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 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.

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 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 Low abundance members of the gut microbiome are potent drivers of immune cell education.

2021 ◽  
Author(s):  
Gen Goo Han ◽  
Hien Luong ◽  
Shipra Vaishnava
Keyword(s):  
Gene Expression ◽  
Community Structure ◽  
Bacterial Community ◽  
Mhc Class Ii ◽  
Gut Microbiome ◽  
Class Ii ◽  
Global Changes ◽  
Disease Pathogenesis ◽  
Presentation Pathway ◽  
Microbial Exposure

One of the main goals of microbiome research is to identify bacterial members that significantly affect host phenotypes and understand their contributions to disease pathogenesis. Studies identifying bacterial members that dictate host phenotype have focused mainly on the dominant members, and the role of low abundance microbes in determining host phenotypes and pathogenesis of diseases remains unexplored. In this study, we compared the gut bacterial community of mice with wide-ranging microbial exposure to determine if low abundance bacteria vary based on microbial exposure or remain consistent. We noted that similar to the high abundance bacterial community, a core community of low abundance bacteria made up a significant portion of the gut microbiome irrespective of microbial exposure. To determine the effect of low abundance bacteria on community structure and host gene expression, we devised a microbiome dilution strategy to delete out low abundance bacteria and engrafted the diluted microbiomes into germ-free mice. Our approach successfully excluded low abundance bacteria from small and large intestinal bacterial communities and induced global changes in microbial community structure and composition in the large intestine. Gene expression analysis of intestinal tissue revealed that loss of low abundance bacteria resulted in a drastic reduction in expression of multiple genes involved MHC class II antigen presentation pathway and T-cell cytokine production in the small intestine. The effect of low abundance bacteria on MHC class II expression was found specific to the intestinal epithelium at an early timepoint post-colonization and correlated with bacteria belonging to the family Erysipelotrichaceae. We conclude that low abundance bacteria have a significantly higher immuno-stimulatory effect compared to dominant bacteria and are thus potent drivers of early immune education in the gut. Therefore, characterizing the immune interaction of low abundance bacteria with the host will offer greater insight into the intestinal immune landscape and disease pathogenesis.

scholarly journals High GILT Expression and an Active and Intact MHC Class II Antigen Presentation Pathway Are Associated with Improved Survival in Melanoma

2019 ◽  
Vol 203 (10) ◽  
pp. 2577-2587 ◽  
Author(s):  
Kenneth H. Buetow ◽  
Lydia R. Meador ◽  
Hari Menon ◽  
Yih-Kuang Lu ◽  
Jacob Brill ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway ◽  
Class Ii Antigen ◽  
Mhc Class Ii Antigen
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