scholarly journals Eimeria falciformisBayerHaberkorn1970 and novel wild derived isolates from house mice: differences in parasite lifecycle, pathogenicity and host immune reactions

2019 ◽  
Author(s):  
E. Al-khlifeh ◽  
A. Balard ◽  
V.H. Jarquín-Díaz ◽  
A. Weyrich ◽  
G. Wibbelt ◽  
...  
Keyword(s):  
Weight Loss ◽  
Plasma Cells ◽  
Immune Cell ◽  
Laboratory Strain ◽  
Cytokine Gene Expression ◽  
House Mice ◽  
Evolutionary Divergence ◽  
List Type ◽  
Immune Reactions ◽  
Natural Systems

AbstractSpecies ofEimeria(Apicomplexa:Coccidia) differ in the timing of lifecycle progression and resulting infections vary in host immune reactions and pathology they induce.Eimeriainfections in house mice are used as models for basic immunology and the most commonly used isolates have been passaged in laboratory mice for over 50 years. We questioned in how far such isolates are still representative for infections in natural systems.In the current study, we address this question by comparing the “laboratory isolate”E. falciformisBayerHaberkorn1970 with a novel, wild derived isolateE. falciformisBrandenburg88, and contrast this with another novel wild derived isolate,E. ferrisiBrandenburg64. We compare parasite lifecycle progression. We relate this to immune cell infiltration at the site of infection (in the caecum) and cytokine gene expression in the spleen as a measure of host immune response. We assess host weight loss as a measure of pathogenicity.A species-specific slower parasite lifecyle progression and higher pathogenicity are observed forE. falciformis vs. E. ferrisi.Host cytokines, in contrast, are expressed at significantly higher level in the spleen of mice infected with theE. falciformislaboratory isolate than in both wild derived isolates, irrespective of the species. Differences in histopathology are observable between all three isolates: TheE. falciformisBayerHaberkorn1970 laboratory isolate induces the strongest inflammation and cellular infiltration (with lymphocytes, plasma cells and eosinophilic granulocytes) followed by the wild derivedE. falciformisBrandenburg88 isolate.E. ferrisiBrandenburg64 is inducing milder histological changes than bothE. falciformisisolates.It can be speculated that the serial passaging ofE. falciformisBayerHaberkorn1970 has resulted in evolutionary divergence rendering this isolate more virulent in NMRI mice. Caution is needed when findings from experimental infection with laboratory strains should be integrated with observations in natural systems.HighlightsE. ferrisihas a shorter pre-patency thanwild-derived and laboratory isolates ofE. falciformis.E. ferrisiis less virulent than bothE. falciformisisolates and the timing of maximal oocyst shedding relative to host weight loss differs.The laboratory strain ofE. falciformisinduces stronger cytokine expression in the spleen than both wild derived strains ofE. falciformisandE. ferrisi.The laboratory strain ofE. falciformisinduces stronger tissue infiltration of immune cells than the wild-derived strain.E. ferrisiinfections are associated with the lowest infiltration.

A METHOD FOR EVALUATING AN EXPERIMENTAL ATHYREOSIS

1972 ◽  
Vol 70 (2) ◽  
pp. 289-294 ◽  
Author(s):  
K. Schimmelpfennig ◽  
A. Kaul ◽  
U. Haberland
Keyword(s):  
Weight Loss ◽  
Thyroid Tissue ◽  
Cervical Region ◽  
List Type ◽  
Experimental Animals

ABSTRACT A micro-131I-test is presented which allows an easy separation of completely surgically thyroidectomised experimental animals from animals with aberrant or residual thyroid tissue. The application of the method is easy and not time-consuming: the total time spent on one animal is approximately 3 min. The method is based on the principle that the 131I storage is measured over the cervical region. The application of this method gives the following advantages: When performing studies with proven athyroid rats it is not necessary subsequently to demonstrate athyreosis (histologically, BMR, or PBI). Time-consuming experiments with animals which are not definitely athyroid can be avoided. The additional fractionated radio-iodine resection after surgical thyroidectomy, used by many authors to destroy residual thyroid tissue, becomes superfluous. Such a procedure takes 4 to 8 weeks. The animals may be used after a 5-day-period. This excludes secondary changes like weight loss and disturbed development which have to be taken into consideration when using a radio-iodine resection.

scholarly journals Simultaneous Expression of Th1- and Treg-Associated Chemokine Genes and CD4+, CD8+, and Foxp3+ Cells in the Premalignant Lesions of 4NQO-Induced Mouse Tongue Tumorigenesis

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1835
Author(s):  
Hana Yamaguchi ◽  
Miki Hiroi ◽  
Kazumasa Mori ◽  
Ryosuke Ushio ◽  
Ari Matsumoto ◽  
...  
Keyword(s):  
Immune Cell ◽  
Tongue Cancer ◽  
Immunohistochemical Analysis ◽  
Premalignant Lesions ◽  
Cytokine Gene Expression ◽  
Cell Infiltration ◽  
Mrna Levels ◽  
Cell Recruitment ◽  
T Cell Infiltration ◽  
Immunohistochemical Analyses

Chemokines and cytokines in the tumor microenvironment influence immune cell infiltration and activation. To elucidate their role in immune cell recruitment during oral cancer development, we generated a mouse tongue cancer model using the carcinogen 4-nitroquinoline 1-oxide (4NQO) and investigated the carcinogenetic process and chemokine/cytokine gene expression kinetics in the mouse tongue. C57/BL6 mice were administered 4NQO in drinking water, after which tongues were dissected at 16 and 28 weeks and subjected to analysis using the RT2 Profiler PCR Array, qRT-PCR, and pathologic and immunohistochemical analyses. We found that Th1-associated chemokine/cytokine (Cxcl9, Cxcl10, Ccl5, and Ifng) and Treg-associated chemokine/cytokine (Ccl17, Ccl22, and Il10) mRNA levels were simultaneously increased in premalignant lesions of 4NQO-treated mice at 16 weeks. Additionally, although levels of Gata3, a Th2 marker, were not upregulated, those of Cxcr3, Ccr4, and Foxp3 were upregulated in the tongue tissue. Furthermore, immunohistochemical analysis confirmed the infiltration of CD4+, CD8+, and Foxp3+ cells in the tongue tissue of 4NQO-treated mice, as well as significant correlations between Th1- or Treg-associated chemokine/cytokine mRNA expression and T cell infiltration. These results indicate that CD4+, CD8+, and Foxp3+ cells were simultaneously recruited through the expression of Th1- and Treg-associated chemokines in premalignant lesions of 4NQO-induced mouse tongue tissue.

scholarly journals POS1223 RAS GUANYL RELEASING PROTEIN 1 (RASGRP1) IN PERIPHERAL B CELLS LINKS RA TO COVID-19

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 895.2-895
Author(s):  
S. Hannawi ◽  
F. Alqutami ◽  
M. Y. Hachim
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Immune Cell ◽  
In Silico Analysis ◽  
Differentially Expressed ◽  
Transcriptional Enhancer ◽  
Activated T Cells

Background:Changes in the B cell subpopulations is a hallmark of the antiviral response against SARS-CoV-2 and is associated with COVID-19 severity (1). Recently our group showed common derangement observed in rheumatoid arthritis (RA) and COVID-19 (2). In RA, synovium attracts potentially autoreactive—B cells and plasma cells that play a central role in RA pathogenesis (3). We were interested to know the similarity in B cell’s transcriptomic changes specific to RA and COVID-19.Objectives:Identify similar upregulated genes in synovium and B cells in RA and at the same time are differentially expressed in B cells infected with SARS-CoV-2 or from COVID-19 patients.Methods:RNAseq dataset (GSE89408) of (218) samples isolated from joint synovial biopsies from subjects with and without rheumatoid arthritis were retrieved from GEO online database. Differentially expressed genes (DRGs) specific to RA were identified after exclusion of those upregulated in Osteoarthritis or other joint condition samples in the same dataset. The RA specific genes were intersected with DEGs between B cells from healthy versus RA as extracted from (GSE110999) dataset. The shortlisted genes specifically upregulated in B cells of RA were identified and were explored in B cells COVID-19 transcriptome datasets using (https://metascape.org/COVID).Results:60 genes were found to be specifically upregulated in RA synovium and B cells and are changed in B cells infected with SARS-CoV-2 or from COVID-19 patients, Figure (1-A). Those genes were involved in interferon signaling, antiviral and immune cell activation. RASGRP1 was common between B cells of RA and COVID-19 and might play a role in the pathogenesis of both, Figure (1-B). RASGRP1 controls ERK/MAPK kinase cascade needed in B-/T-cell differentiation and development. It is vital to protect against viral infection and the autoimmune associated proliferation of activated T-cells like RA (4). We checked its level in another dataset (GSE152641) of the whole blood RNASeq of 62 COVID-19 patients and 24 healthy controls. RASGRP1 was significantly down in COVID-19 compared to healthy control, Figure (1-C).Conclusion:SARS-CoV-2 impair B and T’s cells’ immune response through its action on RASGRP1 and that can be a novel mechanistic explanation of how the virus decreases immune cells and impair the B cell’s humoral immunity.References:[1]Sosa-Hernández VA, Torres-Ruíz J, Cervantes-Díaz R, Romero-Ramírez S, Páez-Franco JC, Meza-Sánchez DE, et al. B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients. Frontiers in Immunology. 2020;11(3244).[2]Hachim MY, Hachim IY, Naeem KB, Hannawi H, Al Salmi I, Hannawi S. C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis. Translational Medicine Communications. 2020;5(1):14.[3]Doorenspleet ME, Klarenbeek PL, de Hair MJ, van Schaik BD, Esveldt RE, van Kampen AH, et al. Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity. Ann Rheum Dis. 2014;73(4):756-62.[4]Molineros JE, Singh B, Terao C, Okada Y, Kaplan J, McDaniel B, et al. Mechanistic Characterization of RASGRP1 Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility. Frontiers in Immunology. 2019;10(1066).Disclosure of Interests:None declared

scholarly journals Immune Cell Profiles and Cytokine Levels of Patients with Interstitial Cystitis/Bladder Pain Syndrome

2020 ◽  
Author(s):  
Robert M. Moldwin ◽  
Vishaan Nursey ◽  
Oksana Yaskiv ◽  
Siddhartha Dalvi ◽  
Michael Funaro ◽  
...  
Keyword(s):  
Interstitial Cystitis ◽  
Plasma Cells ◽  
Immune Cell ◽  
Pain Syndrome ◽  
Fold Increase ◽  
Bladder Pain Syndrome ◽  
Bladder Tissue ◽  
Bladder Pain ◽  
Tnf Α ◽  
Significant Difference

AbstractAimsTo quantify the number of immune cells in the bladder urothelium and concentrations of urinary cytokines in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). To identify differences in these measures in IC/BPS patients with Hunner’s lesions (IC/BPS-HL) and without Hunner’s lesions (IC/BPS-NHL).MethodsBladder tissue biopsies were obtained from 48 patients with IC/BPS-HL and unaffected controls (UC) and stained with antibodies for various immune cell markers such as CD138, CD20 and CD56. Levels of cytokines (Interferon (IFN)-γ, Interleukin (IL)-1β, IL-2, IL- 4, IL-6, IL-8, IL12P70, IL-13, and TNF-α) were measured from normalized urine obtained from 18 IC/BPS-HL, 18 IC/BPS-NHL, and 4 UC.ResultsNumbers of CD138+ plasma cells, CD20+ B cells, and CD3+ T cells were significantly increased (50 fold, 30 fold, and an almost 3 fold increase, respectively; p-values: 1.34E-06, 3.26E-04, and 2.52E-6) in the bladders of IC/BPS-HL patients compared to UC. Patients with IC/BPS-HL had significantly elevated urinary levels of IL-6 (p=0.0028) and TNF-α (p=0.009) compared to patients with IC/BPS-NHL and UC. In contrast, IL-12p70 levels were significantly higher in the patients with IC/BPS-NHL than in HL patients (p=0.033). No significant difference in IL-12p70 levels were observed between IC/BPS-HL and UC.ConclusionDifferent cytokines were elevated in the urine of IC/BPS patients with and without HL, suggesting differences in underlying disease processes. Elevated levels of CD138+, CD20+, and CD3+ cells in HL indicate B and T-cell involvement in lesion formation. Determining which cytokines and immunological pathways are present in IC/BPS-HL could elucidate the disease mechanism.

scholarly journals 822 GraphITE: unsupervised graph embeddings approach to multiplex immunofluorescence image exploration reveals new insights into NSCLC and HNSCC tumor microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A860-A860
Author(s):  
Michael Surace ◽  
Helen Angell ◽  
Christopher Innocenti ◽  
Zhenning Zhang ◽  
Isabelle Gaffney ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Spatial Information ◽  
Immune Cell ◽  
Predictive Biomarkers ◽  
Tumor Stroma ◽  
List Type ◽  
Graph Embeddings ◽  
Cell Content ◽  
Ffpe Tumor ◽  
Image Exploration

BackgroundPredictive biomarkers for response to IO therapies remain insufficient. Although multiplex immunofluorescence has the potential to provide superior biomarkers, the information garnered from these studies is frequently underleveraged. Due to the large number of markers that must be analyzed (6 - 40 +), and the complexity of the spatial information, the number of hypotheses is large and must be tested systematically and automatically. GraphITE (Graphs-based Investigation of Tissues with Embeddings) is a novel method of converting multiplex IF image analysis results into embeddings, numerical vectors which represent the phenotype of each cell as well as the immediate neighborhood. This allows for the clustering of embeddings based on similarity as well as the discovery of novel predictive biomarkers based on both the spatial and multimarker data in multiplex IF images. Here we demonstrate initial observations from deployment of GraphITE on 564 commercially-sourced NSCLC and HNSCC resections stained with a multiplex IF panel containing CD8, PDL1, PD1, CD68, Ki67, and CK.Methods4 μm FFPE tumor sections were stained with CD8, PDL1, PD1, CD68, Ki67, and CK at Akoya Biosciences using OPAL TSA-linked fluorophores and imaged on a Vectra Polaris. Images were analyzed by Computational Biology (AstraZeneca). Graphs were built by mapping each cell in the mIF image as a node, using the X, Y coordinates and connecting nodes with edges according to distance. 64-dimensional embeddings were generated using Deep Graph InfoMax (DGI).1 Embeddings are downprojected to 2 dimensions using UMAP.2. Details are available in the preprint of the GraphITE methods manuscript.3ResultsA single downprojection was developed using embeddings from 158 HNSCC and 406 NSCLC cases. 60–80 distinct clusters were observed, some of which contained embeddings from both indications and others which were exclusive to one indication. Exclusive clusters describe tissue neighborhoods observed only in one indication. Drivers of cluster exclusivity included increased cell density in HNSCC as compared to NSCLC both in PD-L1- tumor centers with few infiltrating lymphocytes as well as in PD-L1- macrophagedominated neighborhoods. HNSCC and NSCLC embeddings were more colocalized in PD-L1+ tumor centers and in tumor stroma with high CD8+ or CD68+ immune cell content and high PD-L1+ expression.ConclusionsThis study demonstrates the utility and potential of the GraphITE platform to discriminate between and describe both unique and common neighborhood-level features of the tumor microenvironment. Deploying GraphITE across multiple indications effectively leverages spatial heterogeneity and multimarker information from multiplex IF panels.References1. Veličković P, Fedus W, Hamilton WL, Liò P, Bengio Y, DevonHjelm R. Deep Graph Infomax. 2018. arxiv:1809.10341 [stat.ML].2. McInnes L, Healy J, Melville J. UMAP: Uniform manifold approximationand projection for dimension reduction. 2020; arxiv:1802.03426 [stat.ML].3. Innocenti C, Zhang Z, Selvaraj B, Gaffney I, Frangos M, Cohen-Setton J, Dillon LAL, Surace MJ, Pedrinaci C, Hipp J, Baykaner K. An unsupervised graph embeddings approach to multiplex immunofluorescence image explorationbioRxiv 2021.06.09.447654; doi: https://doi.org/10.1101/2021.06.09.447654Ethics ApprovalThe study was approved by AstraZeneca.

scholarly journals 909 Differentiation subgroups within LKB1-deficient lung cancer influence both the immune exclusion phenotype and cellular composition of the immune microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A954-A955
Author(s):  
Jacob Kaufman ◽  
Doug Cress ◽  
Theresa Boyle ◽  
David Carbone ◽  
Neal Ready ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Plasma Cells ◽  
Immune Cell ◽  
Expression Profiles ◽  
Neuroendocrine Differentiation ◽  
Gene Expression Profiles ◽  
Immune Microenvironment ◽  
Immune Exclusion

BackgroundLKB1 (STK11) is a commonly disrupted tumor suppressor in NSCLC. Its loss promotes an immune exclusion phenotype with evidence of low expression of interferon stimulated genes (ISG) and decreased microenvironment immune infiltration.1 2 Clinically, LKB1 loss induces primary immunotherapy resistance.3 LKB1 is a master regulator of a complex downstream kinase network and has pleiotropic effects on cell biology. Understanding the heterogeneous phenotypes associated with LKB1 loss and their influence on tumor-immune biology will help define and overcome mechanisms of immunotherapy resistance within this subset of lung cancer.MethodsWe applied multi-omic analyses across multiple lung adenocarcinoma datasets2 4–6 (>1000 tumors) to define transcriptional and genetic features enriched in LKB1-deficient lung cancer. Top scoring phenotypes exhibited heterogeneity across LKB1-loss tumors, and were further interrogated to determine association with increased or decreased markers of immune activity. Further, immune cell-types were estimated by Cibersort to identify effects of LKB1 loss on the immune microenvironment. Key conclusions were confirmed by blinded pathology review.ResultsWe show that LKB1 loss significantly affects differentiation patterns, with enrichment of ASCL1-expressing tumors with putative neuroendocrine differentiation. LKB1-deficient neuroendocrine tumors had lower expression of Interferon Stimulated Genes (ISG), MHC1 and MHC2 components, and immune infiltration compared to LKB1-WT and non-neuroendocrine LKB1-deficient tumors (figure 1).The abundances of 22 immune cell types assessed by Cibersort were compared between LKB1-deficient and LKB1-WT tumors. We observe skewing of immune microenvironmental composition by LKB1 loss, with lower abundance of dendritic cells, monocytes, and macrophages, and increased levels of neutrophils and plasma cells (table 1). These trends were most pronounced among tumors with neuroendocrine differentiation, and were concordant across three independent datasets. In a confirmatory subset of 20 tumors, plasma cell abundance was assessed by a blinded pathologist. Pathologist assessment was 100% concordant with Cibersort prediction, and association with LKB1 loss was confirmed (P=0.001).Abstract 909 Figure 1Immune-associated Gene Expression Profiles Affected by Neuroendocrine Differentiation within LKB1-Deficient Lung Adenocarcinomas. Gene expression profiles corresponding to five immune-associated phenotypes are shown with bars indicating average GEP scores for tumors grouped according to LKB1 and neuroendocrine status as indicated. P-values represent results from Student’s T-test between groups as indicated.Abstract 909 Table 1LKB1 Loss Affects Composition of Immune Microenvironment. Values indicate log10 P-values comparing LKB1-loss to LKB1-WT tumors. Positive (red) indicates increased abundance in LKB1 loss. Negative (blue) indicates decreased abundance.ConclusionsWe conclude that tumor differentiation patterns strongly influence the immune microenvironment and immune exclusion characteristics of LKB1-deficient tumors. Neuroendocrine differentiation is associated with the strongest immune exclusion characteristics and should be evaluated clinically for evidence of immunotherapy resistance. A novel observation of increased plasma cell abundance is observed across multiple datasets and confirmed by pathology. Causal mechanisms linking differentiation status to immune activity is not well understood, and the functional role of plasma cells in the immune biology of LKB1-deficient tumors is undefined. These questions warrant further study to inform precision immuno-oncology treatments for these patients.AcknowledgementsThis work was funded by SITC AZ Immunotherapy in Lung Cancer grant (SPS256666) and DOD Lung Cancer Research Program Concept Award (LC180633).ReferencesSkoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 2015;5:860–77.Schabath MB, Welsh EA, Fulp WJ, et al. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene 2016;35:3209–16.Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discovery 2018;8:822-835.Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543–50.Chitale D, Gong Y, Taylor BS, et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 2009;28:2773–83.Shedden K, Taylor JM, Enkemann SA, et al. Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 2008;14:822–7.

scholarly journals Neutrophils associate with Bowman’s capsule rupture specifically in PR3-ANCA glomerulonephritis

2021 ◽  
Author(s):  
Samy Hakroush ◽  
Björn Tampe
Keyword(s):  
Plasma Cells ◽  
Immune Cell ◽  
Renal Involvement ◽  
Kidney Injury ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Stage Renal Disease ◽  
End Stage ◽  
Bowman's Capsule ◽  
Tubulointerstitial Inflammation ◽  
Capsule Rupture

Abstract Background Renal involvement is a common and severe complication of ANCA (antineutrophil cytoplasmic antibody) associated vasculitis (AAV) potentially resulting in a pauci-immune necrotizing and crescentic antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. We recently described that Bowman’s capsule rupture links glomerular damage to tubulointerstitial inflammation in ANCA-associated glomerulonephritis. Herein we provide a comprehensive histological subtyping of immune cell infiltrates in association with Bowman’s capsule rupture in ANCA GN. Methods A total of 44 kidney biopsies with ANCA GN were retrospectively included in a single-center observational study. Within a renal biopsy specimen, each glomerulus was scored separately for the presence of extensive and focal Bowman’s capsule rupture in injured glomeruli. Infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the area of total cortical inflammation. Results Extensive Bowman’s capsule rupture was associated with tubulointerstitial inflammation containing infiltrates of neutrophils, eosinophils and plasma cells. A similar association was observed for the presence of focal Bowman’s capsule rupture, correlating with tubulointerstitial inflammation containing neutrophils, eosinophils and plasma cells. Multiple logistic regression confirmed that extensive Bowman’s capsule rupture correlated with tubulointerstitial inflammation containing neutrophils, and focal Bowman’s capsule rupture correlated with neutrophil and plasma cell infiltration. Furthermore, this association was specifically observed in PR3-ANCA GN. Conclusion To our knowledge, this is the first report linking Bowman’s capsule rupture directly to tubulointerstitial inflammation by immune cell subtypes. This underscores a pathomechanistic link between tubulointerstitial and glomerular lesions in ANCA GN and needs further investigation. Graphical abstract

Blood-borne human plasma cells in steady state are derived from mucosal immune responses

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2461-2469 ◽  
Author(s):  
Henrik E. Mei ◽  
Taketoshi Yoshida ◽  
Wondossen Sime ◽  
Falk Hiepe ◽  
Kathi Thiele ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Immune Responses ◽  
Plasma Cells ◽  
Immunoglobulin A ◽  
Low Frequency ◽  
Substantial Contribution ◽  
Immune Reactions ◽  
Humoral Immune ◽  
Humoral Immune Responses

AbstractProviding humoral immunity, antibody-secreting plasma cells and their immediate precursors, the plasmablasts, are generated in systemic and mucosal immune reactions. Despite their key role in maintaining immunity and immunopathology, little is known about their homeostasis. Here we show that plasmablasts and plasma cells are always detectable in human blood at low frequency in any unimmunized donor. In this steady state, 80% of plasmablasts and plasma cells express immunoglobulin A (IgA). Expression of a functional mucosal chemokine receptor, C-C motif receptor 10 (CCR10) and the adhesion molecule β7 integrin suggests that these cells come from mucosal immune reactions and can return to mucosal tissue. These blood-borne, CCR10+ plasmablasts also are attracted by CXCL12. Approximately 40% of plasma cells in human bone marrow are IgA+, nonmigratory, and express β7 integrin and CCR10, suggesting a substantial contribution of mucosal plasma cells to bone marrow resident, long-lived plasma cells. Six to 8 days after parenteral tetanus/diphtheria vaccination, intracellular IgG+ cells appear in blood, both CD62L+, β7 integrin−, dividing, vaccine-specific, migratory plasmablasts and nondividing, nonmigratory, CD62L− plasma cells of different specificities. Systemic vaccination does not impact on peripheral IgA+ plasmablast numbers, indicating that mucosal and systemic humoral immune responses are regulated independent of each other.

Identification of a Metabolism-Related Risk Signature to Predict the Outcome and Immune Infiltration of Esophageal Squamous Cell Carcinoma

2020 ◽  
Author(s):  
Yu Liu ◽  
Liyu Wang ◽  
Hengchang Liu ◽  
He Tian ◽  
Tao Fan ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Plasma Cells ◽  
Immune Cell ◽  
Gene Signature ◽  
Metabolic Reprogramming ◽  
Immune Cell Infiltration ◽  
Related Gene ◽  
Prognostic Signature ◽  
Immune Infiltration

Abstract Background: Metabolic reprogramming is associated with tumor heterogeneity and progression. Understanding the characteristics of metabolic reprogramming in esophageal squamous cell carcinoma (ESCC) might help us to uncover new biomarkers for patient outcomes and targets for therapies.Methods: In this study, metabolism-related genes were screened from mRNA microarray data (GSE53624, GSE53622). Consensus clustering analysis was used to divide tumors into subgroups. Survival analysis and univariate Cox analysis were performed to select prognostic genes. A metabolism-related gene signature was established with multivariate Cox proportional hazards regression (PHR) analysis in the training group (GSE53624). Gene set enrichment analysis (GSEA) and CIBERSORT were used to analyze functional enrichment and immune cell infiltration.The gene signature and immune infiltration were verified in two public databases (GSE53622, TCGA-ESCC) and in two independent cohorts, 95 and 119 ESCC patients, by immunohistochemistry (IHC) analysis. Results: Based on prognosis-related metabolic gene expression, three cluster subgroups (k = 3) were identified with significantly different immune cell infiltration patterns, clinical features and overall survival (OS) times. Then, we developed a multigene (INPP5E, CD38 and POLR3G) prognostic signature that showed better predictive ability and was found to be an independent prognostic risk factor in ESCC database and two public database analyses. This result could also be verified by multicenter IHC experiment and indicated the clinical application potential. In addition, GSEA showed that several tumor-related pathways were associated with the prognostic signature. Furthermore, the immune cell infiltration of regulatory T cells (Tregs) and plasma cells displayed an obvious correlation with prognostic signature and IHC experiment in 119 cohort also support this result.Conclusions: Our study indicated that the metabolism-related prognostic gene could stratify patients into subgroups and was associated with immune infiltration, clinical features and outcomes. The three-gene prognostic signature from metabolic-related gene displays a good ability to predict OS and the infiltration of immunosuppressive Tregs and plasma cells.

scholarly journals Prostanoid Receptor Subtypes and Its Endogenous Ligands with Processing Enzymes within Various Types of Inflammatory Joint Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Mohammed A. Al-Madol ◽  
Mohammed Shaqura ◽  
Thilo John ◽  
Rudolf Likar ◽  
Reham Said Ebied ◽  
...  
Keyword(s):  
Synovial Tissue ◽  
Expression Profile ◽  
Inflammatory Process ◽  
Plasma Cells ◽  
Immune Cell ◽  
Receptor Subtypes ◽  
Prostanoid Receptor ◽  
Processing Enzymes ◽  
Target Molecules ◽  
Cox 2

A complex inflammatory process mediated by proinflammatory cytokines and prostaglandins commonly occurs in the synovial tissue of patients with joint trauma (JT), osteoarthritis (OA), and rheumatoid arthritis (RA). This study systematically investigated the distinct expression profile of prostaglandin E2 (PGE2), its processing enzymes (COX-2), and microsomal PGES-1 (mPGES-1) as well as the corresponding prostanoid receptor subtypes (EP1-4) in representative samples of synovial tissue from these patients (JT, OA, and RA). Quantitative TaqMan®-PCR and double immunofluorescence confocal microscopy of synovial tissue determined the abundance and exact immune cell types expressing these target molecules. Our results demonstrated that PGE2 and its processing enzymes COX-2 and mPGES-1 were highest in the synovial tissue of RA, followed by the synovial tissue of OA and JT patients. Corresponding prostanoid receptor, subtypes EP3 were highly expressed in the synovium of RA, followed by the synovial tissue of OA and JT patients. These proinflammatory target molecules were distinctly identified in JT patients mostly in synovial granulocytes, in OA patients predominantly in synovial macrophages and fibroblasts, whereas in RA patients mainly in synovial fibroblasts and plasma cells. Our findings show a distinct expression profile of EP receptor subtypes and PGE2 as well as the corresponding processing enzymes in human synovium that modulate the inflammatory process in JT, OA, and RA patients.

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