The autoinflammatory diseases.

Summary The monogenic autoinflammatory syndromes are conditions caused by mutations of genes coding for proteins that play a pivotal role in the regulation of the inflammatory response. Due to their genetic nature, most of these disorders have an early onset. Clinically they are characterised by recurrent flares of systemic inflammation presenting most of the time as sudden fever episodes associated with elevation of acute phase reactants and with a number of clinical manifestations such as rash, serositis, lymphadenopathy and arthritis. Symptom-free intervals are characterised by complete wellbeing, normal growth and complete normalisation of acute phase reactants. Familial Mediterranean fever (FMF), mevalonate-kinase deficiency (MKD) and tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) are the three monogenic disorders subsumed under the term periodic fevers, while a systemic inflammation dominated by a characteristic urticarial rash associated with a number of other clinical manifestations is typical of familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous and articular syndrome (CINCA). These diseases represent the clinical spectrum of different mutations of a gene named cold-induced autoinflammatory syndrome 1 (CIAS-1, or NLRP3) coding for a protein called cryopyrin. Hence these disorders are also known as cryopyrin-associated periodic syndromes (CAPS). Other conditions are characterised by typical granulomatous formations (granulomatous disorders). Blau's syndrome (familial juvenile systemic granulomatosis) presents with non-caseating granulomatous inflammation affecting the joint, skin, and uveal tract (the triad of arthritis, dermatitis and uveitis) and is associated with mutations of the NACHT domain of the gene CARD15 (or NOD2)

CC-chemokine ligand 16 induces a novel maturation program in human immature monocyte-derived dendritic cells

Dendritic cells (DCs) are indispensable for initiation of primary T cell responses and a host's defense against infection. Many proinflammatory stimuli induce DCs to mature (mDCs), but little is known about the ability of chemokines to modulate their maturation. In the present study, we report that CCL16 is a potent maturation factor for monocyte-derived DCs (MoDCs) through differential use of its four receptors and an indirect regulator of Th cell differentiation. MoDCs induced to mature by CCL16 are characterized by increased expression of CD80 and CD86, MHC class II molecules, and ex novo expression of CD83 and CCR7. They produce many chemokines to attract monocytes and T cells and are also strong stimulators in activating allogeneic T cells to skew toward Th1 differentiation. Interestingly, they are still able to take up Ag and express chemokine receptors usually bound by inflammatory ligands and can be induced to migrate to different sites where they capture Ags. Our findings indicate that induction of MoDC maturation is an important property of CCL16 and suggest that chemokines may not only organize the migration of MoDCs, but also directly regulate their ability to prime T cell responses

Design of ideal vibrational signals for stinkbug male attraction through vibrotaxis experiments

Many groups of insects utilize substrate-borne vibrations for intraspecific communication. This characteristic makes them a suitable model for exploring the vibrations as a tool for pest control in alternative to chemicals. The detailed knowledge of the species communication is a prerequisite to select the best signals to use. In this sense, this study aimed at exploring the use of substrate-borne vibrations for pest control of the brown marmorated stink bug (BMSB), Halyomorpha halys Stål (Heteroptera: Pentatomidae). To this purpose, in a first set of experiments, we identified the spectral and temporal characteristics that best elicit male responsiveness. Bioassays were conducted with artificial signals that mimicked the natural female calling signal. In a second part, we used the acquired knowledge to synthesize new signals endowed with different degrees of attractiveness in single and two choice bioassays using a wooden custom-made T stand

Interstitial lung disease in a newborn affected by mevalonic aciduria

Introduction: Mevalonic aciduria (MA) is the most severe phenotype of mevalonate-kinase deficiency (MKD), with a onset in early infancy and poor prognosis. MA diagnosis may be challenging in the neonatal period given its rarity and its unspecific symptoms that frequently recall those of other neonatal diseases. To our knowledge, interstial lung involvement has never been described as onset feature in a newborn with MKD. Objectives: We report the case of a newborn affected by MKD characterized by interstitial lung disease. Methods: The patient underwent laboratory and radiology evaluation as clinically indicated. Direct Sanger sequencing was used to screen the 10 exons of the MVK gene. Results: A female neonate born at term from consanguineous parents was referred to our hospital at 16 days of life (DOL) for mild hypotonia and persistent raised inflammatory markers despite antibiotic therapy. Infectious work-up was negative for both viral and bacterial infections. Chest x-ray revealed bilateral perihilar peribronchial thickening. Electroencephalography (EEG) reported moderate diffuse anomalies of background activity without major abnormalities. On DOL 20 the first episode of fever was recorded. Due to worsening tachypnea and persistent abnormal chest x-ray, a pulmonary CT scan was performed and showed diffuse ground-glass bilateral infiltrates consistent with alveolar-interstitial lung disease. On DOL 22 a palpable maculo-papular skin rash appeared on feet and hands, vanishing spontaneously 24 hours later. Bone marrow examination and levels of perforins, neuron-specific enolase and urinary catabolites of catecholamines were normal. A total body MRI was normal except for a mild cerebellar hypoplasia and the known interstitial lung disease. The patient kept presenting hypotonia, relapsing episodes of fever and skin rashes, developed anemia requiring blood transfusions and failure to thrive became evident. Type-I IFN signature was negative. A genetic test was requested, as well as quantification of urinary levels of mevalonic acid, which were markedly above the normal range. Direct Sanger sequencing allowed to detect a homozygous c.709A>T missense mutation in the exon 8 of the MVK gene, coding for a protein substitution p.T237S already classified as pathogenic in the INFEVERS database (http://fmf.igh.cnrs.fr/ISSAID/infevers/) and therefore consistent with the diagnosis of MKD. Both parents and her sister were found to be heterozygous carriers of the same mutation. On DOL 38 treatment with anakinra was started, with prompt regression of fever and skin rash, decrease in inflammatory markers, increase in reticulocytes count and weight gain. Hypotonia improved but persisted. The patient was discharged from hospital on DOL 56 in good clinical conditions, with acute phase reactants within the normal range and mild hypotonia. She is now 4 months old, still on anakinra treatment without adverse events. Conclusion: Autoinflammatory diseases in the neonatal period are a diagnostic challenge. Clinical suspicion is crucial in order to perform specific laboratory and genetic testing and start appropriate treatment. Interstitial lung involvement may be present in MKD and, together with increased inflammatory markers, could be the first manifestation of the disease