scholarly journals Low Abundance Members of the Gut Microbiome are Potent Drivers of Immune Cell Education.

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

Abstract Background: 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.Results: 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. Conclusions: 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 immune interaction of low abundance bacteria with the host will offer greater insight into the intestinal immune landscape and disease pathogenesis.Keywords: Gut microbiome, Low abundance bacteria, Immune education, MHC class II, Erysipelotrichaceae

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.

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 Bacterial community structure alterations within the colorectal cancer gut microbiome

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mark Loftus ◽  
Sayf Al-Deen Hassouneh ◽  
Shibu Yooseph
Keyword(s):  
Colorectal Cancer ◽  
Community Structure ◽  
Bacterial Community ◽  
Gut Microbiome ◽  
Late Stage ◽  
Bacterial Community Structure ◽  
Whole Genome ◽  
Human Gut ◽  
Fecal Samples ◽  
Human Gut Microbiome

Abstract Background Colorectal cancer is a leading cause of cancer-related deaths worldwide. The human gut microbiome has become an active area of research for understanding the initiation, progression, and treatment of colorectal cancer. Despite multiple studies having found significant alterations in the carriage of specific bacteria within the gut microbiome of colorectal cancer patients, no single bacterium has been unequivocally connected to all cases. Whether alterations in species carriages are the cause or outcome of cancer formation is still unclear, but what is clear is that focus should be placed on understanding changes to the bacterial community structure within the cancer-associated gut microbiome. Results By applying a novel set of analyses on 252 previously published whole-genome shotgun sequenced fecal samples from healthy and late-stage colorectal cancer subjects, we identify taxonomic, functional, and structural changes within the cancer-associated human gut microbiome. Bacterial association networks constructed from these data exhibited widespread differences in the underlying bacterial community structure between healthy and colorectal cancer associated gut microbiomes. Within the cancer-associated ecosystem, bacterial species were found to form associations with other species that are taxonomically and functionally dissimilar to themselves, as well as form modules functionally geared towards potential changes in the tumor-associated ecosystem. Bacterial community profiling of these samples revealed a significant increase in species diversity within the cancer-associated gut microbiome, and an elevated relative abundance of species classified as originating from the oral microbiome including, but not limited to, Fusobacterium nucleatum, Peptostreptococcus stomatis, Gemella morbillorum, and Parvimonas micra. Differential abundance analyses of community functional capabilities revealed an elevation in functions linked to virulence factors and peptide degradation, and a reduction in functions involved in amino-acid biosynthesis within the colorectal cancer gut microbiome. Conclusions We utilize whole-genome shotgun sequenced fecal samples provided from a large cohort of late-stage colorectal cancer and healthy subjects to identify a number of potentially important taxonomic, functional, and structural alterations occurring within the colorectal cancer associated gut microbiome. Our analyses indicate that the cancer-associated ecosystem influences bacterial partner selection in the native microbiota, and we highlight specific oral bacteria and their associations as potentially relevant towards aiding tumor progression.

Abstract 095: CD74 Deficient Mice are Resistant to Toll-Like Receptor-Induced Preeclampsia

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Mohamad Hatahet ◽  
Olga Y Gasheva ◽  
Valorie L Chiasson ◽  
Piyali Chatterjee ◽  
Kelsey R Bounds ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Endothelial Dysfunction ◽  
Mhc Class Ii ◽  
Immune Cells ◽  
Immune Cell ◽  
Class Ii ◽  
Poly I:C ◽  
Hypertensive Disorder ◽  
Toll Like Receptor

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by vascular endothelial dysfunction and excessive immunity and inflammation. Activation of the dsRNA receptor Toll-like receptor 3 (TLR3) or the ssRNA receptor TLR7 elicits a pregnancy-dependent PE-like syndrome in mice by inducing a pro-inflammatory immune response. CD74 (MHC Class II invariant chain) acts as a chaperone for MHC Class II surface expression on immune cells during antigen presentation and is cleaved into Class II-Associated Invariant Peptide (CLIP) following polyclonal activation of immune cell TLRs. The presence of CLIP in the groove of MHC Class II prevents T cell-dependent death leading to persistent immune cell activation. We hypothesized that genetic deletion of CD74 and subsequent depletion of CLIP on immune cells prevents TLR-induced immune responses and the development of PE in mice. Pregnant WT and CD74 KO mice were given i.p. injections of normal saline (P), poly I:C (TLR3 agonist; P-PIC), or R837 (TLR7 agonist; P-R837) on gestational days 13, 15, and 17 and euthanized on day 18. P-PIC and P-R837 WT mice had significantly increased splenic levels of pro-inflammatory CD3+/gd T cells and plasma levels of the gd T cell-derived cytokines IFNg, TNFa, and IL-17 compared to P WT mice whereas P-PIC and P-R837 CD74 KO mice had significantly increased anti-inflammatory CD3+/gd T cells and no significant increases in plasma IFNg, TNFa, and IL-17 levels. P-PIC and P-R837 CD74 KO mice did not develop the hypertension (gd17 SBP in mmHg: P WT=102±3, P CD74 KO=100±3, P-PIC WT=147±4*, P-PIC CD74 KO=95±3, P-R837 WT=133±2*, P-R837 CD74 KO=97±1; *p<0.05 vs. P WT), endothelial dysfunction, proteinuria, or placental necrosis seen in P-PIC and P-R837 WT mice. In conclusion, CD74 is crucial for the development of TLR-induced PE-like symptoms in mice and CD74/CLIP depletion may be a promising therapeutic target for women with PE.

Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X

Cell ◽  
1988 ◽  
Vol 53 (6) ◽  
pp. 897-906 ◽  
Author(s):  
W. Reith ◽  
S. Satola ◽  
C. Herrero Sanchez ◽  
I. Amaldi ◽  
B. Lisowska-Grospierre ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Binding Protein ◽  
Class Ii ◽  
Hla Dr ◽  
Congenital Immunodeficiency ◽  
Regulatory Defect

scholarly journals H2-M and H2-O as Targeting Vehicles for the MHC Class II Processing Compartment Promote Antigen-Specific CD4+ T Cell Activation

Vaccines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1053
Author(s):  
Lucia Lapazio ◽  
Monika Braun ◽  
Kaj Grandien
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway ◽  
Class Ii Antigen ◽  
Mhc Class Ii Antigen

CD8 and CD4 T cell activation are both required for a strong and long-lasting T cell immune response. Endogenously expressed proteins are readily processed by the MHC class I antigen presentation pathway, enabling activation of CD8+ T cells. However, the MHC class II antigen presentation pathway, necessary for CD4+ T cell activation, is generally not sufficiently accessible to endogenously expressed proteins, limiting the efficiency of mRNA- or DNA-based vaccines. In the current study, we have evaluated the feasibility of using antigen sequences fused to sequences derived from the H2-M and H2-O proteins, two complexes known to participate in MHC class II antigen processing, for the enhancement of CD4 T-cell activation. We analyzed T cell activation after genetic immunization with mRNA-encoding fusion proteins with the model antigen ovalbumin and sequences derived from H2-M or H2-O. Our results show that H2-M- or H2-O-derived sequences robustly improve antigen-specific CD4 T-cell activation when fused to the antigen of interest and suggest that the approach could be used to improve the efficiency of mRNA- or DNA-based vaccines.

scholarly journals Cross-linking of major histocompatibility complex class II molecules by staphylococcal enterotoxin A superantigen is a requirement for inflammatory cytokine gene expression.

1995 ◽  
Vol 182 (5) ◽  
pp. 1573-1577 ◽  
Author(s):  
K Mehindate ◽  
J Thibodeau ◽  
M Dohlsten ◽  
T Kalland ◽  
R P Sékaly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Messenger Rna ◽  
Class Ii ◽  
Cytokine Gene Expression ◽  
Cross Linking ◽  
Staphylococcal Enterotoxin A ◽  
Cytokine Gene ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Staphylococcal enterotoxin A (SEA) has two distinct binding sites for major histocompatibility complex (MHC) class II molecules. The aspartic acid located at position 227 (D227) in the COOH terminus of SEA is one of the three residues involved in its interaction with the DR beta chain, whereas the phenylalanine 47 (F47) of the NH2 terminus is critical for its binding to the DR alpha chain. Upon interaction with MHC class II molecules, SEA triggers several cellular events leading to cytokine gene expression. In the present study, we have demonstrated that, contrary to wild-type SEA, stimulation of the THP1 monocytic cell line with SEA mutated at position 47 (SEAF47A) or at position 227 (SEAD227A) failed to induce interleukin 1 beta and tumor necrosis factor-alpha messenger RNA expression. Pretreatment of the cells with a 10-fold excess of either SEAF47A or SEAD227A prevented the increase in cytokine messenger RNA induced by wild-type SEA. However, cross-linking of SEAF47A or SEAD227A bound to MHC class II molecules with F(ab')2 anti-SEA mAb leads to cytokine gene expression, whereas cross-linking with F(ab) fragments had no effect. Taken together, these results indicate that cross-linking of two MHC class II molecules by one single SEA molecule is a requirement for cytokine gene expression.

scholarly journals Engagement of major histocompatibility complex class II molecules by superantigen induces inflammatory cytokine gene expression in human rheumatoid fibroblast-like synoviocytes.

1992 ◽  
Vol 175 (2) ◽  
pp. 613-616 ◽  
Author(s):  
W Mourad ◽  
K Mehindate ◽  
T J Schall ◽  
S R McColl
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Inflammatory Cytokine ◽  
Class Ii ◽  
Type B ◽  
Major Histocompatibility ◽  
Ifn Gamma ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Cells in the rheumatoid synovium express high levels of major histocompatibility complex (MHC) class II molecules in vivo. We have therefore examined the ability of engagement of MHC class II molecules by the superantigen Staphylococcal enterotoxin A (SEA) to activate interleukin 6 (IL-6) and IL-8 gene expression in type B synoviocytes isolated from patients with rheumatoid arthritis. SEA had a minimal or undetectable effect on the expression of either gene in resting synoviocytes, as determined by Northern blot and specific enzyme-linked immunosorbent assay. However, induction of MHC class II molecule expression after treatment of synoviocytes with interferon gamma (IFN-gamma) enabled the cells to respond to SEA in a dose-dependent manner, resulting in an increase in both the level of steady-state mRNA for IL-6 and IL-8, and the release of these cytokines into the supernatant. IFN-gamma by itself had no effect on the expression of either cytokine. Pretreatment of the cells with the transcription inhibitor actinomycin D prevented the increase in cytokine mRNA induced by SEA, whereas cycloheximide superinduced mRNA for both cytokines after stimulation by SEA. Taken together, these results indicate that signaling through MHC class II molecules may represent a novel mechanism by which inflammatory cytokine production is regulated in type B rheumatoid synoviocytes, and potentially provides insight into the manner by which superantigens may initiate and/or propagate autoimmune diseases.

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