Class Of Immune Response Research Articles

Virom/SARS-CoV2 interakcija - upražnjeno mesto za prirodne komponente

One of the most striking marks of infection caused by the SARS-CoV-2 is the distinguishing heterogeneity of the clinical presentations in a population that varies from asymptomatic to severe forms. Pandemic proportion brings into the foreground the number of people with severe forms of the disease, putting aside the fact that a large portion of the population is an asymptomatic, making them silent carriers of the virus. Additional confusion is made by inconsistent data about the presence of the virus in the nasopharyngeal region and the manifestation of the disease symptoms. Different tissue distribution of virus in the body starting from guts, liver, muscles, kidney etc. without any signs of tissue destruction, opens up the possibility that individuals with negative results of PCR test in the nasopharyngeal swab may also be latent carriers of the infection. Overall clinical presentation of the disease is influenced by the initial protection gained through the accumulated "experience" collected from previous encountering of corona family and noncorona viruses, resulting in overlapping of the humoral and cellular immunity. Apart from this, unjustifiably neglected but very significant form of host defense against infection is disease tolerance based on cohabitation with pathogen. It is important to note that consequences of the disease tolerance in terms of pathological and epidemiological aspects are quite different then classical antiviral immune response. This work will elaborate the impact of virome on the course of infection at all stages taking into account both immune resistance, as an ability of the host immune system to eliminate pathogen, and disease tolerance, as a form of host defense with neutral to positive impact to pathogen load. Also, in accordance with the above mentioned, the potential of naturally occurring compounds to profile the course of infection and to support currently available protocols for COVID-19 treatment was discussed.

Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include up-Regulated Innate Immune Modulators

The formation of pathological anti-FVIII antibodies, referred to as "inhibitors", is the most serious complication of therapeutic FVIII infusions, affecting up to one third of severe Hemophilia A (HA) patients. Intensive FVIII therapy, i.e. "Immune Tolerance Induction" (ITI), enables ~2/3 of treated patients to achieve peripheral tolerance to FVIII. FVIII inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development versus immune tolerance, achieved with or without ITI therapy, are not well understood. To address these questions, we carried out temporal transcriptomics profiling of FVIII-stimulated peripheral blood mononuclear cells (PBMCs) from HA subjects with and without a current or historic inhibitor using RNA-seq. PBMCs were isolated from 40 subjects in the following groups: (A) HA with an inhibitor that resolved either following ITI or spontaneously; (B) HA with a current inhibitor; (C) HA with no inhibitor history and (D) non-HA healthy controls. PBMCs were rested overnight and then stimulated with 5 nM FVIII, and total RNA was isolated 4, 16, 24 and 48 hours following stimulation. RNA from unstimulated cells at t = 4 hrs served as a negative control. Time-series differential expression analysis was performed with DESeq2 and genes with a log likelihood ratio test FDR <0.05 and an absolute fold change >1.25 at at least one stimulation time point compared to control were deemed significant. Subjects with a resolved past inhibitor (Group A) showed differential expression of only 15 genes. In contrast, subjects with a current inhibitor (Group B) showed differential expression of 56 genes. A clustering analysis divided the temporal trajectories of Group B genes into 3 distinct clusters. Twenty-three genes were up-regulated at 16 hr and 21 genes at 48 hr post-stimulation, respectively. Interestingly, gene ontology (GO) enrichment analysis of these genes revealed enrichments for innate immune modulators, including NLRP3, TLR8, IL32, CLEC10A and COLEC12.NLRP3 and TLR8 are associated with enhanced secretion of the pro-inflammatory cytokines IL-1beta and TNF-alpha, while IL32, which has several isoforms, has been associated with both inflammatory and regulatory immune processes. Expression levels of NLRP3, TLR8, CLEC10A and IL32 transcripts were validated by real time PCR, and changes in RNA transcript abundances correlated well with the RNA-seq results. IL-32 results were validated by both RT-qPCR on an aliquot of the original RNA sample and ELISA to measure the cytokine in supernatants at t=48 hrs. HA subjects with no inhibitor history (Group C) had 195 differentially expressed genes whose temporal profiles fell into 4 distinct clusters. GO enrichment analysis revealed biological processes related to epithelial cell proliferation, responses to toxic substances, and positive/negative regulation of cytokine secretion (TNF, NQO1, PMEPA1). The non-HA healthy control subjects (Group D) also showed cellular responses to ex vivo FVIII stimulation. A total of 63 differentially regulated genes fell into 4 distinct clusters. GO analysis identified expression patterns associated with leukocyte-mediated immunity, T-cell activation, and a hypoxia response. Overall, distinct transcriptional signatures were identified for each of the four groups, providing clues as to cellular mechanisms leading to or accompanying their disparate anti-FVIII antibody responses. We are currently characterizing PBMC immune cell subsets, e.g. macrophages and CD4+ T cells, to identify specific cell types responsible for the differentially regulated genes. Cellular responses of tolerized HA subjects and healthy non-HA controls were consistent with the known immunogenicity of FVIII, including persistence of FVIII-specific CD4+ T cells even in individuals with no measurable FVIII inhibitor. The inflammatory status of HA patients suffering from an ongoing inhibitor clearly includes up-regulation of innate immune modulators, some of which may act as ongoing danger signals that influence the responses to, and eventual outcome of, ITI therapy. Disclosures Pratt: Grifols, Inc: Research Funding; Bloodworks NW: Patents & Royalties: inventor on patents related to FVIII immunogenicity.

Intestinal Barrier Function in Gluten-Related Disorders.

Gluten-related disorders include distinct disease entities, namely celiac disease, wheat-associated allergy and non-celiac gluten/wheat sensitivity. Despite having in common the contact of the gastrointestinal mucosa with components of wheat and other cereals as a causative factor, these clinical entities have distinct pathophysiological pathways. In celiac disease, a T-cell mediate immune reaction triggered by gluten ingestion is central in the pathogenesis of the enteropathy, while wheat allergy develops as a rapid immunoglobulin E- or non-immunoglobulin E-mediated immune response. In non-celiac wheat sensitivity, classical adaptive immune responses are not involved. Instead, recent research has revealed that an innate immune response to a yet-to-be-defined antigen, as well as the gut microbiota, are pivotal in the development in this disorder. Although impairment of the epithelial barrier has been described in all three clinical conditions, its role as a potential pathogenetic co-factor, specifically in celiac disease and non-celiac wheat sensitivity, is still a matter of investigation. This article gives a short overview of the mucosal barrier of the small intestine, summarizes the aspects of barrier dysfunction observed in all three gluten-related disorders and reviews literature data in favor of a primary involvement of the epithelial barrier in the development of celiac disease and non-celiac wheat sensitivity.

Chlorine-based disinfection for controlling horizontal transmission of VNN in a seawater recirculating aquaculture system growing European seabass

An innovative physicochemical approach for treating the recycled water within a seawater recirculating aquaculture systems (RAS) has been recently developed, which includes inherent disinfection within the ammonia electro-oxidation cycle. The efficiency of the inherent disinfection was tested in comparison to a RAS consisting of a bio-treatment unit (which did not include a disinfection component), both systems operating under similar fish densities and makeup water flow rates. Neural necrosis virus (NNV) was chosen as a model pathogen, due to its pathogenicity to sea bass (Dicentrarchus labrax) and many other aquaculture species. The course of infection (exposure → immune response → infection) was monitored in a cohabitation experiment, testing the horizontal transmission of NNV using immunological and molecular methods, in addition to recording clinical signs. Results indicate that under the conditions prevailing in the RAS in which the physicochemical method was applied, the NNV horizontal transmission pathway was blocked. No immune response to viral neural necrosis (VNN) was detected in the fish sampled during the experiment, in contrast to a significant and classic immune response observed in the fish held in the RAS based on bio-treatment. Challenged fish in both systems showed typical outbreak profile, however in the bio-treated RAS, a slow disease course was observed, hypothesized by us to be the result of a high concentration of humic substances present in the water. The results indicated that the off-host phase of the NNV can be controlled by effective chlorine-based disinfection. The disinfection effect in the physico-chemically-treated RAS and C∙t (chlorine concentration times the retention time) value quantified in the present work are most likely sufficient to reduce infection of a wide range of other aquaculture pathogens.

Immune paradigm and immunosuppressive dominance in the pathogenesis of major diseases of the modern man

The article discusses the determining role of immunopathogenesis of the main diseases of the modern man (cancer, atherosclerosis, autoimmune, allergic and infectious diseases). In this regard, the concept of «immune paradigm» is introduced. There is evidence that any pathology is based on the classical immune response to the antigen, whether auto- or xenoantigen, with all stages of its development and parallel changes in the state of immune tolerance: its breakdown in cases of autoimmune and allergic diseases and atherosclerosis; its establishment in cases of cancer and infectious diseases. In the meantime, it is emphasized that the immunopathogenesis is based on insufficient or increased function of immunocompetent regulatory cells with suppressive activity. Here the concept of «immunosuppressive dominant» is introduced. Finally, we discuss the need for fundamental changes in treatment of these diseases, with a focus on molecular and cellular immunotherapy methods and development of integrated approaches to their application.

Phagocytosis in the Brain: Homeostasis and Disease.

Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, and diseased states. Phagocytosis is a highly complex process that is specialized for the uptake and removal of opsonized and non-opsonized targets, such as pathogens, apoptotic cells, and cellular debris. While the role of phagocytosis in mediating classical innate and adaptive immune responses has been known for decades, it is now appreciated that phagocytosis is also critical throughout early neural development, homeostasis, and initiating repair mechanisms. As such, modulating phagocytic processes has provided unexplored avenues with the intent of developing novel therapeutics that promote repair and regeneration in the CNS. Here, we review the functional consequences that phagocytosis plays in both the healthy and diseased CNS, and summarize how phagocytosis contributes to overall pathophysiological mechanisms involved in brain injury and repair.

Disentangling the immune response and host-pathogen interactions in Francisella noatunensis infected Atlantic cod

The genetic repertoire underlying teleost immunity has been shown to be highly variable. A rare example is Atlantic cod and its relatives Gadiformes that lacks a hallmark of vertebrate immunity: Major Histocompatibility Complex class II. No immunological studies so far have fully unraveled the functionality of this particular immune system. Through global transcriptomic profiling, we investigate the immune response and host-pathogen interaction of Atlantic cod infected with the facultative intracellular bacterium Francisella noatunensis. We find that Atlantic cod displays an overall classic innate immune response with inflammation, acute-phase proteins and cell recruitment through up-regulation of e.g. IL1B, fibrinogen, cathelicidin, hepcidin and several chemotactic cytokines such as the neutrophil attractants CXCL1 and CXCL8. In terms of adaptive immunity, we observe up-regulation of interferon gamma followed by up-regulation of several MHCI transcripts and genes related to antigen transport and loading. Finally, we find up-regulation of immunoglobulins and down-regulation of T-cell and NK-like cell markers. Our analyses also uncover some contradictory transcriptional findings such as up-regulation of anti-inflammatory IL10 as well as down-regulation of the NADPH oxidase complex and myeloperoxidase. This we interpret as the result of host-pathogen interactions where F. noatunensis modulates the immune response. In summary, our results suggest that Atlantic cod mounts a classic innate immune response as well as a neutrophil-driven response. In terms of adaptive immunity, both endogenous and exogenous antigens are being presented on MHCI and antibody production is likely enabled through direct B-cell stimulation with possible neutrophil help. Collectively, we have obtained novel insight in the orchestration of the Atlantic cod immune system and determined likely targets of F. noatunensis host-pathogen interactions.

In Vitro Granuloma Models of Tuberculosis: Potential and Challenges.

Despite intensive research efforts, several fundamental disease processes for tuberculosis (TB) remain poorly understood. A central enigma is that host immunity is necessary to control disease yet promotes transmission by causing lung immunopathology. Our inability to distinguish these processes makes it challenging to design rational novel interventions. Elucidating basic immune mechanisms likely requires both in vivo and in vitro analyses, since Mycobacterium tuberculosis is a highly specialized human pathogen. The classic immune response is the TB granuloma organized in three dimensions within extracellular matrix. Several groups are developing cell culture granuloma models. In January 2018, NIAID convened a workshop, entitled "3-D Human in vitro TB Granuloma Model" to advance the field. Here, we summarize the arguments for developing advanced TB cell culture models and critically review those currently available. We discuss how integrating complementary approaches, specifically organoids and mathematical modeling, can maximize progress, and conclude by discussing future challenges and opportunities.

Downregulation of Microparticle Release and Pro-Inflammatory Properties of Activated Human Polymorphonuclear Neutrophils by LMW Fucoidan

Exposition of neutrophils (polymorphonuclear neutrophils, PMNs) to bacterial products triggers exacerbated activation of these cells, increasing their harmful effects on host tissues. We evaluated the possibility of interfering with the classic immune innate responses of human PMNs exposed to bacterial endotoxin (lipopolysaccharide, LPS), and further stimulated with bacterial formyl peptide (N-formyl-methionine-leucine-phenylalanine, fMLP). We showed that the low- molecular-weight fucoidan (LMW-Fuc), a polysaccharide extracted from brown algae, attenuated the exacerbated activation induced by fMLP on LPS-primed PMNs, in vitro, impairing chemotaxis, NET formation, and the pro-survival and pro-oxidative effects. LMW-Fuc also inhibited the activation of canonical signaling pathways, AKT, bad, p47phox and MLC, activated by the exposition of PMN to bacterial products. The activation of PMN by sequential exposure to LPS and fMLP induced the release of L-selectin⁺ microparticles, which were able to trigger extracellular reactive oxygen species production by fresh PMNs and macrophages. Furthermore, we observed that LMW-Fuc inhibited microparticle release from activated PMN. In vivo experiments showed that circulating PMN-derived microparticles could be detected in mice exposed to bacterial products (LPS/fMLP), being downregulated in animals treated with LMW-Fuc. The data highlight the autocrine and paracrine role of pro-inflammatory microparticles derived from activated PMN and demonstrate the anti-inflammatory effects of LMW-Fuc on these cells.

How Should We Classify Kawasaki Disease?

The exact classification of Kawasaki disease (KD) has been debated. Infectious disease specialists have claimed it as an infection with a classic immune responses to an as yet unidentified pathogen that localizes to the coronary arteries. Others have favored an autoreactive hypothesis that KD is triggered by an antigen that shares homology with structures in the vascular wall, and molecular mimicry resulting in an immune response directed to that tissue. Rheumatologists have classified it as a systemic vasculitis, while some immunologists have stressed the robust nature of the innate immune response that causes both systemic inflammation as well as damage to the coronary arterial wall and questioned whether KD falls within the spectrum of autoinflammatory diseases. This review will describe the evidences available up to now regarding these hypotheses.

Modifying clonal selection theory with a probabilistic cell.

SummaryProblem‐solving strategies in immunology currently utilize a series of ad hoc, qualitative variations on a foundation of Burnet's formulation of clonal selection theory. These modifications, including versions of two‐signal theory, describe how signals regulate lymphocytes to make important decisions governing self‐tolerance and changes to their effector and memory states. These theories are useful but are proving inadequate to explain the observable genesis and control of heterogeneity in cell types, the nonlinear passage of cell fate trajectories and how the input from multiple environmental signals can be integrated at different times and strengths. Here, I argue for a paradigm change to place immune theory on a firmer philosophical and quantitative foundation to resolve these difficulties. This change rejects the notion of identical cell subsets and substitutes the concept of a cell as comprised of autonomous functional mechanical components subject to stochastic variations in construction and operation. The theory aims to explain immunity in terms of cell population dynamics, dictated by the operation of cell machinery, such as randomizing elements, division counters, and fate timers. The effect of communicating signals alone and in combination within this system is determined with a cellular calculus. A series of models developed with these principles can resolve logical cell fate and signaling paradoxes and offer a reinterpretation for how self‐non‐self discrimination and immune response class are controlled.

NKG2D-Based CAR T Cells and Radiotherapy Exert Synergistic Efficacy in Glioblastoma.

Chimeric antigen receptor (CAR) T-cell therapy is an emerging immunotherapy against several malignancies including glioblastoma, the most common and most aggressive malignant primary brain tumor in adults. The challenges in solid tumor immunotherapy comprise heterogenously expressed tumor target antigens and restricted trafficking of CAR T cells to and impaired long-term persistence at the tumor site, as well as the unaddressed integration of CAR T-cell therapy into conventional anticancer treatments. We addressed these questions using a NKG2D-based chimeric antigen receptor construct (chNKG2D) in fully immunocompetent orthotopic glioblastoma mouse models. ChNKG2D T cells demonstrated high IFNγ production and cytolytic activity in vitro Upon systemic administration in vivo, chNKG2D T cells migrated to the tumor site in the brain, did not induce adverse events, prolonged survival, and cured a fraction of glioma-bearing mice. Surviving mice were protected long-term against tumor rechallenge. Mechanistically, this was not solely the result of a classical immune memory response, but rather involved local persistence of chNKG2D T cells. A subtherapeutic dose of local radiotherapy in combination with chNKG2D T-cell treatment resulted in synergistic activity in two independent syngeneic mouse glioma models by promoting migration of CAR T cells to the tumor site and increased effector functions. We thus provide preclinical proof-of-concept of NKG2D CAR T-cell activity in mouse glioma models and demonstrate efficacy, long-term persistence, and synergistic activity in combination with radiotherapy, providing a rationale to translate this immunotherapeutic strategy to human glioma patients.Significance: These findings provide evidence for synergy of conventional anticancer therapy and CAR T cells and heralds future studies for other treatment combinations. Cancer Res; 78(4); 1031-43. ©2017 AACR.

Impact of Chronic Viral Infection on T-Cell Dependent Humoral Immune Response.

During the last decades, considerable efforts have been done to decipher mechanisms supported by microorganisms or viruses involved in the development, differentiation, and function of immune cells. Pathogens and their associated secretome as well as the continuous inflammation observed in chronic infection are shaping both innate and adaptive immunity. Secondary lymphoid organs are functional structures ensuring the mounting of adaptive immune response against microorganisms and viruses. Inside these organs, germinal centers (GCs) are the specialized sites where mature B-cell differentiation occurs leading to the release of high-affinity immunoglobulin (Ig)-secreting cells. Different steps are critical to complete B-cell differentiation process, including proliferation, somatic hypermutations in Ig variable genes, affinity-based selection, and class switch recombination. All these steps require intense interactions with cognate CD4+ helper T cells belonging to follicular helper lineage. Interestingly, pathogens can disturb this subtle machinery affecting the classical adaptive immune response. In this review, we describe how viruses could act directly on GC B cells, either through B-cell infection or by their contribution to B-cell cancer development and maintenance. In addition, we depict the indirect impact of viruses on B-cell response through infection of GC T cells and stromal cells, leading to immune response modulation.

The Human CMV IE1 Protein: An Offender of PML Nuclear Bodies.

PML nuclear bodies (PML-NBs) are SUMOylation-dependent, highly complex protein assemblies that accumulate in the interchromosomal territories of the cell nucleus. Research of the last two decades revealed that many viruses have evolved effector proteins that modify PML-NBs. This correlates with antagonization of individual PML-NB components which act as host cell restriction factors. The multifunctional immediate-early protein IE1 of human cytomegalovirus directly interacts with the PML protein resulting in a disruption of the dot-like structure of PML-NBs. This review summarizes recent advances on the functional consequences of PML-NB modification by IE1. In particular, we describe that PML exerts a novel co-regulatory role during the interferon response which is abrogated by IE1. Via binding to PML, IE1 is able to compromise both intrinsic antiviral defense mechanisms and classical innate immune responses. These interactions of IE1 with innate host defenses are crucial for the onset of lytic replication and, consequently, may represent promising targets for antiviral strategies.

IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.

IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses. (Hepatology 2017;65:89-103).

Immune-class regulation in chronic Hepatitis B virus (HBV) infection and the effects of liver micro-environment on this regulation

The immune system contains a lot of humoral and cellular components and defends the human body. But in the case of chronic HBV infection, it becomes ineffective. HBV is a hepatotropic virus infecting 350 million people around the World chronically. HBV can be transmitted through sexual intercourse, blood transfusion and prenatally. After viral entry into the hepatocytes, the virus uncoats itself in the nuclear area and tries to escape from the immune system. This escape may occur only in the 4% of the cases which ends up with chronic HBV infection. In the first 6-8 weeks of the infection, a very weak innate immune response may be detected. In the following 12 weeks, delayed and poor adaptive immune response is mounted due to the weak innate immune response. As it’s known, the immune response against viruses is T cell-mediated. T cells defend against HBV by removing infected hepatocytes. This process changes the micro-environment of the liver determining which class of immune response should be mounted. The micro-environment and the tissue components educate dentritic cells to activate T-helper (Th) cells stimulating and recruiting proper immune cells controlling the proper immune-class. Two types of immune classes have been accounted for in this hypothesis: Th1, which is recruited in viral and bacterial infections and Th2 recruited basically in parasitic infections. The changes in the micro-environment of liver and some components of the HBV such as HBeAg may affect the immune class and even convert it from Th1 to Th2 in the case of HBV infection. The question in this hypothesis is whether the class switching (Th1 → Th2) may play role in chronicity of HBV and ineffectiveness of the adaptive immune response mounted against virus. In the light of this information, here we hypothesize that chronic HBV infection may be eradicated and prevented by keeping the liver micro-environment intact inducing Th1 immune-class and novel treatments as wells as new diagnosis methods for chronic HBV infections can be developed based on Th1 → Th2 immune class switching.

Regulation of IgE-Mediated Food Allergy by IL-9 Producing Mucosal Mast Cells and Type 2 Innate Lymphoid Cells.

Due to the increasing prevalence and number of life-threatening cases, food allergy has emerged as a major health concern. The classic immune response seen during food allergy is allergen-specific IgE sensitization and hypersensitivity reactions to foods occur in the effector phase with often severe and deleterious outcomes. Recent research has advanced understanding of the immunological mechanisms occurring during the effector phase of allergic reactions to ingested food. Therefore, this review will not only cover the mucosal immune system of the gastrointestinal tract and the immunological mechanisms underlying IgE-mediated food allergy, but will also introduce cells recently identified to have a role in the hypersensitivity reaction to food allergens. These include IL-9 producing mucosal mast cells (MMC9s) and type 2 innate lymphoid cells (ILC2s). The involvement of these cell types in potentiating the type 2 immune response and developing the anaphylactic response to food allergens will be discussed. In addition, it has become apparent that there is a collaboration between these cells that contributes to an individual's susceptibility to IgE-mediated food allergy.

Fast, Ultrasensitive Detection of Reactive Oxygen Species Using a Carbon Nanotube Based-Electrocatalytic Intracellular Sensor.

Herein, we report a highly sensitive electrocatalytic sensor-cell construct that can electrochemically communicate with the internal environment of immune cells (e.g., macrophages) via the selective monitoring of a particular reactive oxygen species (ROS), hydrogen peroxide. The sensor, which is based on vertically aligned single-walled carbon nanotubes functionalized with an osmium electrocatalyst, enabled the unprecedented detection of a local intracellular “pulse” of ROS on a short second time scale in response to bacterial endotoxin (lipopolysaccharide-LPS) stimulation. Our studies have shown that this initial pulse of ROS is dependent on NADPH oxidase (NOX) and toll like receptor 4 (TLR4). The results suggest that bacteria can induce a rapid intracellular pulse of ROS in macrophages that initiates the classical innate immune response of these cells to infection.

Role of indoleamine 2,3-dioxygenase (IDO) in testicular immune-privilege

Event Abstract Back to Event Role of indoleamine 2,3-dioxygenase (IDO) in testicular immune-privilege Gisela S. Gualdoni1, Patricia V. Jacobo1, Cristian M. Sobarzo1, Christian Höcht2, Marcelo Hill3, Ignacio Anegon4, Livia Lustig1 and Vanesa A. Guazzone1* 1 INBIOMED. UBA-CONICET. Facultad de Medicina- Universidad de Buenos Aires, Argentina 2 Cátedra de Farmacología. Facultad de Farmacia y Bioquímica. UBA., Argentina 3 Instituto Pasteur, Uruguay 4 INSERM UMR 1064, France Problem The production, differentiation, and presence of male gametes represent inimitable challenge to immune system, as they appear long after the establishment of normal immune tolerance mechanisms. The ability of the testes to tolerate autoantigenic germ cells as well as survival in the testicular interstitium of transplanted foreign tissues has led to the testis being considered an immunologically privileged site. Disruption of the immune privilege status following trauma, tumor, or autoimmune orchitis often results in male infertility. There is strong evidence that IDO mediates potent immunosupression in classical immune responses as well as in fetal tolerance, tumor immune resistance, and regulation of autoimmunity. However, in spite of considerable progress the relevance of IDO in testis pathophysiology have not yet been explored. Here we evaluated the in vivo role of IDO in experimental autoimmune orchitis (EAO), a well-established model of autoimmune testicular inflammation associated with subfertility and infertility Method of Study EAO was induced in adult Wistar rats with testicular homogenate and adjuvants. Control (C) rats injected with saline and adjuvants, and normal untreated rats (N) were also studied. IDO localization and level of expression in the testis was analyzed by immunostaining and Western blot, respectively. Testis tryptophan and kynurenine concentrations were measured by HPLC. To inhibit IDO, EAO rats received 1-methyl-tryptophan during the immunization period. Results A similar localization of IDO expression was detected in N, C and EAO rats. In testicular interstitium, IDO was detected in mononuclear and endothelial cells. A reduced IDO expression was detected, by Western blot, in seminiferous tubule fractions from EAO compared with N and C rats. This phenomenom was concomitant to a significant reduction of tryptophan-degrading activity in EAO testis. In vivo inhibition of IDO increased the severity of the disease. Conclusion Our results unveil a down regulation of IDO-based tolerance when testicular immune privilege is disrupted. Keywords: Testis, autoimmune orchitis, Immune Privilege, indoleamine 2,3-dioxygenase, Infertility, Male Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Immunology of reproduction Citation: Gualdoni GS, Jacobo PV, Sobarzo CM, Höcht C, Hill M, Anegon I, Lustig L and Guazzone VA (2015). Role of indoleamine 2,3-dioxygenase (IDO) in testicular immune-privilege. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00105 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 May 2015; Published Online: 14 Sep 2015. * Correspondence: Dr. Vanesa A Guazzone, INBIOMED. UBA-CONICET. Facultad de Medicina- Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina, ciruba@fmed.uba.ar Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gisela S Gualdoni Patricia V Jacobo Cristian M Sobarzo Christian Höcht Marcelo Hill Ignacio Anegon Livia Lustig Vanesa A Guazzone Google Gisela S Gualdoni Patricia V Jacobo Cristian M Sobarzo Christian Höcht Marcelo Hill Ignacio Anegon Livia Lustig Vanesa A Guazzone Google Scholar Gisela S Gualdoni Patricia V Jacobo Cristian M Sobarzo Christian Höcht Marcelo Hill Ignacio Anegon Livia Lustig Vanesa A Guazzone PubMed Gisela S Gualdoni Patricia V Jacobo Cristian M Sobarzo Christian Höcht Marcelo Hill Ignacio Anegon Livia Lustig Vanesa A Guazzone Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury

IL-17 is a cytokine mainly from IL-17-producing T cells, which are one of subsets of CD4+ T cells and play a role in adaptive immune system. Recent studies have demonstrated that IL-17A can act rapidly as an innate immune responder during infection before the onset of its classic adaptive immune response. This role of IL-17A in innate immune response is implicated in lipopolysaccharide (LPS)-induced lung inflammation. Very recently, we have reported that endoplasmic reticulum (ER) stress is involved in LPS-induced lung inflammation in vivo and in vitro. This study aimed to elucidate the role of IL-17A in LPS-induced lung injury, focusing on the link with ER stress. We treated a murine model of LPS-induced lung injury with IL-17A neutralizing antibody and 4-phenylbutyrate (4-PBA), a representative ER stress inhibitor. In addition, we evaluated the effects of IL-17A on ER stress in LPS-stimulated bronchial epithelial cells. Our results showed that inhibition of IL-17A decreased LPS-induced pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-κB (NF-κB), infiltration of dendritic cells, increased expression of Toll-like receptor 4 (TLR4), activation of NLRP3 inflammasome, and increased ER stress in the lung. 4-PBA or TAK-242, a TLR4 inhibitor attenuated expression of IL-17A thereby improving LPS-induced lung inflammation. Intriguingly, we observed that stimulation with LPS increased expression of IL-17A in airway epithelial cells and co-stimulation with IL-17A further increased ER stress and NF-κB activation. This study indicates that the interrelationship between IL-17A and ER stress plays an important role in LPS-induced injury showing a positive feedback in airway epithelial cells and suggests that targeting their interaction can be a potential therapeutic approach to overcome one of severe refractory pulmonary disorders.