scholarly journals Selective Inhibition of Ii-dependent Antigen Presentation by Helicobacter pylori Toxin VacA

1998 ◽  
Vol 187 (1) ◽  
pp. 135-140 ◽  
Author(s):  
Maurizio Molinari ◽  
Mariolina Salio ◽  
Carmela Galli ◽  
Nathalie Norais ◽  
Rino Rappuoli ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Membrane Trafficking ◽  
Chronic Infection ◽  
Antigen Processing ◽  
Class Ii ◽  
Proteolytic Processing ◽  
Presentation Pathway ◽  
H Pylori

A major virulence factor in the stomach chronic infection by Helicobacter pylori is a protein toxin (VacA), which alters cell membrane trafficking of late endosomal/prelysosomal compartments. Its role in the chronic infection established by H. pylori is unknown. To test the possibility that VacA alters antigen processing taking place in prelysosomal compartments, we have used the well-established model of antigen processing and presentation consisting of tetanus toxoid–specific human (CD4+) T cells stimulated by autologous antigen-pulsed Epstein-Barr virus-transformed B cells. We found that VacA interferes with proteolytic processing of tetanus toxin and toxoid and specifically inhibits the Ii-dependent pathway of antigen presentation mediated by newly synthesized major histocompatibility complex (MHC) class II, while leaving unaffected the presentation pathway dependent on recycling MHC class II. The results presented here suggest that VacA may contribute to the persistence of H. pylori by interfering with protective immunity and that this toxin is a new useful tool in the study of the different pathways of antigen presentation.

Immune-related gene expression deficit of leukemia stem cells (LSC) in AML.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7011-7011
Author(s):  
Kamal Chamoun ◽  
Christopher Brent Benton ◽  
Ahmed AlRawi ◽  
Rodrigo Jacamo ◽  
Patrick Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Differentially Expressed Gene ◽  
Enrichment Analysis ◽  
Class Ii ◽  
Differentially Expressed ◽  
Pathway Gene ◽  
Presentation Pathway

7011 Background: AML LSC are believed to be responsible for residual and resistant leukemic disease leading to relapse. Understanding differences between bulk AML and the LSC subpopulation may allow the identification of novel LSC targets, especially for the most adverse risk AML where few patients are cured. Targeting LSC may be needed to eradicate AML, and immune-based therapies provide an approach for eliminating LSC. The transcriptional landscape of immune-related genes in LSC is not well understood. Methods: Samples were collected at diagnosis from 12 patients with high-risk AML prior to therapy. Bulk (CD45-dim blasts) and LSC (Lin-CD34+CD38-CD123+) AML marrow cells were FACS-sorted and analyzed using whole genome RNA-sequencing. Transcriptomes were analyzed using AltAnalyze software to identify differentially expressed genes in bulk AML cells and in AML LSC populations. These genes were further assessed by gene enrichment analysis using data from Gene Ontology (GO) and the Cancer Genome Atlas Project (CGAP). Results: Sixty-eight genes were identified with greater than 3-fold differential expression between bulk AML and LSC. GO enrichment analysis demonstrated more than 10-fold enrichment of genes involved in the molecular functions, biologic processes, and cell components related to the antigen presentation pathway, with the comparative down-regulation occurring in LSC. Among the top differentially expressed gene clusters, both the MHC class II and interferon-gamma signaling/response pathway gene expression was blunted in LSC. Additional expression analysis revealed that 42% of a CGAP-curated list of 201 antigen-processing and -presentation genes had significantly decreased expression in the LSC subpopulation compared to bulk AML. Conclusions: LSC from primary AML patient samples are characterized by reduction in expression of MHC class II receptor and antigen presentation genes compared to bulk AML. These results suggest that impairment in the presentation and/or processing of tumor associated antigens by MHC class II on LSC, along with tonic sponging of immune response cells and diversion away from LSC by bulk AML, may contribute to LSC evasion of immune surveillance and response.

scholarly journals Differential signal transduction, membrane trafficking, and immune effector functions mediated by FcγRI versus FcγRIIa

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 318-327 ◽  
Author(s):  
Xilei Dai ◽  
Manikandan Jayapal ◽  
Hwee Kee Tay ◽  
Renji Reghunathan ◽  
Gen Lin ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Membrane Trafficking ◽  
Immune Complexes ◽  
Antigen Processing ◽  
Fc Receptors ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Human Leukocyte ◽  
Differential Signal ◽  
Proinflammatory Mediators

Abstract Receptors for the fragment crystallizable region of immunoglobulin-G (FcγRs) play an important role in linking the humoral and cellular arms of the immune response. In this study, we present a comprehensive functional comparison of 2 human Fc-receptors, FcγRI and FcγRIIa. Activation of FcγRI results in a novel signaling cascade that links phospholipase D1 to sphingosine kinase-1 in U937 cells and primary human monocytes. This induces the expression of proinflammatory mediators and is associated with trafficking of immune complexes into human leukocyte antigen-DM positive antigen-processing compartments coupled with improved MHC class II–mediated antigen presentation to T lymphocytes. In contrast, activation of FcγRIIa elicits signaling through phospholipase Cγ1, resulting in increases in intracellular calcium, activation of nicotinamide adenine dinucleotide phosphate-oxidative burst, and differential membrane trafficking combined with impaired antigen presentation and proinflammatory cytokine expression. These data provide a mechanistic insight into the disparate activities associated with Fc receptors in immunity, namely, reinforcement of immune responses through stimulation of proinflammatory signaling and antigen presentation, versus the maintenance of immunologic homeostasis through the noninflammatory clearance of immune complexes.

scholarly journals Alternative Endogenous Protein Processing via an Autophagy-Dependent Pathway Compensates for Yersinia-Mediated Inhibition of Endosomal Major Histocompatibility Complex Class II Antigen Presentation

2010 ◽  
Vol 78 (12) ◽  
pp. 5138-5150 ◽  
Author(s):  
Holger Rüssmann ◽  
Klaus Panthel ◽  
Brigitte Köhn ◽  
Stefan Jellbauer ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Virulence Factors ◽  
Antigen Processing ◽  
Class Ii ◽  
T Cell Response ◽  
Histocompatibility Complex ◽  
Class Ii Antigen ◽  
Mhc Class Ii Antigen

ABSTRACT Extracellular Yersinia pseudotuberculosis employs a type III secretion system (T3SS) for translocating virulence factors (Yersinia outer proteins [Yops]) directly into the cytosol of eukaryotic cells. Recently, we used YopE as a carrier molecule for T3SS-dependent secretion and translocation of listeriolysin O (LLO) from Listeria monocytogenes. We demonstrated that translocation of chimeric YopE/LLO into the cytosol of macrophages by Yersinia results in the induction of a codominant antigen-specific CD4 and CD8 T-cell response in orally immunized mice. In this study, we addressed the requirements for processing and major histocompatibility complex (MHC) class II presentation of chimeric YopE proteins translocated into the cytosol of macrophages by the Yersinia T3SS. Our data demonstrate the ability of Yersinia to counteract exogenous MHC class II antigen presentation of secreted hybrid YopE by the action of wild-type YopE and YopH. In the absence of exogenous MHC class II antigen presentation, an alternative pathway was identified for YopE fusion proteins originating in the cytosol. This endogenous antigen-processing pathway was sensitive to inhibitors of phagolysosomal acidification and macroautophagy, but it did not require the function either of the proteasome or of transporters associated with antigen processing. Thus, by an autophagy-dependent mechanism, macrophages are able to compensate for the YopE/YopH-mediated inhibition of the endosomal MHC class II antigen presentation pathway for exogenous antigens. This is the first report demonstrating that autophagy might enable the host to mount an MHC class II-restricted CD4 T-cell response against translocated bacterial virulence factors. We provide critical new insights into the interaction between the mammalian immune system and a human pathogen.

HLA-DM and the MHC class II antigen presentation pathway

1999 ◽  
Vol 20 (2) ◽  
pp. 195-205 ◽  
Author(s):  
Peter E. Jensen ◽  
Dominique A. Weber ◽  
Wesley P. Thayer ◽  
Xinjian Chen ◽  
Chin T. Dao
Keyword(s):  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway ◽  
Class Ii Antigen ◽  
Mhc Class Ii Antigen

scholarly journals Immunization of Mice with Urease Vaccine Affords Protection against Helicobacter pylori Infection in the Absence of Antibodies and Is Mediated by MHC Class II–restricted Responses

1998 ◽  
Vol 188 (12) ◽  
pp. 2277-2288 ◽  
Author(s):  
Thomas H. Ermak ◽  
Paul J. Giannasca ◽  
Richard Nichols ◽  
Gwendolyn A. Myers ◽  
John Nedrud ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
B Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Knockout Mice ◽  
Class Ii ◽  
Helicobacter Pylori Infection ◽  
Wild Type ◽  
H Pylori

We examined the roles of cell- and antibody-mediated immunity in urease vaccine–induced protection against Helicobacter pylori infection. Normal and knockout mice deficient in major histocompatibility complex (MHC) class I, MHC class II, or B cell responses were mucosally immunized with urease plus Escherichia coli heat-labile enterotoxin (LT), or parenterally immunized with urease plus aluminum hydroxide or a glycolipid adjuvant, challenged with H. pylori strain X47-2AL, and H. pylori organisms and leukocyte infiltration in the gastric mucosa quantified. In an adjuvant/route study in normal mice, there was a direct correlation between the level of protection and the density of T cells recruited to the gastric mucosa. In knockout studies, oral immunization with urease plus LT protected MHC class I knockout mice [β2-microglobulin (−/−)] but not MHC class II knockout mice [I-Ab (−/−)]. In B cell knockout mice [μMT (−/−)], vaccine-induced protection was equivalent to that observed in immunized wild-type (+/+) mice; no IgA+ cells were detected in the stomach, but levels of CD4+ cells equivalent to those in the wild-type strain (+/+) were seen. These studies indicate that protection of mice against H. pylori infection by immunization with the urease antigen is dependent on MHC class II–restricted, cell-mediated mechanisms, and antibody responses to urease are not required for protection.

scholarly journals Oxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Laure-Anne Ligeon ◽  
Maria Pena-Francesch ◽  
Liliana Danusia Vanoaica ◽  
Nicolás Gonzalo Núñez ◽  
Deepti Talwar ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Class Ii ◽  
Oxygen Species ◽  
Cellular Processes ◽  
Oxidative Inactivation ◽  
Wide Range

AbstractLC3-associated phagocytosis (LAP) contributes to a wide range of cellular processes and notably to immunity. The stabilization of phagosomes by the macroautophagy machinery in human macrophages can maintain antigen presentation on MHC class II molecules. However, the molecular mechanisms involved in the formation and maturation of the resulting LAPosomes are not completely understood. Here, we show that reactive oxygen species (ROS) produced by NADPH oxidase 2 (NOX2) stabilize LAPosomes by inhibiting LC3 deconjugation from the LAPosome cytosolic surface. NOX2 residing in the LAPosome membrane generates ROS to cause oxidative inactivation of the protease ATG4B, which otherwise releases LC3B from LAPosomes. An oxidation-insensitive ATG4B mutant compromises LAP and thereby impedes sustained MHC class II presentation of exogenous Candida albicans antigens. Redox regulation of ATG4B is thereby an important mechanism for maintaining LC3 decoration of LAPosomes to support antigen processing for MHC class II presentation.

scholarly journals Helicobacter pylori-Associated Gastritis in Mice is Host and Strain Specific

1999 ◽  
Vol 67 (6) ◽  
pp. 3040-3046 ◽  
Author(s):  
Nathalie E. M. van Doorn ◽  
Ferry Namavar ◽  
Marion Sparrius ◽  
Jeroen Stoof ◽  
Emmelien P. van Rees ◽  
...  
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
Mhc Class Ii ◽  
Neutrophil Count ◽  
Class Ii ◽  
Spontaneous Mutant ◽  
H Pylori ◽  
Over Time

ABSTRACT The vacA and cagA geno- and phenotypes of two mouse-adapted strains of Helicobacter pylori, SS1 and SPM326, were determined. The SS1 strain, which had thecagA + and vacA s2-m2 genotype, induced neither vacuole formation in HeLa cells nor interleukin-8 (IL-8) production in KATO III cells. In contrast, H. pyloriSPM326, with the cagA + and vacAs1b-m1 genotype, induced vacuoles as well as IL-8 production in vitro. Furthermore, a spontaneous mutant of SPM326, which produced a vacuolating cytotoxin but was not able to induce IL-8 production (SPM326/IL-8−), was detected. C57Bl/6 and BALB/c mice were infected with these three strains to investigate the colonization pattern and the effect on the immune response in vivo. The SS1 strain colonized the stomachs of all mice in large numbers which remained constant over time. Colonization with the SPM326/IL-8+ and SPM326/IL-8− strains was lesser, or even absent, and decreased over time. At 5 weeks postinoculation all three H. pylori strains induced a mild increase of neutrophil count in the gastric corpus of C57Bl/6 mice, which disappeared by 12 weeks. At both 5 and 12 weeks postinoculation C57Bl/6 mice colonized with SPM326/IL-8+ showed an increased expression of major histocompatibility complex (MHC) class II antigen in the cardia which was accompanied by an increased number of T cells. C57Bl/6 mice that were infected with SS1 and SPM326/IL-8− did not show chronic inflammation. BALB/c mice colonized with SS1 and SPM326/IL-8− also showed an increase in neutrophil count at 5 weeks, which normalized again by 12 weeks postinoculation. At this time point SS1-infected mice showed inflammation in the corpus and antrum. At these sites an increased expression of MHC class II antigens and an increased number of T cells were observed. Although small lymphoid follicles were already observed 5 weeks after inoculation with SS1, their incidence as well as their number was increased at 12 weeks. These results show that inflammation induced by H. pyloridepends both on the bacterial strain and the host.

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