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Helicobacter pylori infection
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Diane Bimczok, Anne Müller, Phillip D. Smith
In contrast, H. pylori recognition involves TLR2 activation. TLR2 is an important surface-expressed PRR that collaborates with TLR1, TLR6, TLR10, and other receptors to recognize bacterial and fungal products. An array of H. pylori-derived molecules, including LPS, heat shock protein 60 (HP-HSP60), and HP-NAP, induce TLR2 activation. Activation of TLR2 leads to NF-κB signaling and induction of cytokine expression by epithelial cells, as well as macrophages, DCs, neutrophils, and B cells. In addition, TLR2 engagement by H. pylori leads to activation of the inflammasome pathway through the Nod-like receptor family member NLRP3, which in turn causes activation of IL-1β, a key pro-inflammatory mediator. H. pylori also signals through TLR9, an intracellular PRR activated by bacterial DNA that can activate both pro-inflammatory and anti-inflammatory pathways. Interestingly, H. pylori DNA is delivered to the intracellular TLR9 through the T4SS encoded by the cag pathogenicity island, through a similar pathway that delivers H. pylori peptidoglycan to NOD1.
Preterm labor and birth
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Vincenzo Berghella, Eduardo da Fonseca
There are several recent studies and reviews on possible genetic etiologies, or at least associations, with PTB (3–5). These in general confirm the different pathways associated so far with PTB and risk factors. For example, a recent review highlighted genetic variants detected by whole exome (or genome in some cases) sequencing (WES) pointing to the negative regulation (dampening) of the innate immune response (e.g., CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (e.g., DEFB1, MBL2) associated with PTB (3). These genetic associations support the concept that PTB, at least in part, has an inflammatory etiology, which can be induced either by pathogens (i.e., intra-amniotic infection) or “danger signals” (e.g., alarmins) released during cellular stress or necrosis (i.e., sterile intra-amniotic inflammation) (3). PTB has a polygenic basis that involves mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. WES is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous PTB (3).
Dendritic Cells Control the Balance between Tolerance and Autoimmunity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Simon W. F. Milling, G. Gordon MacPherson
In common with the other cells of the innate immune system, DCs express molecules that enable them to detect structures not normally found in self-tissues. These “pattern recognition receptors” include Dectin-1,42 DC-SIGN,43-44 and molecules of the toll-like receptor (TLR) family. TLRs 1 to 10 form a group of ten microbe-recognition receptors that are central to effective innate immunity. These transmembrane signaling receptors bind a wide variety of ligands, including proteins (flagellin), modified lipids, lipopolysaccarides (LPS), and nucleic acids (DNA and double-stranded RNA).45 Human peripheral blood DCs can be differentiated based on the TLR molecules they express. For instance, plasmacytoid pre-DCs express high levels of TLR7 (natural ligand unknown) and TLR9 (binds CpG oligonucleotides) and low levels of TLR1 (natural ligand unknown), TLR6 (heterodimer with TLR2, and possibly others) and TLR10 (ligand unknown). On the other hand, CD11c+ immature DCs in blood express TLR1 (heterodimer with TLR2), TLR2 (binds peptidoglycan) and TLR3 (binds poly I:C), TLR4 (binds LPS), TLR5 (binds flagellin), TLR6 and TLR8 (ligand unknown) (see Table 1).46 CpG, the ligand for TLR9 caused plasmacytoid DCs, which express TLR9, to stimulate a Th1 response. On the other hand, CD11c+ DCs stimulated the development of a Th1 response after exposure to the TLR4 ligand, LPS.41 These data suggest that DC subsets are highly plastic in their responses to infection and that the type of the CD4+ T cell response depends not only on the type of DC which is initially activated, but also on the antigen dose, the state of maturation of the DC, and the ligation of pattern recognition receptors on the DC surface. Expression by DCs of overlapping groups of TLRs recognizing a wide variety of microbial structures provides important redundancy and helps ensure rapid innate recognition of diverse microbial threats.
The potential interplay between opioid and the toll-like receptor 4 (TLR-4)
Published in Immunopharmacology and Immunotoxicology, 2023
Nasrin Zare, Marjan Pourhadi, Golnaz Vaseghi, Shaghayegh Haghjooy Javanmard
Toll-like receptors (TLRs), a family of pattern recognition receptors, contain 12 members (TLR-1–TLR-9, TLR-11–TLR-13) in mouse and 10 members (TLR-1–TLR-10) in human. TLRs are located in the cell surface (TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, and TLR-10) or in the endoplasmic reticulum, endosome, and lysosome (TLR-3, TLR-7, TLR-8, and TLR-9). TLRs could discern pathogen-associated molecular patterns (PAMPs) and damage-associated molecules patterns (DAMPs) including lipid, lipoprotein, protein, and nucleic acid to trigger an innate immune response. They have an ectodomain of leucine-rich repeats for recognition of PAMPs and DAMPs and a cytosolic domain of Toll/interleukin-1 (IL-1) receptor (TIR) that conducts downstream pathways [11–13]. TLR-4 is present on antigen-presenting cells (APC) and also other types of cells such as endothelial cells, myocytes, thyroid cells, endometrial cells, mesangial cells, fibroblasts, central nervous system, etc. Upon binding of PAMPs and DAMPs to TLR s, they are dimerized and then recruit the two main downstream TIR domain-containing adaptor proteins, MyD88 and TRIF. TLRs trigger signaling pathways and activate NF-κB, IRFs, or MAP kinases and thus adjust the expression levels of cytokines, chemokines, and type I IFNs [14].
Toll-like receptor agonist combinations augment mouse T-cell anti-tumor immunity via IL-12- and interferon ß-mediated suppression of immune checkpoint receptor expression
Published in OncoImmunology, 2022
Donghwan Jeon, Douglas G. McNeel
TLR agonists have been used as vaccine adjuvants for several human vaccines. For example, Shingrix, a vaccine for herpes zoster approved by FDA in 2017, uses a TLR4 agonist.53 Recently developed mRNA-based vaccines for COVID-19 have used TLR agonism for robust immune responses.54 However, there has been little exploration of the mechanism of action of multiple TLR stimulation in humans. In fact, while human TLRs share common characteristics with murine TLRs, they have different tissue expression patterns and signal intensity,55,56 suggesting that dosing of TLR agonists for similar effects on T-cell activation might be different in humans. Furthermore, TLR10 is only expressed in humans, and hence could not be studied in our murine models.57 Future studies are needed to determine whether human TLR agonists, including TLR10, can similarly affect the expression of IL-12 and IFNß and suppress T-cell checkpoint expression on activated CD8+ T-cells. Nevertheless, our findings suggest that specific TLR agonists, notably TLR3 and TLR9 agonists, might be specifically evaluated with anti-tumor vaccines to determine if they modulate the effector and memory function, and expression of T-cell checkpoint receptors, of human CD8+ T-cells.
Statins as an adjunctive therapy for COVID-19: the biological and clinical plausibility
Published in Immunopharmacology and Immunotoxicology, 2021
Tarek Kashour, Rabih Halwani, Yaseen M. Arabi, M. Rizwan Sohail, John C. O’Horo, Andrew D. Badley, Imad M. Tleyjeh
The innate immunity serves as the first defense line against invading pathogens and nonpathogenic residues of damaged cells [33]. Among the most important regulators of the innate immunity is the TLR family that comprises 10 cell membrane and intracellular proteins (TLR1–TLR10) in humans. Antigen-presenting cells (APCs) like dendritic cells (DCs) recognize microorganism antigens through TLRs and mediate innate immune response by the activation of two main downstream pathways, the myeloid differentiation factor 88 (MyD88)-dependent pathway, and the TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathway. Both pathways lead to activation of the nuclear factor-kappa B (NF-κB) and induction of inflammatory cytokines and type-I interferon response, which are key contributors to antiviral response [34].