scholarly journals Dysregulation of Adenosinergic Signaling in Systemic and Organ-Specific Autoimmunity

2019 ◽  
Vol 20 (3) ◽  
pp. 528 ◽  
Author(s):  
Marta Vuerich ◽  
Rasika Harshe ◽  
Simon Robson ◽  
Maria Longhi
Keyword(s):  
Immune Responses ◽  
Cell Function ◽  
Immune Cell ◽  
Purinergic Signaling ◽  
Extracellular Nucleotides ◽  
Extracellular Adenosine ◽  
Pathological Conditions ◽  
Clinical Toxicity ◽  
Organ Specific ◽  
P1 Receptor

Exact causes for autoimmune diseases remain unclear and no cures are available. Breakdown of immunotolerance could set the stage for unfettered immune responses that target self-antigens. Impaired regulatory immune mechanisms could have permissive roles in autoreactivity. Abnormal regulatory immune cell function, therefore, might be a major determinant of the pathogenesis of autoimmune disease. All current treatments are associated with some level of clinical toxicity. Treatment to specifically target dysregulated immunity in these diseases would be a great advance. Extracellular adenosine is a signaling mediator that suppresses inflammation through activation of P1 receptors, most active under pathological conditions. Mounting evidence has linked alterations in the generation of adenosine from extracellular nucleotides by ectonucleotidases, and associated perturbations in purinergic signaling, to the immunological disruption and loss of immunotolerance in autoimmunity. Targeted modulation of the purinergic signaling by either targeting ectonucleotidases or modulating P1 purinergic receptors could therefore restore the balance between autoreactive immune responses; and thereby allow reestablishment of immunotolerance. We review the roles of CD39 and CD73 ectoenzymes in inflammatory states and with the dysregulation of P1 receptor signaling in systemic and organ-specific autoimmunity. Correction of such perturbations could be exploited in potential therapeutic applications.

scholarly journals Prostaglandin E2 Signaling Mediates Oenocytoid Immune Cell Function and Lysis, Limiting Bacteria and Plasmodium Oocyst Survival in Anopheles gambiae

2021 ◽  
Vol 12 ◽  
Author(s):  
Hyeogsun Kwon ◽  
David R. Hall ◽  
Ryan C. Smith
Keyword(s):  
Immune Responses ◽  
Prostaglandin E2 ◽  
Anopheles Gambiae ◽  
Cell Function ◽  
Immune Cell ◽  
Protective Effects ◽  
Immune Cell Function ◽  
Humoral Immune ◽  
High Concentrations ◽  
Prostaglandin E2 Receptor

Lipid-derived signaling molecules known as eicosanoids have integral roles in mediating immune and inflammatory processes across metazoans. This includes the function of prostaglandins and their cognate G protein-coupled receptors (GPCRs) to employ their immunological actions. In insects, prostaglandins have been implicated in the regulation of both cellular and humoral immune responses, yet in arthropods of medical importance, studies have been limited. Here, we describe a prostaglandin E2 receptor (AgPGE2R) in the mosquito Anopheles gambiae and demonstrate that its expression is most abundant in oenocytoid immune cell populations. Through the administration of prostaglandin E2 (PGE2) and AgPGE2R-silencing, we demonstrate that prostaglandin E2 signaling regulates a subset of prophenoloxidases (PPOs) and antimicrobial peptides (AMPs) that are strongly expressed in populations of oenocytoids. We demonstrate that PGE2 signaling via the AgPGE2R significantly limits both bacterial replication and Plasmodium oocyst survival. Additional experiments establish that PGE2 treatment increases phenoloxidase (PO) activity through the increased expression of PPO1 and PPO3, genes essential to anti-Plasmodium immune responses that promote oocyst killing. We also provide evidence that the mechanisms of PGE2 signaling are concentration-dependent, where high concentrations of PGE2 promote oenocytoid lysis, negating the protective effects of lower concentrations of PGE2 on anti-Plasmodium immunity. Taken together, our results provide new insights into the role of PGE2 signaling on immune cell function and its contributions to mosquito innate immunity that promote pathogen killing.

scholarly journals Soluble Ecto-5′-nucleotidase (5′-NT), Alkaline Phosphatase, and Adenosine Deaminase (ADA1) Activities in Neonatal Blood Favor Elevated Extracellular Adenosine

2013 ◽  
Vol 288 (38) ◽  
pp. 27315-27326 ◽  
Author(s):  
Matthew Pettengill ◽  
Simon Robson ◽  
Megan Tresenriter ◽  
José Luis Millán ◽  
Anny Usheva ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Adenosine Deaminase ◽  
Whole Blood ◽  
Cell Function ◽  
Immune Cell ◽  
Expression Patterns ◽  
Plasma Concentrations ◽  
Metabolizing Enzymes ◽  
Extracellular Adenosine ◽  
Neonatal Blood

Extracellular adenosine, a key regulator of physiology and immune cell function that is found at elevated levels in neonatal blood, is generated by phosphohydrolysis of adenine nucleotides released from cells and catabolized by deamination to inosine. Generation of adenosine monophosphate (AMP) in blood is driven by cell-associated enzymes, whereas conversion of AMP to adenosine is largely mediated by soluble enzymes. The identities of the enzymes responsible for these activities in whole blood of neonates have been defined in this study and contrasted to adult blood. We demonstrate that soluble 5′-nucleotidase (5′-NT) and alkaline phosphatase (AP) mediate conversion of AMP to adenosine, whereas soluble adenosine deaminase (ADA) catabolizes adenosine to inosine. Newborn blood plasma demonstrates substantially higher adenosine-generating 5′-NT and AP activity and lower adenosine-metabolizing ADA activity than adult plasma. In addition to a role in soluble purine metabolism, abundant AP expressed on the surface of circulating neonatal neutrophils is the dominant AMPase on these cells. Plasma samples from infant observational cohorts reveal a relative plasma ADA deficiency at birth, followed by a gradual maturation of plasma ADA through infancy. The robust adenosine-generating capacity of neonates appears functionally relevant because supplementation with AMP inhibited whereas selective pharmacologic inhibition of 5′-NT enhanced Toll-like receptor-mediated TNF-α production in neonatal whole blood. Overall, we have characterized previously unrecognized age-dependent expression patterns of plasma purine-metabolizing enzymes that result in elevated plasma concentrations of anti-inflammatory adenosine in newborns. Targeted manipulation of purine-metabolizing enzymes may benefit this vulnerable population.

Emerging Mechanisms of Immunosuppression in Oral Cancers

2006 ◽  
Vol 85 (12) ◽  
pp. 1061-1073 ◽  
Author(s):  
A. Jewett ◽  
C. Head ◽  
N.A. Cacalano
Keyword(s):  
Oral Cancer ◽  
Immune Responses ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Oral Cancers ◽  
Oral Cancer Patients ◽  
And Function

Mounting effective anti-tumor immune responses against tumors by both the innate and adaptive immune effectors is important for the clearance of tumors. However, accumulated evidence indicates that immune responses that should otherwise suppress or eliminate transformed cells are themselves suppressed by the function of tumor cells in a variety of cancer patients, including those with oral cancers. Signaling abnormalities, spontaneous apoptosis, and reduced proliferation and function of circulating natural killer cells (NK), T-cells, dendritic cells (DC), and tumor-infiltrating lymphocytes (TILs) have been documented previously in oral cancer patients. Several mechanisms have been proposed for the functional deficiencies of tumor-associated immune cells in oral cancer patients. Both soluble factors and contact-mediated immunosuppression by the tumor cells have been implicated in the inhibition of immune cell function and the progression of tumors. More recently, elevated levels and function of key transcription factors in tumor cells, particularly NFκB and STAT3, have been shown to mediate immune suppression in the tumor microenvironment. This review will focus on these emerging mechanisms of immunosuppression in oral cancers.

scholarly journals Tumors induce de novo steroid biosynthesis in T cells to evade immunity

2018 ◽  
Author(s):  
Bidesh Mahata ◽  
Jhuma Pramanik ◽  
Louise van der Weyden ◽  
Krzysztof Polanski ◽  
Gozde Kar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
De Novo ◽  
Steroid Biosynthesis ◽  
Genetic Ablation ◽  
Tumor Immunosuppression

ABSTRACTTumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a novel transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway was sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

scholarly journals Myeloid-Derived Suppressor Cells Participate in Preventing Graft Rejection

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yan Wang ◽  
Xiaodong Gu ◽  
Jianbin Xiang ◽  
Zongyou Chen
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Suppressor Cells ◽  
Heterogeneous Population ◽  
Myeloid Derived Suppressor Cells ◽  
Transplant Tolerance ◽  
Pathological Conditions ◽  
T Cell Immune Responses

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells and have a tremendous potential to suppress immune responses. MDSCs accumulate during tumor progression, autoimmunity, chronic infection, transplantation, and other pathological conditions and can potently suppress T-cell function. Here, we discuss recent findings that describe the molecular mechanisms of MDSCs suppressing T-cell immune responses as well as recent observations that MDSCs may have roles in transplant tolerance.

scholarly journals Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002273
Author(s):  
Kevin T Lynch ◽  
Samuel J Young ◽  
Max O Meneveau ◽  
Nolan A Wages ◽  
Victor H Engelhard ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Prognostic Significance ◽  
Regulatory Function ◽  
Lymphocyte Infiltration ◽  
Peripheral Tissues ◽  
Melanoma Metastases

BackgroundTertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but it is unknown whether TLS have prognostic significance independent of CBT in melanoma. We hypothesized that TLS in melanoma metastases would be associated with increased intratumoral lymphocyte infiltration, but that the intra-TLS immunological milieu would be distinct from the intratumoral immunological milieu. We also hypothesized that the presence of TLS would be associated with improved survival, and that TLS maturation or intra-TLS lymphocyte activity would also correlate with survival.MethodsCutaneous melanoma metastases (CMM) from 64 patients were evaluated by multiplex immunofluorescence for the presence and maturation status of TLS. Intra-TLS lymphocyte density, proliferation and B-cell Ig somatic hypermutation (AID+) were analyzed, as were markers of T-cell exhaustion and Th1/Tc1 differentiation. Associations between TLS maturation and intra-TLS immunologic activity were assessed, as well as associations with intratumoral immune cell infiltration. Independent associations with overall survival (OS) were assessed using log-rank tests and Cox proportional hazards models.ResultsTLS were identified in 30 (47%) of 64 CMM (TLS+) and were associated with increased intratumoral lymphocyte infiltration. However, proliferation of intra-TLS lymphocytes did not correlate with intratumoral lymphocyte proliferation. Most were early TLS; however, subsets of primary or secondary follicle-like TLS were also present. TLS+ lesions were associated with lower risk of tumor recurrence after metastasectomy and with improved OS in multivariate analyses (HR 0.51, p=0.04). OS was longer for TLS with low fractions of CD21+ B-cells (HR 0.29, p=0.02) and shorter for those with low AID+ fraction of B-cells (HR 2.74, p=0.03).ConclusionsThe presence of TLS in CMMs is associated with improved OS in patients treated with surgery before CBT, but TLS vary widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Importantly, these features have additional prognostic significance, which suggest that some TLS may have regulatory function, while others functioning to support antigen-driven immune responses, depending on the cellular composition and activation status.

scholarly journals Identification of a prostaglandin E2 receptor that regulates mosquito oenocytoid immune cell function in limiting bacteria and parasite infection

2020 ◽  
Author(s):  
Hyeogsun Kwon ◽  
David R. Hall ◽  
Ryan C. Smith
Keyword(s):  
Immune Responses ◽  
Prostaglandin E2 ◽  
Cell Function ◽  
Immune Cell ◽  
Protective Effects ◽  
Immune Cell Function ◽  
Humoral Immune ◽  
High Concentrations ◽  
Prostaglandin E2 Receptor

AbstractLipid-derived signaling molecules known as eicosanoids have integral roles in mediating immune and inflammatory processes across metazoans. This includes the function of prostaglandins and their cognate G protein-coupled receptors (GPCRs) to employ their immunological actions. In insects, prostaglandins have been implicated in the regulation of both cellular and humoral immune responses, yet studies have been limited by the absence of a described prostaglandin receptor. Here, we characterize a prostaglandin E2 receptor (AgPGE2R) in the mosquito Anopheles gambiae and examine its contributions to innate immunity. AgPGE2R expression is most abundant in circulating hemocytes where it is primarily localized to oenocytoid immune cell populations. Through the administration of prostaglandin E2 (PGE2) and AgPGE2R-silencing by RNAi, we demonstrate that PGE2 signaling regulates the expression of a subset of prophenoloxidases (PPOs) and antimicrobial peptides (AMPs). PGE2 priming via the AgPGE2R significantly limited bacterial replication and suppressed Plasmodium oocyst survival. Additional experiments establish that PGE2 priming increases phenoloxidase (PO) activity through the increased expression of PPO1 and PPO3, which significantly influence Plasmodium oocyst survival. We also provide evidence that PGE2 priming is concentration-dependent, where high concentrations of PGE2 promote oenocytoid lysis, negating the protective effects of PGE2 priming on anti-Plasmodium immunity. Taken together, our results characterize the AgPGE2R and the role of prostaglandin signaling on immune cell function, providing new insights into the role of PGE2 on anti-bacterial and anti-Plasmodium immune responses in the mosquito host.

Regulatory T Cell-Based Immunotherapy

2013 ◽  
pp. 112-136 ◽  
Author(s):  
Sonja Schallenberg ◽  
Cathleen Petzold ◽  
Julia Riewaldt ◽  
Karsten Kretschmer
Keyword(s):  
Immune Responses ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
Clinical Settings ◽  
Host Immune Responses ◽  
Forkhead Box ◽  
Cell Induction ◽  
Organ Specific ◽  
Treg Cell Function

CD4+CD25+ regulatory T (Treg) cells expressing the forkhead box transcription factor Foxp3 have a vital function in the maintenance of immune homeostasis and the prevention of fatal multi-organ autoimmunity throughout life. In the last decade, Foxp3+ Treg cells have raised the hope for novel cell-based therapies to achieve tolerance in clinical settings of unwanted immune responses such as autoimmunity and graft rejection. Conceptually, the antigen-specific enhancement of Treg cell function is of particular importance because such strategies will minimize the requirements for pharmaceutical immunosuppression, sparing desired protective host immune responses to infectious and malignant insults. This chapter discusses current concepts of Treg cell-based immunotherapy with particular emphasis on antigen-specific Treg cell induction from conventional CD4+ T cells to deal with organ-specific autoimmunity.

Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1123-1130 ◽  
Author(s):  
Jennifer L. Brogdon ◽  
Yongyao Xu ◽  
Susanne J. Szabo ◽  
Shaojian An ◽  
Francis Buxton ◽  
...  
Keyword(s):  
Immune Responses ◽  
Histone Deacetylases ◽  
Cell Activation ◽  
Effector Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Critical Role ◽  
High Specificity ◽  
Hdac Inhibition ◽  
T Helper 1

Abstract Histone deacetylases (HDACs) play a critical role in regulating gene expression and key biological processes. However, how HDACs are involved in innate immunity is little understood. Here, in this first systematic investigation of the role of HDACs in immunity, we show that HDAC inhibition by a small-molecule HDAC inhibitor (HDACi), LAQ824, alters Toll-like receptor 4 (TLR4)–dependent activation and function of macrophages and dendritic cells (DCs). Surprisingly, pan-HDAC inhibition modulates only a limited set of genes involved in distinct arms of immune responses. Specifically, it inhibited DC-controlled T helper 1 (Th1) effector but not Th2 effector cell activation and migration. It also inhibited macrophage- and DC-mediated monocyte but not neutrophil chemotaxis. These unexpected findings demonstrate the high specificity of HDAC inhibition in modulating innate and adaptive immune responses, and highlight the potential for HDACi to alter the Th1 and Th2 balance in therapeutic settings.

scholarly journals Implications of Inflammatory States on Dysfunctional Immune Responses in Aging and Obesity

2021 ◽  
Vol 2 ◽  
Author(s):  
Alyssa L. Thomas ◽  
Pablo C. Alarcon ◽  
Senad Divanovic ◽  
Claire A. Chougnet ◽  
David A. Hildeman ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Function ◽  
Immune Cell ◽  
Accelerated Aging ◽  
Clinical Problem ◽  
Cell Types ◽  
Low Grade ◽  
Potential Contribution ◽  
Altered State ◽  
Low Grade Inflammation

Aging and obesity are two conditions characterized by chronic, low-grade inflammation. While both conditions are also associated with dysfunctional immune responses, the shared and distinct underlying mechanisms are just starting to be uncovered. In fact, recent findings have suggested that the effects of obesity on the immune system can be thought of as a state of accelerated aging. Here we propose that chronic, low-grade inflammation seen in obesity and aging is complex, affects multiple cell types, and results in an altered basal immune state. In aging, part of this altered state is the emergence of regulatory immune populations that lead to further immune dysfunction in an attempt to reduce chronic inflammation. While in obesity, part of the altered state is the effect of expanding adipose tissue on immune cell function. Thus, in this review, we compare, and contrast altered immune states in aging and obesity and discuss their potential contribution to a shared clinical problem- decreased vaccine responsiveness.

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