STAT5B phosphorylation upon interleukin-2 stimulation of the patients' lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and is associated with abnormal actin cytoskeleton remodeling as well as Treg phenotype, culminating in immune dysregulation and severe early-onset autoimmunity.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndromes de Inmunodeficiencia / Enfermedades del Sistema Inmune Límite: Humans / Male Idioma: En Revista: Blood Año: 2023 Tipo del documento: Article País de afiliación: Francia
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndromes de Inmunodeficiencia / Enfermedades del Sistema Inmune Límite: Humans / Male Idioma: En Revista: Blood Año: 2023 Tipo del documento: Article País de afiliación: Francia