Recently, a novel disorder coined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome was identified in patients with adult-onset inflammatory syndromes, often accompanied by myelodysplastic syndrome1. All patients had myeloid lineage-restricted somatic mutations in UBA1 affecting the Met41 residue of the protein and resulting in decreased cellular ubiquitylation activity and hyperinflammation. We here describe the clinical disease course of two VEXAS syndrome patients with somatic UBA1 mutations of which one with a mild phenotype characterized by recurrent rash and symmetric polyarthritis, and another who was initially diagnosed with idiopathic multicentric Castleman disease and developed macrophage activation syndrome as a complication of the VEXAS syndrome. The latter patients was treated with anti-IL6 therapy (siltuximab) leading to a resolution of systemic symptoms and reduction of transfusion requirements.

Objectives The pandemic spread of the coronavirus SARS‐CoV‐2 is due, in part, to the immunological properties of the host–virus interaction. The clinical presentation varies from individual to individual, with asymptomatic carriers, mild‐to‐moderate‐presenting patients and severely affected patients. Variation in immune response to SARS‐CoV‐2 may underlie this clinical variation. Methods Using a high‐dimensional systems immunology platform, we have analysed the peripheral blood compartment of 6 healthy individuals, 23 mild‐to‐moderate and 20 severe COVID‐19 patients. Results We identify distinct immunological signatures in the peripheral blood of the mild‐to‐moderate and severe COVID‐19 patients, including T‐cell lymphopenia, more consistent with peripheral hypo‐ than hyper‐immune activation. Unique to the severe COVID‐19 cases was a large increase in the proportion of IL‐10‐secreting regulatory T cells, a lineage known to possess anti‐inflammatory properties in the lung. Conclusion As IL‐10‐secreting regulatory T cells are known to possess anti‐inflammatory properties in the lung, their proportional increase could contribute to a more severe COVID‐19 phenotype. We openly provide annotated data ( https://flowrepository.org/experiments/2713 ) with clinical correlates as a systems immunology resource for the COVID‐19 research community.

Background The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease. Objective Our aim was to expand the spectrum of SEC61A1 -mediated disease to include autosomal dominant SCN. Methods Whole exome sequencing findings were validated, and reported mutations were compared by Western blotting, Ca2 + flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, quantitative PCR for unfolded protein response (UPR) genes, and single-cell RNA sequencing on whole bone marrow. Results We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum. In vitro differentiation of CD34 + cells recapitulated the patient’s clinical arrest in granulopoiesis. The impact of Q92R-Sec61α1 on neutrophil maturation was validated by using HL-60 cells, in which transduction reduced differentiation into CD11b + CD16 + cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone marrow revealing perturbed UPR in myeloid precursors and in vitro differentiation of primary CD34 + cells revealing upregulation of CCAAT/enhancer-binding protein homologous protein and immunoglobulin heavy chain binding protein UPR-response genes. Conclusion Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR.

STING-associated vasculopathy with onset in infancy (SAVI) is an autosomal dominant disorder due to gain-of-function mutations in STING1 , also known as TMEM173 , encoding for STING. It was reported as a vasculopathy of infancy. However, since its description a wider spectrum of associated manifestations and disease-onset has been observed. We report a kindred with a heterozygous STING mutation (p.V155M) in which the 19-year-old proband suffered from isolated adult-onset ANCA-associated vasculitis. His father suffered from childhood-onset pulmonary fibrosis and renal failure attributed to ANCA-associated vasculitis, and died at the age of 30 years due to respiratory failure. In addition, an overview of the phenotypic spectrum of SAVI is provided highlighting (a) a high phenotypic variability with in some cases isolated manifestations, (b) the potential of adult-onset disease, and (c) a novel manifestation with ANCA-associated vasculitis.

Inborn errors of immunity (IEI) are a heterogenous group of disorders driven by genetic defects that functionally impact the development and/or function of the innate and/or adaptive immune system. The majority of these disorders are thought to have polygenic background. However, the use of next-generation sequencing in patients with IEI has led to an increasing identification of monogenic causes, unravelling the exact pathophysiology of the disease and allowing the development of more targeted treatments. Monogenic IEI are not only seen in a pediatric population but also in adulthood, either due to the lack of awareness preventing childhood diagnosis or due to a delayed onset where (epi)genetic or environmental factors can play a role. In this review, we discuss the mechanisms accounting for adult-onset presentations and provide an overview of monogenic causes associated with adult-onset IEI.