Disturbing immune homeostasis by neutrophil loss of Uba1 induces VEXAS-like autoinflammatory disease in mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

ABSTRACT Objective VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an identified haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells. We report Uba1 loss various mouse cell types leads to diverse effects, with approximately 70% depletion neutrophils inducing non-lethal VEXAS-like symptoms. Methods Using nine different Cre/flox-mediated conditional-knockout (CKO) models, we interrogated the phenotypes of . Neutrophil-specific were validated and examined. Results HSCs induces extensive death while B or T cells, megakaryocytes corresponsive but these mutants appear normal. monocytes failed induce are viable. Among only manifests autoinflammatory symptoms including increased counts percentage neutrophils, proinflammatory cytokines, vacuoles myeloid cells dermatitis. Residual about 30% mutant which manifest disturbed cellular hemostasis. Genetic Morrbid partially mitigated Conclusion Our study reveals effects establishes a murine model, facilitating understanding potential treatments for this prevalent aged men. HIGHLIGHTS WHAT IS ALREADY KNOWN ON THIS TOPIC recently hematological immunological adult man rarely woman. Somatic E1-enzyme encoding gene driver on top genetic etiology disease. However, major pathogenic type(s) has not been experimentally examined models recapitulating lacking. STUDY ADDS pleiotropic ubiquitin activation enzyme types; results demonstrated that among tested CKO mutants, neutrophil disease; The S100a8Cre-CKO mice include: white blood serum level cytokines (IL-1β, IL-6 TNFα), observation vacuoles, survival, phagocytosis neutrophils; Pharmacological IL-1 inflammatory pathway inhibitors Anakinra Canakinumab pro-survival regulator mutants; HOW MIGHT AFFECT RESEARCH, PRACTICE OR POLICY reports technical strategy developing syndrome. In addition, dissects molecular mechanisms, especially cell-type-dependent tolerance pathogenicity function , occurrence autoinflammation diseases mice. provides translational implications treatment choices newly-identified clinical management.

Language: Английский

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Erythroid‐stimulating agents in VEXAS syndrome: A retrospective study from an Italian multicentre cohort

British Journal of Haematology, Journal Year: 2025, Volume and Issue: unknown

Published: May 13, 2025

Language: Английский

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Distinct bone marrow findings associated with a noncanonical UBA1 variant in VEXAS syndrome

American Journal of Hematology, Journal Year: 2024, Volume and Issue: 99(7), P. 1400 - 1402

Published: April 6, 2024

Language: Английский

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Allogenic haematopoietic stem cell transplantation in VEXAS: A review of 33 patients

Clinical Rheumatology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 30, 2024

Language: Английский

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Deep Learning‐Based Blood Abnormalities Detection as a Tool for VEXAS Syndrome Screening

International Journal of Laboratory Hematology, Journal Year: 2024, Volume and Issue: 47(1), P. 120 - 129

Published: Sept. 14, 2024

ABSTRACT Introduction VEXAS is a syndrome described in 2020, caused by mutations of the UBA1 gene, and displaying large pleomorphic array clinical hematological features. Nevertheless, these criteria lack significance to discriminate from other inflammatory conditions at screening step. This work hence first focused on singling out dysplastic features indicative among peripheral blood (PB) polymorphonuclears (PMN). A deep learning algorithm then proposed for automatic detection Methods multicentric dataset, comprising 9514 annotated PMN images was gathered, including mutated ( n = 25), wildtype myelodysplastic 14), cytopenic patients 25). Statistical analysis subset performed screen significant abnormalities. Detection PB automated with convolutional neural network (CNN) multilabel classification. Results Significant differences were observed proportions PMNs pseudo‐Pelger, nuclear spikes, vacuoles, hypogranularity between both controls. Automatic abnormalities yielded AUCs range [0.85–0.97] F1‐score 0.70 test set. score proposed, leveraging model outputs predicting mutational status 0.82 sensitivity 0.71 specificity patients. Conclusion study suggests that computer‐assisted smears, focusing suspected cases, can provide valuable insights determining which should undergo molecular testing. The presented approach help hematologists direct their suspicions before initiating further analyses.

Language: Английский

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A case of VEXAS with microcytic anemia: don’t be mislead by an associated condition!

Acta Clinica Belgica, Journal Year: 2024, Volume and Issue: 79(4), P. 303 - 305

Published: July 3, 2024

VEXAS syndrome encompasses a wide range of rheumatological and hematological manifestations, which often features myelodysplastic accompanied by either macrocytic anemia or macrocytosis.

Language: Английский

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How Protein Ubiquitination Can Influence Cytokine Expression—Updated Review on Autoinflammatory VEXAS Syndrome

Immuno, Journal Year: 2024, Volume and Issue: 4(3), P. 286 - 300

Published: Sept. 23, 2024

VEXAS syndrome is a new disease entity with symptoms that can mimic hematological, rheumatic and dermatological diseases. It important to take multidisciplinary approach patient care, taking into account genetic testing, in which the presence of mutations UBA1 gene confirm diagnosis. mutation has been shown be involved induction inflammatory response through many different mechanisms. NF-κB TNF-α pathways appear most syndrome. There are result outcomes, suggesting it possible prognostic factor. Furthermore, differ how they impair function. Cytokines have significantly altered patients; however, their exact expression importance were not clearly defined. Interleukins, such as interleukin (IL)-6, IL-1, IL-2R others, reported expressed at an level, similarly other cytokines, IFN-γ or TNF-α. worth noting certain cytokines vary between patients, poses therapeutic difficulties selecting right drug. Therefore, aim this review was describe associate mutation.

Language: Английский

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Novel use of Siltuximab in a patient with VEXAS Syndrome

Annals of Hematology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 17, 2024

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an increasingly recognized disorder that occurs due to somatic mutations of a ubiquitin-activating enzyme encoded by ubiquitin-like modifier activating 1 gene, UBA1. Clinical findings associated with include recurrent fevers, polychondritis, periorbital edema, pleural effusions, myocarditis and/or pericarditis, hepatosplenomegaly, myelodysplastic syndrome, cytopenias, inflammatory arthritis, neutrophilic dermatosis, and deep venous thrombosis. Novel renal manifestations like interstitial nephritis are infrequent, our knowledge, acute failure C3 glomerulonephritis (C3GN) has not yet been reported. Overwhelming systemic inflammation can result in morbid end-organ damage death. While there no formal guideline or established protocol for its management, treatment tocilizumab, interleukin-6 (IL-6)-directed therapy, described the literature. Here, we report case 71-year-old male patient presenting C3GN as initial manifestation explore rationale approach IL-6 blockade. Our was initially treated two inpatient doses tocilizumab successful transition siltuximab outpatient setting. He continues benefit from ongoing more than one year date without any safety issues relapse syndrome.

Language: Английский

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VEXAS syndrome: an adult-onset autoinflammatory disorder with underlying somatic mutation

Current Opinion in Rheumatology, Journal Year: 2024, Volume and Issue: 37(1), P. 21 - 31

Published: Oct. 25, 2024

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) was first described in 2020, where a cohort of adults with unexplained fever or inflammation, systematic genetic testing performed and 25 men median age 64 years somatic mutations the UBA1 gene were identified. In current review, we aim to discuss relevant literature from January 2023 until July 2024 give new insights into pathophysiology, epidemiology, diagnosis treatment VEXAS.

Language: Английский

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Methodology and clinical utility of longitudinal UBA1 tracking in VEXAS syndrome

British Journal of Haematology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 13, 2024

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) is a haemato-inflammatory syndrome genetically defined by mutations in the X-linked UBA1 gene, typically Val/Thr/Leu substitutions at Met41 hotspot. Clinical manifestations are heterogeneous and refractory to most haemato-rheumatological treatments. To date, no guidelines exist for management of VEXAS, scarce evidence on methodology clinical significance longitudinal clonal burden evaluation upon therapy. Here, we validated method quantify explored its applicability patients with VEXAS. Given different treatment interactions, droplet digital polymerase chain reaction (ddPCR) may allow informed therapeutic decisions implementation personalized strategies.

Language: Английский

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