IL-26, a Cytokine With Roles in Extracellular DNA-Induced Inflammation and Microbial Defense

Interleukin 26 (IL-26) is the most recently identified member of the IL-20 cytokine subfamily, and is a novel mediator of inflammation overexpressed in activated or transformed T cells. Novel properties have recently been assigned to IL-26, owing to its non-conventional cationic, and amphipathic features. IL-26 binds to DNA released from damaged cells and, as a carrier molecule for extracellular DNA, links DNA to inflammation. This observation suggests that IL-26 may act both as a driver and an effector of inflammation, leading to the establishment of a deleterious amplification loop and, ultimately, sustained inflammation. Thus, IL-26 emerges as an important mediator in local immunity/inflammation. The dysregulated expression and extracellular DNA carrier capacity of IL-26 may have profound consequences for the chronicity of inflammation. IL-26 also exhibits direct antimicrobial properties. This review summarizes recent advances on the biology of IL-26 and discusses its roles as a novel kinocidin

IL-26 inhibits hepatitis C virus replication in hepatocytes

Publisher Copyright: © 2021 European Association for the Study of the LiverBackground & Aims: Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. Methods: We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity. Results: We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. Conclusions: These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. Lay summary: This study sheds new light on the body's arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.Peer reviewe

The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination

Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1-383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (Δ215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Igκ+:Igλ+ B cell ratio and decreased recombination of Igh, Igκ, Igλ, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1Δ215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways, including control of the balance between short- and long-range recombination

Le syndrome de Wiskott-Aldrich

International audienceW iskott-Aldrich syndrome (WAS) is a primary immunode- ficiency disorder, characterized by a classic triad of microthrombocytopenia, eczema and infections. It is a monogenic X-linked recessive disorder. X-linked thrombocy- topenia (XLT) is now part of this syndrome with clinical forms initially described as less severe, but whose non-serious evolution is now questioned. WAS/XLT usually occurs during childhood, but a neonatal onset is possible. This pathology is associated with an increased risk of autoimmune manifesta- tions and onco-hematological complications which can occur regardless of the initial severity. The first manifestations are hemorrhagic (petechiae, bruising, purpura, epistaxis, oral or intracranial bleeding, bloody diarrhea). The second characte- ristic is acute or chronic eczema. Due to the immune deficiency, there are infectious manifestations (airways, digestive tract, skin) due to conventional or opportunistic bacteria. The severity of the disease, in addition to severe infectious complications, is linked to autoimmune manifestations in more than 40% of cases (hemolytic anemia and/or autoimmune neutropenia, vasculitis, inflammatory colitis, glomerulopathy, inflammatory joint pathologies). Patients with WAS also have an increased risk of developing tumors (especially lymphomas) at any age. Therapeutic progress in recent years are based on better management of complications, better results of bone marrow transplantation and development of gene therapy

Vaccins, adjuvants et réponse immunitaire post-vaccinale : bases immunologiques

International audienceLa vaccination a pour but d'induire une réponse immunitaire mémoire capable de protéger l'hôte contre la survenue d'une maladie liée à un agent infectieux. Au-delà de cette protection individuelle, les vaccins confèrent une protection collective en limitant le risque de transmission aux sujets qui ne peuvent être vaccinés ou ne répondent pas aux vaccins. La protection vaccinale repose sur les anticorps, qui neutralisent les toxines ou agents pathogènes ou favorisent la phago-cytose, mais également sur les cellules T helper nécessaires à la génération de lymphocytes B mémoires et de lymphocytes T cytotoxiques qui peuvent détruire les cellules infectées. Les principaux types de vaccins sont les vaccins vivants atténués, les vaccins inactivés à germes entiers et les vaccins inertes peptidiques. Les vaccins vivants atténués sont intrinsèquement immunogènes mais, du fait de leur potentiel réplicatif, sont contre-indiqués en cas d'immunosuppression. Les vaccins inactivés à germes entiers ne présentent plus ce risque mais nécessitent des rappels vaccinaux en raison d'une moindre immunogénicité. Les vaccins inertes peptidiques ne présentent plus de signaux de danger mais seulement les épitopes antigéniques et requièrent donc l'ajout d'adjuvants. Les effets secondaires avérés des vaccins correspondent à la réaction inflammatoire induite initialement et qui participe à la génération d'une réponse immunitaire mémoire cellulaire efficiente. La détermination d'un lien de causalité entre un effet indésirable et un vaccin repose sur la consistance, la force de l'association, la spécificité de l'évènement indésirable, de la relation temporelle et de la vraisemblance biologique entre l'injection vaccinale et l'évènement indésirable. Les effets secondaires sévères des vaccins restent exceptionnels

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations

Diagnostic biologique des déficits immunitaires primitifs

International audienceLe diagnostic précoce des déficits immuni-taires primitifs (DIP) est un élément clé pour une prise en charge adéquate des patients, afin de limiter la survenue de complications. Les manifestations cliniques et biologiques des DIP sont variées, incluant les infections récurrentes, mais aussi des manifestations oncologiques ou auto immunes. Des exa-mens biologiques simples, tels que l'hémo-gramme, le dosage pondéral des immuno-globulines et les sérologies post-vaccinales, peuvent permettre d'orienter le diagnostic étiologique. Des analyses plus spécialisées, comme le phénotypage lymphocytaire ou le dosage des sous classes d'IgG peuvent être réalisées en seconde intention. L'ensemble de ces examens nécessitent une interpré-tation rigoureuse en tenant notamment compte de l'âge du patient et du spectre infectieux

CD21 deficiency in two siblings with recurrent respiratory infections and hypogammaglobulinemia

International audienceno abstrac

CD21 deficiency in two siblings with recurrent respiratory infections and hypogammaglobulinemia

International audienceno abstrac

Apport de l’immunologie à la prise en charge diagnostique et thérapeutique des glomérulonéphrites extramembraneuses

International audienceLa glomérulonéphrite extra-membraneuse idiopathique peut désormais être qualifiée de maladie autoimmune glomérulaire. Un certain nombre d’autoanticorps a été décrit contre des composants glomérulaires ou contre des protéines alimentaires usuelles. Certains de ces autoanticorps, tel que les anticorps anti-PLA2R et les anticorps anti-THSD7A sont utiles pour suivre l’activité de la maladie et la réponse au traitement. Il existe certainement une susceptibilité génétique pour l’apparition de la maladie. La meilleure connaissance de la physiopathologie est le support rationnel à de nouvelles approches thérapeutiques en cours d’évaluation