scholarly journals Antigen Capture of Porphyromonas gingivalis by Human Macrophages Is Enhanced but Killing and Antigen Presentation Are Reduced by Endotoxin Tolerance

2007 ◽  
Vol 76 (2) ◽  
pp. 477-485 ◽  
Author(s):  
Manoj Muthukuru ◽  
Christopher W. Cutler
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Porphyromonas Gingivalis ◽  
Inflammatory Cytokines ◽  
Adaptive Immune Response ◽  
Endotoxin Tolerance ◽  
Costimulatory Molecules ◽  
T Cell Proliferation ◽  
Human Macrophages ◽  
Adaptive Immune

ABSTRACT The innate and the adaptive arms of the mucosal immune system must be coordinated to facilitate the control of pathogenic invasion while maintaining immune homeostasis. Toll-like receptors, able to activate the cell to produce bactericidal and inflammatory cytokines but also able to upregulate antigen (Ag)-presenting and costimulatory molecules, are particularly important in this regard. We have previously shown that the chronically infected oral mucosa is in a state of endotoxin tolerance, as evidenced by the downregulation of Toll-like receptors 2 and 4 and of inflammatory cytokines and the upregulation of SH2-containing inositol phosphatase, an inhibitor of NF-κB signaling. In the present study, we hypothesized that endotoxin tolerance would influence the ability of human macrophages to engage in Ag capture and killing of the oral pathogen Porphyromonas gingivalis and to upregulate costimulatory molecules and stimulate autologous T-cell proliferation. We show that uptake, but not killing, of P. gingivalis 381 is enhanced by endotoxin tolerance. Reduced killing is possibly due to a reduction of the intracellular lysosomes. We further show that the expression of the Ag-presenting molecule HLA-DR and costimulatory molecules CD40 and CD86 is dampened by endotoxin tolerance to the constitutive level. This, along with our previous evidence for reduction in immunostimulatory cytokines, is consistent with the observed decrease in the induction of autologous CD4+ T-cell proliferation by endotoxin-tolerized macrophages. Overall, these studies suggest that endotoxin tolerance, as observed in the inflamed oral mucosa, potentiates the innate Ag capture activity of macrophages but diminishes the potential of human macrophages to initiate the adaptive immune response. In conclusion, endotoxin tolerance, while helpful in bacterial clearance and in surmounting excessive inflammatory tissue damage, could potentially reduce the (protective) adaptive immune response during chronic infections such as periodontitis.

scholarly journals PD-L1 Overexpression During Endotoxin Tolerance Impairs the Adaptive Immune Response in Septic Patients via HIF1α

2017 ◽  
Vol 217 (3) ◽  
pp. 393-404 ◽  
Author(s):  
José Avendaño-Ortiz ◽  
Charbel Maroun-Eid ◽  
Alejandro Martín-Quirós ◽  
Víctor Toledano ◽  
Carolina Cubillos-Zapata ◽  
...  
Keyword(s):  
Immune Response ◽  
Adaptive Immune Response ◽  
Endotoxin Tolerance ◽  
Adaptive Immune

scholarly journals BIOM-36. THE UNIQUE METABOLOMICS BASED BIOMARKERS OF RESPONSE TO IMMUNOTHERAPY FOR GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii9-ii9
Author(s):  
Farhad Dastmalchi ◽  
Aida Karachi ◽  
Yusuf Mehkri ◽  
Ram Khattri ◽  
Matthew Merritt ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Ex Vivo ◽  
Adaptive Immune Response ◽  
Metabolic Changes ◽  
T Cell Proliferation ◽  
Adaptive Immune ◽  
Dc Vaccine ◽  
Cell Changes ◽  
Post Therapy

Abstract INTRODUCTION The adaptive immune response requires robust T cell proliferation and activation. These T cell changes are dependent on metabolic program shifts that can be measured using metabolomic analysis. The objective of this project was to identify a metabolomics profile to serve as a biomarker of response to immunotherapy for the treatment of brain tumors. METHODS GL261-gp100 tumor-bearing mice were received anti-PD1 or bone marrow-derived dendritic cell (DC) vaccine that was generated ex vivo. Urine samples were collected for Nuclear Magnetic Resonance (NMR) analysis. A more in-depth Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) revealed global metabolic changes induced with immunotherapy. RESULTS The metabolic changes were most dramatic at 24 hours post DC vaccination and slowly returned to baseline at 7 days post DC vaccination. The main drivers of the differences included creatine, n-dimethyl glycine, alanine, lactate, glucose, glutamine, leucine, citrate and formate. Anti-PD1 therapy-related metabolic changes were largest around day 20 post therapy and the main drivers of the differences included dimethyl sulfone, succinate, lactate and isobutyrate. CONCLUSION Immunotherapy results in systemic metabolic changes that serve as a biomarker treatment effect. These findings have translational relevance in predicting patients who will develop an immune response to immunotherapy and ultimately have better outcomes with treatment.

scholarly journals Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB

2014 ◽  
Vol 22 (3) ◽  
pp. 185-193 ◽  
Author(s):  
Marcell Costa de MEDEIROS ◽  
Sabrina Cruz Tfaile FRASNELLI ◽  
Alliny de Souza BASTOS ◽  
Silvana Regina Perez ORRICO ◽  
Carlos ROSSA JUNIOR
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Cell Proliferation ◽  
P38 Mapk ◽  
Adaptive Immune Response ◽  
Tlr Signaling ◽  
Adaptive Immune ◽  
In Cells

scholarly journals Congenital Asplenia Interrupts Immune Homeostasis and Leads to Excessive Systemic Inflammation in Zebrafish

2021 ◽  
Vol 11 ◽  
Author(s):  
Lang Xie ◽  
Zheyu Chen ◽  
Hui Guo ◽  
Yixi Tao ◽  
Xiaomin Miao ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokines ◽  
Adaptive Immune Response ◽  
Immune Homeostasis ◽  
Biological Processes ◽  
Wild Type ◽  
Adaptive Immune ◽  
Immune Related Genes ◽  
Insight Into ◽  
Pro Inflammatory Cytokines

Splenectomy or congenital asplenia in humans increases susceptibility to infections. We have previously reported that congenital asplenia in zebrafish reduces resistance to Aeromonas hydrophila infection. However, the molecular mechanism of systemic immune response in congenitally asplenic individuals is largely unexplored. In this study, we found that pro-inflammatory cytokines were more highly induced in congenitally asplenic zebrafish than wild-type after pathogenic A. hydrophila infection and lipopolysaccharide exposure. In addition, a higher aggregation of apoptotic cells was observed in congenitally asplenic zebrafish than that in wild-type. Next, we examined the transcriptome profiles of whole kidneys from wild-type and congenitally asplenic zebrafish to investigate the effects of congenital asplenia on innate and adaptive immune responses induced by the inactivated A. hydrophila. Congenital asplenia inactivated the splenic anti-inflammatory reflex, disrupted immune homeostasis, and induced excessive inflammation as evidenced by the highly induced stress response–related biological processes, inflammatory and apoptosis-associated pathways, and pro-inflammatory cytokines/chemokines in congenitally asplenic zebrafish compared with wild-type after vaccination. In addition, complement component genes (c3a.1, c3a.6, c4, c6, and c9) and several important immune-related genes (tabp.1, tap1, hamp, prg4b, nfil3, defbl1, psmb9a, tfr1a, and sae1) were downregulated in congenitally asplenic zebrafish. Furthermore, congenital asplenia impaired adaptive immunity as demonstrated by downregulation of biological processes and signaling pathways involved in adaptive immune response after vaccination in congenitally asplenic zebrafish. The expression of MHCII/IgM was also significantly reduced in the congenitally asplenic zebrafish when compared with wild-type. Together, our study provides an in-depth understanding of spleen function in controlling immune homeostasis and may offer insight into the pathological response in splenectomized or congenitally asplenic patients after infections.

scholarly journals Temporal Metabolic Characteristics and Transcriptomic Landscape of Islets and Liver Reveal Dynamic Pathophysiology and Interorgan Crosstalk in High-fat Diet-induced Diabetes

2020 ◽  
Author(s):  
Rui Gao ◽  
Qi Fu ◽  
He-Min Jiang ◽  
Min Shen ◽  
Rui-Ling Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Immune Response ◽  
Cell Proliferation ◽  
High Fat Diet ◽  
Insulin Action ◽  
Time Course ◽  
Adaptive Immune Response ◽  
High Fat ◽  
Adaptive Immune ◽  
Islet Dysfunction

AbstractObjectiveHyperinsulinemia and insulin resistance are co-existing characteristics of type 2 diabetes, whereas the molecular mechanism underlying this deleterious cycle remains elusive. The temporal transcriptomic landscape of core organs responsible for insulin secretion (islets) and insulin action (liver) could provide new insights.MethodsThe longitudinal profiling of glucose metabolism, insulin sensitivity, islet architecture and secretion were conducted in C57BL/6N mice fed a high-fat diet (HFD) or chow diet for 24 weeks. RNA-sequencing of islets and liver were performed once every 4 weeks. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis were applied to construct networks and evaluate co-ordinated molecular interactions between islets and liver.ResultsMice exhibited progressively deteriorated glucose homeostasis with hyperinsulinemia but impaired first-phase insulin secretion after 4 weeks on HFD. Insulin, glucagon and somatostatin secretion in response to glucose with or without palmitate gradually deteriorated from dysregulation to failure. Systemic insulin resistance developed over 24 weeks with variable time course in tissue-specific insulin action. Our transcriptomic datasets outlined the impact of HFD on dynamics of islet and liver molecular network at different stages. Correlation analyses revealed that both organs jointly programmed β-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage. Alternations of T cell subpopulations validated the participation of adaptive immune response through priming and amplification phases in diabetic progression.ConclusionOur data provide a comprehensive landscape of crosstalk between islets and liver in diet-induced diabetes, elucidating the development of islet dysfunction and insulin resistance.HighlightsDiet-induced diabetes is featured by transition from islet dysfunction to failureInsulin resistance develops with variable time course in different tissuesDynamics of islet and liver molecular network interplay at different stagesCell proliferation and improper immune reaction mediated interorgan crosstalkAdaptive immune response participated via priming and amplification phases

Reciprocal role of hBD2 and hBD3 on the adaptive immune response by measuring T lymphocyte proliferation in terms of CD4 and CCR6 expression

2018 ◽  
Vol 35 (3) ◽  
Author(s):  
Nima Taefehshokr ◽  
Alireza Isazadeh ◽  
Amin Oveisi ◽  
Yashar Azari Key ◽  
Sina Taefehshokr
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Adaptive Immune Response ◽  
T Cell Proliferation ◽  
Peripheral Blood Mononuclear ◽  
Adaptive Immune ◽  
T Lymphocyte Proliferation

Abstract Background Human β-defensins (hBD2 and hBD3) are small cationic antimicrobial peptides of innate immune system which can act as a barrier against the majority of pathogens, contributing to the host immune defence. Objective The aim of study is to determine whether hBD2 and hBD3 play a role in development and proliferation of human effector CD4 T cells or not. Furthermore, if enhanced proliferation is observed in the presence of hBD2 and hBD3, these data will demonstrate whether chemokine receptor type 6 (CCR6) is required to be present for this activity to occur. Methods In this study, we examined the effect of hBD2 and hBD3 on CD4+ T cell proliferation in CCR6+ and CCR6− T cells through co-culture of peripheral blood mononuclear cells with anti-CD3 and anti-CD28 stimulation in the presence or absence of hBD2 and hBD3. Proliferation was assessed using flow cytometry. Results It was demonstrated that, co-culture with hBD2 and hBD3 led to up-regulation of CD4+ T cell proliferation after 72 h whereas, CD4+ T cell proliferation was suppressed after 96 h. On the other hand, CCR6− and CCR6+ T cell proliferation was up-regulated after 72 h. But, CCR6+ only was down-regulated in the second cycle in the presence of hBD3. In contrast, after 96 h CCR6+ and CCR6− T cell proliferation was decreased. Conclusion Collectively, our data indicated that hBD2 and hBD3 play a positive and negative regulatory role in development and proliferation of human effector CD4+ T cells which is essential for optimal adaptive immune responses and the control of immunopathology.

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