RESUMEN
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.
Asunto(s)
Enfermedades del Sistema Inmune , Síndromes de Inmunodeficiencia , Humanos , Masculino , Citoesqueleto de Actina/metabolismo , Autoinmunidad , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Enfermedades del Sistema Inmune/metabolismo , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/genética , Linfocitos T ReguladoresAsunto(s)
Deferasirox , Quelantes del Hierro , Sistema de Registros , Talasemia , Humanos , Deferasirox/uso terapéutico , Deferasirox/administración & dosificación , Talasemia/terapia , Masculino , Femenino , Quelantes del Hierro/uso terapéutico , Quelantes del Hierro/administración & dosificación , Adolescente , Francia/epidemiología , Niño , Transfusión Sanguínea , Pubertad/efectos de los fármacos , Administración Oral , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Terapia por QuelaciónAsunto(s)
Anemia , Hemoglobinas Anormales , Talasemia alfa , Anemia/genética , Femenino , Hemoglobinas Anormales/genética , Homocigoto , Humanos , EmbarazoRESUMEN
BACKGROUND: Miller Fisher syndrome, a variant of Guillain-Barré syndrome, is an acute inflammatory demyelinating polyradiculoneuropathy that may occur weeks after a bacterial or viral infection. Campylobacter jejuni and Haemophilus influenzae are frequently reported etiological agents. PATIENT DESCRIPTION: We describe a boy with Miller Fisher syndrome following Epstein-002DBarr virus primary infectious mononucleosis. He presented with bilateral dysfunction of several cranial nerves and hyporeflexia of the limbs but without ataxia. Miller Fisher syndrome was confirmed by the presence of anti-GQ1b antibodies in a blood sample. Epstein-Barr virus was identified by polymerase chain reaction and serology. CONCLUSION: Epstein-Barr virus should be considered as a Miller Fisher syndrome's causative agent. The physiopathology of this condition may involve cross-reactive T-cells against Epstein-Barr virus antigens and gangliosides.