scholarly journals Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1750-1758 ◽  
Author(s):  
James L. Wynn ◽  
Philip O. Scumpia ◽  
Robert D. Winfield ◽  
Matthew J. Delano ◽  
Kindra Kelly-Scumpia ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Adaptive Immune System ◽  
Neutrophil Recruitment ◽  
Polymicrobial Sepsis ◽  
Type I ◽  
Sepsis Mortality ◽  
Tlr Agonists ◽  
Adaptive Immune ◽  
Increased Risk

Abstract Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell–directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b+ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality.

scholarly journals The neuropeptide receptor NMUR-1 regulates the specificity of C. elegans innate immunity against pathogen infection

2021 ◽  
Author(s):  
Phillip Wibisono ◽  
Shawndra Wibisono ◽  
Jan Watteyne ◽  
Chia-Hui Chen ◽  
Durai Sellegounder ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Genes ◽  
C Elegans ◽  
Adaptive Immune ◽  
Functional Assays

A key question in current immunology is how the innate immune system generates high levels of specificity. Like most invertebrates, Caenorhabditis elegans does not have an adaptive immune system and relies solely on innate immunity to defend itself against pathogen attacks, yet it can still differentiate different pathogens and launch distinct innate immune responses. Here, we have found that functional loss of NMUR-1, a neuronal GPCR homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans survival against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors, which, in turn, controls the expression of distinct immune genes in response to different pathogens. Our study has uncovered a molecular basis for the specificity of C. elegans innate immunity that could provide mechanistic insights into understanding the specificity of vertebrate innate immunity.

scholarly journals Tweaking Innate Immunity: The Promise of Innate Immunologicals as Anti-Infectives

2006 ◽  
Vol 17 (5) ◽  
pp. 307-314 ◽  
Author(s):  
Kenneth L Rosenthal
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Immune Defense ◽  
Innate Immune ◽  
Parasitic Infections ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

New and exciting insights into the importance of the innate immune system are revolutionizing our understanding of immune defense against infections, pathogenesis, and the treatment and prevention of infectious diseases. The innate immune system uses multiple families of germline-encoded pattern recognition receptors (PRRs) to detect infection and trigger a variety of antimicrobial defense mechanisms. PRRs are evolutionarily highly conserved and serve to detect infection by recognizing pathogen-associated molecular patterns that are unique to microorganisms and essential for their survival. Toll-like receptors (TLRs) are transmembrane signalling receptors that activate gene expression programs that result in the production of proinflammatory cytokines and chemokines, type I interferons and antimicrobial factors. Furthermore, TLR activation facilitates and guides activation of adaptive immune responses through the activation of dendritic cells. TLRs are localized on the cell surface and in endosomal/lysosomal compartments, where they detect bacterial and viral infections. In contrast, nucleotide-binding oligomerization domain proteins and RNA helicases are located in the cell cytoplasm, where they serve as intracellular PRRs to detect cytoplasmic infections, particularly viruses. Due to their ability to enhance innate immune responses, novel strategies to use ligands, synthetic agonists or antagonists of PRRs (also known as 'innate immunologicals') can be used as stand-alone agents to provide immediate protection or treatment against bacterial, viral or parasitic infections. Furthermore, the newly appreciated importance of innate immunity in initiating and shaping adaptive immune responses is contributing to our understanding of vaccine adjuvants and promises to lead to improved next-generation vaccines.

SLPI and elafin: one glove, many fingers

2005 ◽  
Vol 110 (1) ◽  
pp. 21-35 ◽  
Author(s):  
Steven E. Williams ◽  
Thomas I. Brown ◽  
Ali Roghanian ◽  
Jean-Michel Sallenave
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune ◽  
Pathological Conditions ◽  
Related Proteins

Elafin and SLPI (secretory leucocyte protease inhibitor) have multiple important roles both in normal homoeostasis and at sites of inflammation. These include antiprotease and antimicrobial activity as well as modulation of the response to LPS (lipopolysaccharide) stimulation. Elafin and SLPI are members of larger families of proteins secreted predominantly at mucosal sites, and have been shown to be modulated in multiple pathological conditions. We believe that elafin and SLPI are important molecules in the controlled functioning of the innate immune system, and may have further importance in the integration of this system with the adaptive immune response. Recent interest has focused on the influence of inflamed tissues on the recruitment and phenotypic modulation of cells of the adaptive immune system and, indeed, the local production of elafin and SLPI indicate that they are ideally placed in this regard. Functionally related proteins, such as the defensins and cathelicidins, have been shown to have direct effects upon dendritic cells with potential alteration of their phenotype towards type I or II immune responses. This review addresses the multiple functions of elafin and SLPI in the inflammatory response and discusses further their roles in the development of the adaptive immune response.

scholarly journals Allergen-associated molecular patterns: a new trend in modern allergology

2019 ◽  
Vol 18 (1) ◽  
pp. 76-83
Author(s):  
V. S. Sviridova ◽  
P. Yu. Isaev ◽  
V. V. Klimov ◽  
M. I. Romanova ◽  
N. S. Koshkarova
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Adaptive Immune System ◽  
Conserved Motifs ◽  
Immune Mechanisms ◽  
Adaptive Immune ◽  
Molecular Patterns

Over the last decade the role of innate immunity has been known to be crucial for the activation of adaptive immune system. The main triggers that upregulate reactions of innate immunity are small exogenous molecules with conserved motifs, molecular patterns. The article discusses a variety of possible roles of molecular patterns in the immune mechanisms, including the participation of Allergen Associated Molecular Patterns (AAMPs) in allergic processes.

scholarly journals Development of Immunopathobiogenesis on SIRS-Sepsis

2009 ◽  
Vol 1 (1) ◽  
pp. 32
Author(s):  
A Guntur Hermawan
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Proinflammatory Cytokines ◽  
Critical Role ◽  
Adaptive Immune System ◽  
Multiple Organ ◽  
Toxic Shock ◽  
Sepsis Diagnosis ◽  
Adaptive Immune ◽  
And Function

Over the past decade, sepsis has been diagnosed according to consensus guidelines established in 1991 as an infection in addition to the symptoms of systemic inflammatory response syndrome (SIRS). In addition to the previous criteria, the 2001 conference added several new diagnostic criteria for sepsis. Of particular interest was the inclusion of the biomarkers procalcitonin (PCT) and C-reactive protein (CRP), despite the overall conclusion that it was premature to use biomarkers for sepsis diagnosis. The primary recommendation of the panel was the implementation of the Predisposition, insult Infection, Response, and Organ dysfunction (PIRO).The immune system has traditionally been devided into innate and adaptive components, each of which has a different role and function in defending the host against infectious agents. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also increasing evidence supports an additional critical role for TLRs in orchestrating the development of adaptive immune responses.The superantigens are able to induce toxic shock syndrome and can sometimes cause multiple organ failure via adaptive immune system. The superantigenic activity of the bacterial exotoxins can be attributed to their ability to cross-link major histocompatibility complex class II molecules on antigen-presenting cells outside the peptide groove with T-cell receptors to form a trimolecular complex. This trimolecular interaction leads to uncontrolled release of a number of proinflammatory cytokines. Proinflammatory cytokines especially IFN-γ and TNF-α, the key cytokines causing toxic shock syndrome.KEYWORDS: sepsis, innate immunity, adaptive

Expression of Toll-Like Receptors on Peripheral Blood Cells After Allogeneic Stem Cell Transplantation: Results of a Prospective Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4071-4071
Author(s):  
Cristina Skert ◽  
Manuela Fogli ◽  
Simone Perucca ◽  
Simona Fiorentini ◽  
Emirena Garrafa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Immune System ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Adaptive Immune System ◽  
Type I ◽  
Ifn Gamma ◽  
Adaptive Immune

Abstract Abstract 4071 Introduction. Emerging trends emphasize the importance of both innate and adaptive immune system in the response against infections, and in the pathogenesis of autoimmune and graft-versus-host (GVHD) diseases. Pattern recognition receptors such as Toll-like receptors (TLRs) play a key role in the cross-talk between innate and adaptive immune system. TLRs belong to type I transmembrane glycoprotein receptor family and recognize pathogen-associated molecular patterns (PAMPs), such as common protein, carbohydrate or DNA/RNA pattern motifs. TLRs are also receptors for endogenous ligands and damaged tissue, suggesting that both pathogen-derived molecules and products of damaged tissue can trigger signals which are responsible for the regulation of innate and adaptive immune responses. Extracellular ligands are recognized by surface TLRs (TLR1,TLR2,TLR4,TLR5, and TLR6). Intracellular TLRs (TLR3,TLR7,TLR8 and TLR9) bind mainly to foreign nucleic acids and sometimes detect self DNA/RNA. Aim of the study. Very little is known about expression and function of TLRs in vivo in patients who underwent allogeneic stem cell transplantation (SCT). The aim of this study was to evaluate the expression of TLRs on lymphocytes and monocytes in relation to the onset of acute GVHD. Methods. The expression of TLRs on lymphocytes and monocytes was analysed by flow cytometry as mean fluorescence intensity at day +30 and at the onset of GVHD. Functional data were obtained by ELISA assay after TLRs activation. The cell supernatants were collected and assayed for TNF-alpha, IFN-gamma and MCP-1. Relative induction of these cytokines was calculated in relation with unstimulated controls. Results. We analyzed 17 healthy donors and 34 patients. Median age was 46 years (range, 22–64) and 22 patients were male. Acute GVHD developed in 19 patients (12 with grade >=2). Clinical and transplant characteristics did not differ in patients with and without GVHD. Lymphocytes and monocytes of patients with acute GVHD showed higher levels of TLR5 (3,5±2,3 vs1,9±1,6 p=0,03; 25,8±25,9 vs 9,0±5,0 p=0,02) and a decreased expression of TLR1 (2,5±2,8 vs 4,3±2,8 p=0,02; 21,4±21,9 vs 54,9±37,4 p=0,005) and TLR9 (63,8±30,4 vs 111,1±62,9 p=0,03; 85,3±73,9 vs 164,2±90,6 p=0,01). IFN-gamma relative induction post-stimulation of TLR2,3,4 and 9 was significantly decreased in patients with acute GVHD (p< 0,04). Conclusions. TLRs show a different profile of expression in patients with acute GVHD in comparison with patients without it. These results suggest that the innate immune response via TLRs activation could be involved in the development of GVHD. In particular, a decreased expression of TLR-9 (receptor of hypomethylated DNA) on lymphocytes and monocytes can promote TLR-7 activation, inducing type I interferons and other pro-inflammatory cytokines. TLR-1 and −5, which are ligands for bacterial cell wall, could also be involved in the pathogenesis of GVHD. Moreover, acute GVHD negatively correlates with IFN-gamma production upon TLR2,3,4 and 9 activation. The assessment of a larger number of patients could be useful to understand the complex interplay among pathogens, self or non-self DNA and RNA, and the immune system. Disclosures: No relevant conflicts of interest to declare.

Developments in anticancer vaccination: budding new adjuvants

2020 ◽  
Vol 401 (4) ◽  
pp. 435-446 ◽  
Author(s):  
Sandra Santos-Sierra
Keyword(s):  
T Cells ◽  
Immune System ◽  
Immune Escape ◽  
Adaptive Immune System ◽  
Cell Detection ◽  
Cancer Vaccination ◽  
Tlr Agonists ◽  
Adaptive Immune ◽  
Anti Cancer ◽  
The Right

AbstractThe immune system has a limited capacity to recognize and fight cells that become cancerous and in cancer patients, the immune system has to seek the right balance between cancer rejection and host-immunosupression. The tumor milieu builds a protective shell and tumor cells rapidly accumulate mutations that promote antigen variability and immune-escape. Therapeutic vaccination of cancer is a promising strategy the success of which depends on a powerful activation of the cells of the adaptive immune system specific for tumor-cell detection and killing (e.g. CD4+ and CD8+ T-cells). In the last decades, the search for novel adjuvants that enhance dendritic cell (DC) function and their ability to prime T-cells has flourished and some Toll-like receptor (TLR) agonists have long been known to be valid immune adjuvants. The implementation of TLR-synthetic agonists in clinical studies of cancer vaccination is replacing the initial use of microbial-derived products with some encouraging results. The purpose of this review is to summarize the latest discoveries of TLR-synthetic agonists with adjuvant potential in anti-cancer vaccination.

scholarly journals Early type I IFN blockade improves the efficacy of viral vaccines

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Nicole Palacio ◽  
Tanushree Dangi ◽  
Young Rock Chung ◽  
Yidan Wang ◽  
Juan Luis Loredo-Varela ◽  
...  
Keyword(s):  
Immune System ◽  
Adaptive Immune System ◽  
Immunological Memory ◽  
Type I Interferons ◽  
Type I ◽  
Short Term ◽  
Adaptive Immune ◽  
Acute Viral Infection ◽  
Rational Vaccine Design ◽  
Viral Vaccines

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor–blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient “spike” in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.

scholarly journals Harnessing the CRISPR-Cas Systems to Combat Antimicrobial Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheng Duan ◽  
Huiluo Cao ◽  
Lian-Hui Zhang ◽  
Zeling Xu
Keyword(s):  
Immune System ◽  
Antimicrobial Resistance ◽  
Global Health ◽  
Adaptive Immune System ◽  
Type I ◽  
Type Ii ◽  
Bacterial Genomes ◽  
Adaptive Immune ◽  
The Past ◽  
Attractive Option

The emergence of antimicrobial-resistant (AMR) bacteria has become one of the most serious threats to global health, necessitating the development of novel antimicrobial strategies. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) system, known as a bacterial adaptive immune system, can be repurposed to selectively target and destruct bacterial genomes other than invasive genetic elements. Thus, the CRISPR-Cas system offers an attractive option for the development of the next-generation antimicrobials to combat infectious diseases especially those caused by AMR pathogens. However, the application of CRISPR-Cas antimicrobials remains at a very preliminary stage and numerous obstacles await to be solved. In this mini-review, we summarize the development of using type I, type II, and type VI CRISPR-Cas antimicrobials to eradicate AMR pathogens and plasmids in the past a few years. We also discuss the most common challenges in applying CRISPR-Cas antimicrobials and potential solutions to overcome them.

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