Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

NEJMAbstract

 

Background

Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.

Methods

We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9–edited zebrafish were used as an in vivo model to assess gene function.

Results

We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.

Conclusions

Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.)

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Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19

 

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19

Abstract

Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based occlusions in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19. Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM and IgA; anti-β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/ prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from COVID-19 patients promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19

 

LA SOCIEDAD CUBANA DE REUMATOLOGIA Y SU GRUPO NACIONAL EN EL ENFRENTAMIENTO A LA SARCOV 2, COVID-19

coronavirusDr.C. Gil Alberto Reyes Llerena
Dra. C. Marlene Guibert Toledano
Dr.C. Alfredo Hernández Martínez
Dra. Zoe A. González Otero
Dr. Eduardo Bicet Dorzón.

Grupo Gestor de trabajo para el enfrentamiento a la COVID 19.

Documento en PDF: peso 177Kb

 

INTRODUCCIÓN Y DESARROLLO

La pandemia por el nuevo coronavirus SARCOV-2, COVID-19, constituye una Pandemia sanitaria de incalculable magnitud. Hoy día se calculan a nivel mundial más de 12 millones de personas contagiadas con el virus que ha impactado sobre los sistemas de salud hasta practicamente su colapso por lo que  se han producido  millares de muertes y una fuerte conmoción de la economia mundial..

Global Rheumatology Panlar: Nueva revista digital de PANLAR

  Global Rheumatology by PANLARr  

Entrar ►►

Global Rheumatology Panlar es la nueva revista de PANLAR que busca una perspectiva global de la reumatología para contribuir al desarrollo, la difusión y el mejoramiento de la reumatología en el mundo y principalmente en nuestro continente.

La revista acoge artículos en las siguientes áreas temáticas:

  • Lupus y otras Enfermedades del Tejido Conectivo 

  • Reumatología pediátrica

Reumatología pediátrica. Segunda edición

En las categorías:

Reumatología pediátrica. Segunda ediciónTítulo: Reumatología pediátrica. Segunda edición

Autor: Coto Hermosilla C y otros

Edición: Norma Collazo Silvariño

Diseño: D.I. José Manuel Oubiña González

ISBN: 978-959-313-787-4

Año: 2020

Obra que constituye un aporte importante para la reumatología pediátrica, escrita por un amplio colectivo de prestigiosos especialistas cubanos, abarca la mayoría de las enfermedades reumáticas de la infancia. Esta segunda edición, además de actualizar los temas anteriores, incluye capítulos que contienen estudios acerca de las enfermedades metabólicas e inflamatorias en esta primera etapa de la vida, así como informes sobre la repercusión del VIH-sida en la reumatología pediátrica. Texto fundamental para los residentes de la especialidad y de obligada consulta para pediatras, médicos generales y todos los profesionales que se vinculen con la atención a niños con estas afecciones.

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