Showing papers by "Alan Sher published in 2013"

Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome.

Abstract: Although adjuvants are critical vaccine components, their modes of action are poorly understood. In this study, we investigated the mechanisms by which the heat-killed mycobacteria in CFA promote Th17 CD4+ T cell responses. We found that IL-17 secretion by CD4+ T cells following CFA immunization requires MyD88 and IL-1β/IL-1R signaling. Through measurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro–IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1– and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators.

Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) in HIV Patients with Culture Confirmed Pulmonary Tuberculosis in India and the Potential Role of IL-6 in Prediction

Abstract: Background: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively. Methods: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS. Results: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14–47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7–16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9–23). Two patients died due to CNS TB-IRIS. Lower CD4 + T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis. Conclusion: Paradoxical TB–IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions.

Plasma Heme Oxygenase-1 Levels Distinguish Latent or Successfully Treated Human Tuberculosis from Active Disease

Abstract: Andrade, Bruno Bezerril. “Documento produzido em parceria ou por autor vinculado a Fiocruz, mas nao consta a informacao no documento”.

Biomarkers of Inflammation and Coagulation Are Associated With Mortality and Hepatitis Flares in Persons Coinfected With HIV and Hepatitis Viruses

Abstract: Background. Hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfection with human immunodeficiency virus (HIV) has a greater risk of mortality than either HCV or HBV infection alone and is frequently associated with hepatitis flares after antiretroviral therapy (ART) initiation. Methods. We performed a retrospective cohort study of 287 HIV-positive persons coinfected with HBV and/ or HCV (70 had HBV coinfection only, 207 had HCV coninfection only, and 10 had HBV and HCV coinfections) who had pre-ART plasma samples evaluated for biomarkers associated with death (within 4 years) and/or hepatitis flare (within 4 months) after ART initiation. A predictive biomarker risk score was calculated. Results. Forty-eight deaths and 50 hepatitis flares occurred. Nonsurvivors were older, had more prior AIDSdefining events, and had higher pre-ART triglycerides and aspartate transaminase levels. Detectable hyaluronic acid and higher D-dimer, interleukin 6, interleukin 8, and soluble CD14 levels were associated with death in univariate models and with a composite biomarker risk score. The risk of hepatitis flares was higher with HBV coinfection only (24.3%) and with HBV and HCV coinfection (50%) than with HCV coinfection only (13.5%). Higher levels of alanine transaminase and interleukin 10 were also associated with hepatitis flares. Conclusions. Among HIV-positive patients coinfected with HBV and/or HCV who are initiating ART, biomarkers of inflammation and coagulation are associated with an increased risk of death, whereas HBV coinfection and higher pre-ART interleukin 10 levels are associated with hepatitis flares.

CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection

Abstract: Synthetic glucocorticoids (GCs) are commonly used in the treatment of inflammatory diseases, but the role of endogenous GCs in the regulation of host-protective immune responses is poorly understood. Here we show that GCs are induced during acute Toxoplasma gondii infection and directly control the T cell response to the parasite. When infected with toxoplasma, mice that selectively lack GC receptor (GR) expression in T cells (GRlck-Cre) rapidly succumb to infection despite displaying parasite burdens indistinguishable from control animals and unaltered levels of the innate cytokines IL-12 and IL-27. Mortality in the GRlck-Cre mice was associated with immunopathology and hyperactive Th1 cell function as revealed by enhanced IFN-γ and TNF production in vivo. Unexpectedly, these CD4+ T lymphocytes also overexpressed IL-10. Importantly, CD4+ T cell depletion in wild-type or GRlck-Cre mice led to ablation of the GC response to infection. Moreover, in toxoplasma-infected RAG−/− animals, adoptive transfer of CD4+ T lymphocytes was required for GC induction. These findings establish a novel IL-10–independent immunomodulatory circuit in which CD4+ T cells trigger a GC response that in turn dampens their own effector function. In the case of T. gondii infection, this self-regulatory pathway is critical for preventing collateral tissue damage and promoting host survival.

Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica

Abstract: Resistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected with Entamoeba histolytica than those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected against E. histolytica via STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanized LEPR Q or R allele at codon 223 were intracecally infected with E. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues were analyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had cleared E. histolytica, whereas 39% of 223R mice were infected. Thirty-seven genes were differentially expressed in response to infection at 72 h, including proinflammatory genes (CXCL2, S100A8/9, PLA2G7, ITBG2, and MMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h postchallenge of infected Q223 versus R223 mice identified a subset of differentially expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection by E. histolytica. As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity.

cells to phylogenetically distinct parasites Unique gene expression profiles of human macrophages and dendritic

Abstract: Ł € Phagocytes (973 articles)Ł € Immunobiology (5019 articles)Ł € Genomics (149 articles)Ł € Gene Expression (1086 articles)Articles on similar topics can be found in the following Blood collectionshttp://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about reproducing this article in parts or in its entirety may be found online at:http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at:http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at:

This information is current as from a Mac-1-Positive Host Cell Population Expression of Infectious Virus Selectively Mycobacterium avium Induces the Infection of HIV-1 Transgenic Mice with

Abstract: Alan SherPatterson, Cecil Fox, Gene M. Shearer, George Englund and T. Mark Doherty, Claire Chougnet, Marco Schito, Bruce K.http://www.jimmunol.org/content/163/3/1506J Immunol€1999; 163:1506-1515; ;Referenceshttp://www.jimmunol.org/content/163/3/1506.full#ref-list-1This article cites 37 articles, 20 of which you can access for free at: Subscriptionshttp://jimmunol.org/subscriptionsInformation about subscribing to The Journal of Immunology is online at: Permissionshttp://www.aai.org/ji/copyright.htmlSubmit copyright permission requests at: Email Alertshttp://jimmunol.org/cgi/alerts/etocReceive free email-alerts when new articles cite this article. Sign up at:

A formulation of mycobacterial components as an adjuvant for inducing th17 responses

Abstract: The invention provides immunogenic compositions comprising CARD9 and/or Caspase 1 agonists and methods of using the composition to induce or enhance an immune response.

-Dependent Effector γ Cell- and IFN- mansoni Requires the Induction of Both B Optimal Vaccination Against Schistosoma

Abstract: Cheever and Alan SherSara Hieny, Patricia Caspar, Stephanie James, Allen W. Dragana Jankovic, Thomas A. Wynn, Marika C. Kullberg,http://www.jimmunol.org/content/162/1/345J Immunol€1999; 162:345-351; ;Referenceshttp://www.jimmunol.org/content/162/1/345.full#ref-list-1This article cites 45 articles, 28 of which you can access for free at: Subscriptionshttp://jimmunol.org/subscriptionsInformation about subscribing to The Journal of Immunology is online at: Permissionshttp://www.aai.org/ji/copyright.htmlSubmit copyright permission requests at: Email Alertshttp://jimmunol.org/cgi/alerts/etocReceive free email-alerts when new articles cite this article. Sign up at:

Formulation de composants mycobactériens comme adjuvant pour induire des réponses th17

Abstract: L'invention concerne des compositions immunogenes comprenant des agonistes de CARD9 et/ou de la caspase 1, ainsi que des procedes d'utilisation de ces compositions pour induire ou renforcer une reponse immunitaire.