Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of IL-1β. We studied a family with dominantly inherited autoinflammatory disease characterised by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. Disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The clinical distinction from FMF, also caused by MEFV mutation, was due to loss of a 14-3-3 binding motif at phosphorylated S242. This interaction represents a guard regulating pyrin activation, which is downstream of bacterial effectors that trigger the pyrin inflammasome. S242R mutation recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND). This unique disease provides evidence that a guard mechanism, originally identified in plant innate immunity, also exists in humans.3 Main textAutoinflammatory diseases are characterized by recurrent episodes of fever with systemic and organ-specific inflammation, as well as uncontrolled activation of the innate immune response in the apparent absence of an infectious trigger(1). Familial Mediterranean fever (FMF, OMIM ID: 249100) is the most common of these monogenic diseases, characterized by short (24-72 h) episodes of fever associated with serositis, progressing to amyloidosis if untreated(2). FMF is an autosomal recessive disease caused by mutations in both alleles of the MEFV (MEditerranean FeVer) locus, which encodes the protein pyrin(3). Normally, pyrin functions as a link between intracellular pathogen sensing and activation of the inflammasome, allowing the production of inflammatory mediators during infection. As a potent checkpoint for the initiation of inflammation, the mechanisms of pyrin regulation are critical, and yet still poorly understood.We studied a three-generation Belgian family of 22 individuals, of whom 12 developed autoinflammatory disease (Figure 1a). The disease was characterized by neutrophilic dermatosis, childhood-onset recurrent episodes of fever lasting several weeks, increased levels of acute-phase reactants, arthralgia and myalgia/myositis (Figure 1b). The neutrophilic dermatosis comprised a spectrum of clinical manifestations including severe acne, sterile skin abscesses, pyoderma gangrenosum and neutrophilic small vessel vasculitis (Figure 1c,d).Pathological examination of affected skin showed a dense, predominantly neutrophilic, vascular, perivascular and interstitial infiltrate (Figure 1d). Serum cytokine analysis revealed elevated inflammatory mediators such as IL-1β, IL-6 and TNFα, and cytokines induced by inflammation such as IL-1Ra (Figure 1e, Figure S1a unlike some of the more typical FMF variants, that naturally occur in other species(7). Despite the association of MEFV mutations w...

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PurposeSpondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.MethodsWe compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.ResultsWe observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.ConclusionsOur data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

Patients with active sJIA and HLH/MAS show distinct cytokine profiles, with highly elevated plasma levels of IFN-γ and IFN-γ-induced proteins typically found in HLH/MAS. In addition to PBMCs, histiocytes, endothelial cells and fibroblasts may contribute to an IFN-γ profile in plasma. Increasing levels of IFN-γ compared with IL-18 may raise suspicion about the development of MAS in sJIA.

Objective. Systemic juvenile idiopathic arthritis (JIA) is an immunoinflammatory disease characterized by arthritis and systemic manifestations. The role of natural killer (NK) cells in the pathogenesis of systemic JIA remains unclear. The purpose of this study was to perform a comprehensive analysis of NK cell phenotype and functionality in patients with systemic JIA.Methods. Transcriptional alterations specific to NK cells were investigated by RNA sequencing of highly purified NK cells from 6 patients with active systemic JIA and 6 age-matched healthy controls. Cytokines (NK cellstimulating and others) were quantified in plasma samples (n 5 18). NK cell phenotype and cytotoxic activity against tumor cells were determined (n 5 10), together with their interferon-g (IFNg)-producing function (n 5 8).Results. NK cells from the systemic JIA patients showed an altered gene expression profile compared to cells from the healthy controls, with enrichment of immunoinflammatory pathways, increased expression of innate genes including TLR4 and S100A9, and decreased expression of immune-regulating genes such as IL10RA and GZMK. In the patients' plasma, interleukin-18 (IL-18) levels were increased, and a decreased ratio of IFNg to IL-18 was observed. NK cells from the patients exhibited specific alterations in the balance of inhibitory and activating receptors, with decreased killer cell lectin-like receptor G1 and increased NKp44 expression. Although NK cells from the patients showed increased granzyme B expression, consistent with intact cytotoxicity and degranulation against a tumor cell line, decreased granzyme K expression in CD56 bright NK cells and defective IL-18-induced IFNg production and signaling were demonstrated.Conclusion. NK cells are active players in the inflammatory environment typical of systemic JIA. Although their cytotoxic function is globally intact, subtle defects in NK-related pathways, such as granzyme K expression and IL-18-driven IFNg production, may contribute to the immunoinflammatory dysregulation in this disease.Systemic juvenile idiopathic arthritis (JIA) is a chronic immunoinflammatory childhood disorder of unknown etiology that is characterized by arthritis and systemic features such as quotidian fever, rash, lymphadenopathy, and serositis (1,2). An interplay of environmental factors and genetic predisposition is considered to underlie the pathogenesis (1). About 10% of systemic JIA patients develop