Immunité innée : Expression cutanée et fonction des récepteurs Toll-like

Les récepteurs Toll-like (TLR) sont des récepteurs membranaires de découverte récente, impliqués dans l’immunité immédiate. Découverts chez la drosophile, ils se sont révélés être des structures phylogénétiquement très conservées. Ubiquitaires dans l’organisme, ils sont particulièrement présents dans les cellules de l’immunité et les tissus barrières. Les TLR, au nombre de 11 chez l’homme, reconnaissent un petit nombre de structures moléculaires propres aux micro-organismes, communes à de nombreux pathogènes. Les TLR peuvent également être activés par des ligands endogènes physiologiques. L’activation d’un TLR est à l’origine d’une cascade signalétique aboutissant à la translocation nucléaire de NF-κB et à la sécrétion de cytokines pro-inflammatoires. La peau, qui constitue une barrière contre les aggressions, exprime de nombreux TLR à la surface des kératinocytes.Toll receptors were first identified as an essential molecule for embryonic patterning in Drosophila and were subsequently shown to be a key in antibacterial and antifungal immunity in adult flies. Toll receptors have been conserved throughout evolution. In mammals, TLRs have been implicated in both inflammatory responses and innate host defense to pathogens. The 11 different TLRs recognize conserved molecular patterns of microbial pathogens termed pathogen-specific molecular patterns (PAMPs), that permit to confer responsiveness to a wide variety of pathogens. Endogenous ligands are also able to activate TLRs. All adult tissue is capable to express at least one of member of TLR family, but a largest repertoire of TLRs is found in tissues exposed to the external environment. The TLR activation induce the NF-κB translocation to the nucleus and cytokine secretion. Since the primary function of skin is to provide an effective barrier against outside agression, it is likely that keratinocytes may play a role in a rapid and efficient host defence system, and the fact that keratinocytes are capable of expressing a wide variety of TLRs is subsequently not surprising

Targeted Immunotherapy with Rituximab Leads to a Transient Alteration of the IgG Autoantibody Profile in Pemphigus Vulgaris

In pemphigus vulgaris (PV), IgG autoantibodies against the ectodomain of desmoglein 3 (Dsg3) have been shown to be directly responsible for the loss of keratinocyteadhesion. The aim of the present study was to study the effect of the B cell depleting anti-CD20 monoclonal antibody, rituximab, on the profile of pathogenic IgG against distinct regions of the Dsg3 ectodomain in 22 PV patients who were followed up clinically and serologically by Dsg3 ELISA over 12-24 months. Prior to rituximab, all the 22 PV patients showed IgG against Dsg3 (Dsc3EC1-5). Specifically, 14/22 showed IgG reactivity against the Dsg3EC1 subdomain, 5/22 patients against Dsg3EC2, 7/22 against Dsg3EC3, 11/22 against Dsg3EC4, and 2/22 against Dsg3EC5. Within 6 months after rituximab, all the patients showed significant clinical improvement and reduced IgG against Dsg3 (5/22) and the various subdomains, that is, Dsg3EC1 (7/22), Dsg3EC2 (3/22), Dsg3EC3 (2/22), sg3EC4 (2/22), and Dsg3EC5 (0/22). During the entire observation period, 6/22 PV patients experienced a clinical relapse which was associated with the reappearance of IgG against previously recognized Dsg3 subdomains, particularly against the Dsg3EC1. Thus, in PV, rituximab only temporarily depletes pathogenic B cell responses against distinct subdomains of Dsg3 which reappear upon clinical relapse

Perspective From the 5th International Pemphigus and Pemphigoid Foundation Scientific Conference

The 5th Scientific Conference of the International Pemphigus and Pemphigoid Foundation (IPPF), “Pemphigus and Pemphigoid: A New Era of Clinical and Translational Science” was held in Orlando, Florida, on May 15–16, 2018. Scientific sessions covered recent, ongoing, and future clinical trials in pemphigus and bullous pemphigoid, disease activity and quality of life instruments, and the IPPF Natural History Study. Furthermore, the meeting provided an opportunity to hear firsthand from patients, investigators, and industry about their experience enrolling for clinical trials

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325

Etude immunologique du syndrome d'hypersensibilité médicamenteuse

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

New Insights into Drug Reaction with Eosinophilia and Systemic Symptoms Pathophysiology

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome, is a severe type of cutaneous drug-induced eruption. DRESS may be a difficult disease to diagnose since the symptoms mimic those of cutaneous and systemic infectious pathologies and can appear up to 3 months after the initial culprit drug exposure. The symptoms of DRESS syndrome include rash development after a minimum of 3 weeks after the onset of a new medication, associated with facial edema, lymphadenopathy, and fever. Biological findings include liver abnormalities, leukocytosis, eosinophilia, atypical lymphocytosis, and reactivation of certain human herpes viruses. In DRESS, liver, kidneys, and lungs are frequently involved in disease evolution. Patients with serious systemic involvement are treated with oral corticosteroids, and full recovery is achieved in the majority of cases. DRESS is a rare disease, and little is known about factors that predict its occurrence. The key features of this reaction are eosinophil involvement, the role of the culprit drug, and virus reactivation that trigger an inappropriate systemic immune response in DRESS patients. Interestingly, it was evidenced that at-risk individuals within a genetically restricted population shared a particular HLA loci. In this respect, a limited number of well-known drugs were able to induce DRESS. This review describes the up-to-date advances in our understanding of the pathogenesis of DRESS

Varicelles nécrotiques de l'enfant

La varicelle nécrotique est une entité clinique assez mal définie dans la littérature. Le but de cette étude a été de déterminer les principales caractéristiques cliniques et évolutives des varicelles nécrotiques chez des enfants. Matériel et méthodes : tous les cas d'enfants atteints de varicelle comportant des éléments nécrotiques vus dans 4 CHU français, de janvier 2002 à février 2004 ont été inclus rétrospectivement. Les données cliniques et évolutives ont été relevées à partir du dossier médical. Résultats : Vingt quatre enfants, d'âge moyen 21,5 +/- 13,5 mois ont été inclus. Une atopie était retrouvée dans 37,5% des cas. Aucun antécédent d'immunodépression n'était retrouvé. La température maximale moyenne était de 39,5 +/- 0,7 C. Les éléments nécrotiques sont survenus en moyenne 4,25 +/- 2,5 jours après le début de l'éruption. Dans les 15 jours pécédant l'hospitalisation, une prise de paracétamol était retrouvée dans 67% des cas, des AINS dans 46% des cas, des anti-istaminiques dans 29% des cas. Une application de Nisapulvol® avait été réalisée dans 21% des cas. Pendant l'hospitalisation, 67% des enfants ont été traités par aciclovir et 96% ont reçu une antibiothérapie intraveineuse. Des complications sont survenues chez 13 enfants (54%), dont 13 infections cutanées sévères. La durée moyenne d'hospitalisation était de 5,7 +/- 2,8 jours. Conclusions: Dans cette étude, la varicelle nécrotique touchait principalement les enfants de moins de 2 ans, immunocompétents, atopiques dans 40% des cas. Une fièvre initialement très élevée était constamment retrouvée, ce qui peut expliquer l'utilisation fréquente d'AINS et de paracétamol. Des surinfections ont été fréquemment observées, ce qui justifie l'utilisation d'une antibiothérapie systématique chez ces patients.ROUEN-BU Médecine-Pharmacie (765402102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

B Cell Modulation Strategies in Autoimmune Diseases: New Concepts

B cells are major effector cells in autoimmunity through antibody production, T cell help and pro-inflammatory cytokine production. Major advances have been made in human B cell biology knowledge using rituximab and type II new anti-CD20 antibodies, anti-CD19 antibodies, anti-CD22 antibodies, autoantigen specific B cell depleting therapy (chimeric antigen receptor T cells), and B cell receptor signaling inhibition (Bruton’s tyrosine kinase inhibitors). However, in certain circumstances B cell depleting therapy may lead to the worsening of the autoimmune disease which is in accordance with the existence of a regulatory B cell population. Current concepts and future directions for B cell modulating therapies in autoimmune diseases with a special focus on pemphigus are discussed