Lien Van Eyck

Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

A mutation in pyrin that disrupts regulation leads to autoinflammatory disease. Guarding inflammation The innate immune system is hard-wired to protect people from infection. However, mutations in these protective genes can lead to uncontrolled inflammation, resulting in autoinflammatory disease. Now, Masters et al. describe a family with an autoinflammatory disease caused by a previously unreported mutation in pyrin. This mutation disrupts pyrin regulation and mimics the effect of pathogen sensing by pyrin, leading to proinflammatory interleukin-1β (IL-1β) production. Indeed, targeting IL-1β resolved disease in one patient. These data suggest that pyrin is regulated through a guard-like mechanism, which guards against autoinflammation in humans. Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus 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. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.

Brief Report: IFIH1 Mutation Causes Systemic Lupus Erythematosus With Selective IgA Deficiency

To identify the underlying genetic defect in a 16‐year‐old girl with severe early‐onset and refractory systemic lupus erythematosus (SLE), IgA deficiency, and mild lower limb spasticity without neuroradiologic manifestations.

Olmsted syndrome: exploration of the immunological phenotype

BackgroundOlmsted syndrome is a rare congenital skin disorder presenting with periorifical hyperkeratotic lesions and mutilating palmoplantar keratoderma, which is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of Olmsted syndrome.MethodsGenetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of Olmsted syndrome.ResultsThe patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation. In depth clinical and immunological analysis found multiple indicators of immune dysregulation, including frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood.ConclusionsThese results provide the first comprehensive assessment of the immunological features of Olmsted syndrome. The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome, and have important clinical consequences with regard to the treatment of Olmsted syndrome patients.

Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

Background Gain‐of‐function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING‐associated vasculopathy with onset in infancy (SAVI). Objectives We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. Methods Genetic analysis, conformational studies, in vitro assays and ex vivo flow‐cytometry were performed. Results Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP‐independent constitutive activation of type I interferon signaling through TBK1 (TANK‐binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. Conclusions Structural analysis indicates that the 3 disease‐associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.

Brief Report: Blockade of TANK-Binding Kinase 1/IKKɛ Inhibits Mutant Stimulator of Interferon Genes (STING)–Mediated Inflammatory Responses in Human Peripheral Blood Mononuclear Cells

Gain‐of‐function mutations in TMEM173, encoding the stimulator of interferon (IFN) genes (STING) protein, underlie a novel type I interferonopathy that is minimally responsive to conventional immunosuppressive therapies and associated with high frequency of childhood morbidity and mortality. STING gain‐of‐function causes constitutive oversecretion of IFN. This study was undertaken to determine the effects of a TANK‐binding kinase 1 (TBK‐1)/IKKɛ inhibitor (BX795) on secretion and signaling of IFN in primary peripheral blood mononuclear cells (PBMCs) from patients with mutations in STING.

TBK1 / IKKE blockade inhibits mutant STING mediated inflammatory response in patient cells

Gain‐of‐function mutations in TMEM173, encoding the stimulator of interferon (IFN) genes (STING) protein, underlie a novel type I interferonopathy that is minimally responsive to conventional immunosuppressive therapies and associated with high frequency of childhood morbidity and mortality. STING gain‐of‐function causes constitutive oversecretion of IFN. This study was undertaken to determine the effects of a TANK‐binding kinase 1 (TBK‐1)/IKKɛ inhibitor (BX795) on secretion and signaling of IFN in primary peripheral blood mononuclear cells (PBMCs) from patients with mutations in STING.

Machine learning identifies the immunological signature of Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease, with a strongly debated pathophysiological origin. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed. Here we profiled the adaptive immune system of 85 JIA patients and 43 age-matched controls, identifying immunological changes unique to JIA and others common across a broad spectrum of childhood inflammatory diseases. The JIA immune signature was shared between clinically distinct subsets, but was accentuated in the systemic JIA patients and those patients with active disease. Despite the extensive overlap in the immunological spectrum exhibited by healthy children and JIA patients, machine learning analysis of the dataset proved capable of diagnosis of JIA patients with ~90% accuracy. These results pave the way for large-scale longitudinal studies of JIA, where machine learning could be used to predict immune signatures that correspond to treatment response group.

ADA2 Deficiency Mimicking Idiopathic Multicentric Castleman Disease

We report on the first case of DADA2 that mimics the clinicopathologic features of MCD. Multicentric Castleman disease (MCD) is a rare entity that, unlike unicentric Castleman disease, involves generalized polyclonal lymphoproliferation, systemic inflammation, and multiple-organ system failure resulting from proinflammatory hypercytokinemia, including, in particular, interleukin-6. A subset of MCD is caused by human herpesvirus-8 (HHV-8), although the etiology for HHV-8–negative, idiopathic MCD (iMCD) cases is unknown at present. Recently, a consensus was reached on the diagnostic criteria for iMCD to aid in diagnosis, recognize mimics, and initiate prompt treatment. Pediatric iMCD remains particularly rare, and differentiation from MCD mimics in children presenting with systemic inflammation and lymphoproliferation is a challenge. We report on a young boy who presented with a HHV-8–negative, iMCD-like phenotype and was found to suffer from the monogenic disorder deficiency of adenosine deaminase 2 (DADA2), which is caused by loss-of-function mutations in CECR1. DADA2 prototypic features include early-onset ischemic and hemorrhagic strokes, livedoid rash, systemic inflammation, and polyarteritis nodosa vasculopathy, but marked clinical heterogeneity has been observed. Our patient’s presentation remains unique, with predominant systemic inflammation, lymphoproliferation, and polyclonal hypergammaglobulinemia but without apparent immunodeficiency. On the basis of the iMCD-like phenotype with elevated interleukin-6 expression, treatment with tocilizumab was initiated, resulting in immediate normalization of clinical and biochemical parameters. In conclusion, iMCD and DADA2 should be considered in the differential diagnosis of children presenting with systemic inflammation and lymphoproliferation. We describe the first case of DADA2 that mimics the clinicopathologic features of iMCD, and our report extends the clinical spectrum of DADA2 to include predominant immune activation and lymphoproliferation.

Gain-of-function mutation in IFIH1 can cause both aicardi-goutières syndrome and systemic lupus erythematosus with IgA-deficiency

Gain-of-function mutations in IFIH1 were identified in Aicardi-Goutieres syndrome (AGS), a rare neuroimmunological disorder associated with elevated levels of type I interferon and characterized by leucoencephalopathy, brain atrophy and intracranial calcifications leading to profound intellectual disability, spasticity and dystonia. IFIH1 functions as an intracellular innate immune receptor that senses viral nucleic acids and leads to the induction of type I interferon and proinflammatory cytokines.