RESUMEN
X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαß+ T cells (αßDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.
Asunto(s)
Síndrome Linfoproliferativo Autoinmune/inmunología , Deficiencia de Magnesio/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Síndrome Linfoproliferativo Autoinmune/genética , Síndrome Linfoproliferativo Autoinmune/patología , Relación CD4-CD8 , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/inmunología , Femenino , Glicosilación , Humanos , Deficiencia de Magnesio/genética , Deficiencia de Magnesio/patología , Masculino , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/patologíaAsunto(s)
Enfermedad Granulomatosa Crónica/inmunología , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Lupus Eritematoso Discoide/inducido químicamente , Lupus Eritematoso Discoide/patología , Pirimidinas/efectos adversos , Luz Solar/efectos adversos , Triazoles/efectos adversos , Biopsia con Aguja , Niño , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/terapia , Humanos , Huésped Inmunocomprometido , Inmunohistoquímica , Enfermedades Pulmonares Fúngicas/inmunología , Enfermedades Pulmonares Fúngicas/microbiología , Masculino , Trastornos por Fotosensibilidad/etiología , Trastornos por Fotosensibilidad/fisiopatología , Pronóstico , Pirimidinas/uso terapéutico , Recurrencia , Índice de Severidad de la Enfermedad , Triazoles/uso terapéutico , VoriconazolRESUMEN
Neutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes (RNP ICs), inducers of NETosis, require mitochondrial reactive oxygen species (ROS) for maximal NET stimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, and when this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathway dependent on the DNA sensor STING. Mitochondrial ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus. This was also observed in individuals with chronic granulomatous disease, who lack NADPH oxidase activity but still develop autoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type I IFN responses in a mouse model of lupus. Together, these findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.