Cytokine Signature in Schnitzler Syndrome: Proinflammatory Cytokine Production Associated to Th Suppression

Background: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown. Objective: To determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel. Methods: We collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology. Results: Spontaneous TNFα, IL-6, IL-1β, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1β serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04). Conclusion: Our data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1β, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra

A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors

Psoriasis lingual : aspects cliniques et associations épidémiologiques chez 313 enfants, avec revue systématique de la littérature

IF 1,051 (2018)International audienceBackground. - Little information is available on the prevalence and clinical aspects of tongue involvement in children with psoriasis. The aim was to evaluate the prevalence, clinical aspects and risk factors concerning tongue involvement in children with psoriasis.Patients and methods. - This study was carried out in two stages. We performed a multicentre, cross-sectional study in 23 French dermatology centers. All children seen for psoriasis during the one-year study were systematically included. The clinical features of the tongue and of psoriasis were recorded. Association with clinical aspects of psoriasis and comorbidities was evaluated. We then carried out a literature review to evaluate the prevalence of tongue involvement in children with psoriasis and its positive predictive value for psoriasis. A search was conducted in the PUBMED database using the following keywords: "child'' and "psoriasis'' and ("tongue'' or "glossitis'' or "migratory glossitis'' or "benign migratory glossitis'' or "geographic tongue'' or "fissured tongue'').Results. - 7.7% of the 313 children with psoriasis had tongue involvement. The clinical aspects were geographic tongue (4.2%), fissured tongue (2.8%) and both (0.64%). There was no association between tongue involvement and the clinical characteristics of the children. Two hundred and ninety-five articles were referenced and 3 were analysed. Psoriasis is very rare in cases of tongue abnormalities.Conclusion. - The prevalence of tongue involvement was 7.7% in children with psoriasis. No clinical or epidemiological association was shown. Tongue involvement does not modify the management of psoriasis. In the literature review it was not possible to evaluate either the prevalence of tongue involvement in psoriasis or the positive predictive value thereof.IntroductionIl y a peu d’informations dans la littérature sur les atteintes de la langue au cours du psoriasis de l’enfant. L’objectif était d’évaluer la fréquence, les aspects cliniques et les facteurs de risque d’atteinte linguale chez les enfants psoriasiques.Patients et méthodesCe travail a été effectué en deux étapes : (1) une étude transversale a été menée dans 23 centres dermatologiques français, notant les aspects cliniques de la langue et du psoriasis chez les enfants atteints de psoriasis, ainsi que les associations et les comorbidités ; (2) une revue systématique de la littérature a ensuite été effectuée afin d’évaluer la prévalence l’atteinte linguale chez l’enfant et sa valeur prédictive du psoriasis. Une recherche a été réalisée en interrogeant la base de données PUBMED. Les mots clés saisis étaient : « child » et « psoriasis » et (« tongue » ou « glossitis » ou « migratory glossitis » ou « benign migratory glossitis » ou « geographic tongue » ou « fissured tongue »).Résultats(1) Parmi 313 enfants atteints de psoriasis 7,7 % présentaient une atteinte linguale sous forme de langue géographique (4,2 %), langue fissurée (2,8 %) ou les deux (0,6 %). L’atteinte linguale n’était associée à aucune particularité démographique ou clinique, ni aucune comorbidité. (2) Parmi 295 articles référencés, 3 ont finalement été retenus. Le psoriasis reste très rare en cas d’anomalie linguale.ConclusionLa prévalence de l’atteinte linguale chez les enfants psoriasiques était de 7,7 %. Aucune association clinique ou épidémiologique n’a été montrée. L’atteinte linguale ne modifie pas la prise en charge du psoriasis. La revue systématique de la littérature ne permettait pas d’évaluer une prévalence de l’atteinte linguale dans le psoriasis ni la valeur prédictive positive de cette atteinte

Quality of life of children with capillary malformations of the lower limbs: Evolution and associated factors. Data from the French national paediatric cohort, CONAPE

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Age-specific characteristics of neutrophilic dermatoses and neutrophilic diseases in children

International audienceBackground Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics. Objectives To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children. Methods We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS). Results Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behcet's disease. Conclusions Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes

Dermatological manifestations of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (poiktmp): a case series of 28 patients

International audienceDear Editor, Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy and Pulmonary Fibrosis (POIKTMP [MIM 615704]) is a recently described autosomal dominant disorder due to missense mutations in the FAM111B gene. Key features are early-onset poikiloderma, muscle contractures in particular of the triceps surae, diffuse progressive fatty myopathy, pulmonary fibrosis in adulthood and exocrine pancreatic insufficiency. Dermatological manifestations seem to be constant and early however, a precise description is lacking

Theme and variations: evolutionary diversification of the HET-s functional amyloid motif

International audienceIn mammals and fungi, Nod-like receptors (NLR) activate downstream cell death execution proteins by a prion-like mechanism. In Podospora anserina, the NWD2 NLR activates the HET-S Helo-domain pore-forming protein by converting its prion-forming domain into a characteristic β-solenoid amyloid fold. The amyloid forming region of HET-S/s comprises two repetitions of a 21 amino acid motif. Herein, we systematically analyze the sequences of C-terminal regions of fungal HeLo and HeLo-like domain proteins to identify HET-s-related amyloid motifs (HRAM). We now identify four novel HRAM subfamilies in addition to the canonical HET-S/s subfamily. These novel motifs share the pseudo-repeat structure of HET-S/s and a specific pattern of distribution of hydrophobic and polar residues. Sequence co-variance analyses predict parallel in-register β-stacking of the two repeats and residue-residue interactions compatible with the β-solenoid fold. As described for HET-S, most genes encoding the HeLo proteins are adjacent to genes encoding NLRs also displaying HRAMs. The motifs of the NLRs are similar to those of their cognate HeLo-domain protein, indicating concerted evolution between repeats. This study shows that HET-s-related amyloid motifs are more common than anticipated and that they have diversified into discrete subfamilies that apparently share a common overall fold. Amyloids are self-templating protein polymers assembled by stacking of β-strands 1. Amyloid formation is often associated with disease, in particular neurodegenerative age-related pathologies such as Alzheimer's or Parkinson's diseases or other conditions like type 2 diabetes 2,3. Amyloid formation has also been linked to cancer with a proposed role of p53 amyloids in tumorogenesis 4. Yet, amyloids also fulfill a range of different functions inside and outside cells 5–7. Such so-called functional amyloids are involved in hormone and toxin storage and release, formation of cell surface structures in microorganisms and scaffolding of pigment synthesis. A role in the regulation of cell states is also described in yeast, where prion amyloids behave as epigenetic regulatory switches 8. Recently, it has also been reported that functional amyloids play a role in cell fate controlling sig-naling cascades both in mammals and fungi. In mammals, the RIP1 and RIP3 kinases which control the necroptosis cell death pathway form an amyloid-like complex assembled via short conserved motifs termed RHIM (for RIP homotypic interaction motifs)

Dermatoscopic and clinical features of congenital or congenital-type nail matrix nevi: A multicenter prospective cohort study by the International Dermoscopy Society

Background: Congenital nail matrix nevi (NMN) are difficult to diagnose because they feature clinical characteristics suggestive of adult subungual melanoma. Nail matrix biopsy is difficult to perform, especially in children. Objective: To describe the initial clinical and dermatoscopic features of NMN appearing at birth (congenital) or after birth but before the age of 5 years (congenital-type). Methods: We conducted a prospective, international, and consecutive data collection in 102 hospitals or private medical offices across 30 countries from 2009 to 2019. Results: There were 69 congenital and 161 congenital-type NMNs. Congenital and congenital-type NMN predominantly displayed an irregular pattern of longitudinal microlines (n = 146, 64%), reminiscent of subungual melanoma in adults. The distal fibrillar (“brush-like”) pattern, present in 63 patients (27.8%), was more frequently encountered in congenital NMN than in congenital-type NMN (P = .012). Moreover, congenital NMN more frequently displayed a periungual pigmentation (P = .029) and Hutchinson's sign (P = .027) than did congenital-type NMN. Limitations: Lack of systematic biopsy-proven diagnosis and heterogeneity of clinical and dermatoscopic photographs. Conclusion: Congenital and congenital-type NMN showed worrisome clinical and dermatoscopic features similar to those observed in adulthood subungual melanoma. The distal fibrillar (“brush-like”) pattern is a suggestive feature of congenital and congenital-type NMN

Biological treatments for paediatric psoriasis (BiPe): A retrospective observational study on biological drug survival in daily practice in childhood psoriasis

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