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 ReguladoresRESUMEN
An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.
Asunto(s)
Anemia Hemolítica Autoinmune , Autoinmunidad , Haploinsuficiencia , Lupus Eritematoso Sistémico , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Humanos , Haploinsuficiencia/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Anemia Hemolítica Autoinmune/genética , Anemia Hemolítica Autoinmune/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Femenino , Masculino , Niño , Autoinmunidad/genética , Adolescente , Mutación , Trombocitosis/genética , Trombocitosis/inmunología , Proteína 1 Supresora de la Señalización de Citocinas/genética , Autoanticuerpos/inmunología , Citocinas/metabolismo , Preescolar , Linfocitos T/inmunología , TrombocitopeniaRESUMEN
IKKα, encoded by CHUK , is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKß. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα's role in canonical NF-κB target gene expression in human.
RESUMEN
TITLE: L9, un nouvel anticorps monoclonal prometteur contre le paludisme. ABSTRACT: Dans le cadre de leur module d'analyse scientifique, des étudiants de la promotion 2020-2021 des Master 2 « Immunologie Translationnelle et Biothérapies ¼ (ITB) et « Immunologie Intégrative et Systémique ¼ (I2S) (Mention Biologie Moléculaire et Cellulaire, Parcours Immunologie, Sorbonne Université) se sont penchés sur la littérature et ont pris la plume pour partager avec les lecteurs de m/s quelques-uns des faits marquants de l'actualité en immunologie. Voici une sélection de quelques-unes de ces nouvelles, illustrant la large palette des axes de recherche en cours sur les mécanismes physiopathologiques des maladies infectieuses, auto-immunes, inflammatoires et tumorales et sur le développement d'immunothérapies pour le traitement de ces maladies.