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Cholangiopathy with Respect to Biliary Innate Immunity  [PDF]
Kenichi Harada,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/793569
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems. 1. Introduction Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and hepatolithiasis in adults and biliary atresia and choledochal cyst in infants are biliary diseases in which different anatomical levels of the biliary tree are specifically affected and characterized by cholangiopathy. The biliary tree, consisting of cholangiocytes, is a system of connecting ducts that drain the bile secreted by hepatocytes into the duodenum. Cholangiocytes provide the first line of defense in the biliary system against luminal microbes originating from the intestines via portal blood and duodenum [1]. In general, although human bile is normally sterile, it can contain bacterial components such as lipopolysaccharide (LPS), lipoteichoic acid, and bacterial DNA fragments, known as pathogen-associated molecular patterns (PAMPs) [2–5], and cultivable bacteria are detectable in bile of patients with biliary diseases [1, 6–8]. Enteric bacteria, in particular, may be responsible for the chronic proliferative cholangitis associated with hepatolithiasis [1, 6]. These findings indicate that cholangiocytes are exposed to bacterial PAMPs under physiological as well as pathological conditions. Innate immunity was initially thought to be limited to immunocompetent cells such as dendritic cells and macrophages, but epithelial cells also possess TLRs and proper innate immune systems reflecting the specific micro-environment and function of each epithelial cell type. Recent studies concerning biliary innate immunity indicate that cholangiocytes express a variety of pathogen-recognition receptors such as Toll-like receptors (TLRs) [9, 10]. Infectious agents have been implicated in the
Cholangiopathy with Respect to Biliary Innate Immunity  [PDF]
Kenichi Harada,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/793569
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems.
Implication of Innate Immunity in the Pathogenesis of Biliary Atresia  [PDF]
Jiin-Haur Chuang,Ming-Huei Chou,Chia-Ling Wu,Yung-Ying Du
Chang Gung Medical Journal , 2006,
Abstract: Biliary atresia (BA) is a complex disorder for which the etiology is still far from clear.Newborn infants that develop BA may carry certain genetic defects, resulting in susceptibilityto uncertain pathogens with characteristic pathogen-associated molecular patterns(PAMPs). The pathogens with their characteristic PAMPs in turn lead to activation of theinnate immune system by triggering pattern recognition receptors on the immune cells. Tolllikereceptors (TLRs) are the most recognized pattern recognition receptors and TLR signalingis the telltale sign of activation of innate immunity. The activation of TLR and the innateimmune system in BA is demonstrated by the up-regulation of TLR7 and by the associationof promoter polymorphism of CD14 with BA. The antimicrobial peptide hepcidin and MxA,a protein downstream of TLR7 signaling, which is also known as a highly specific markerfor type I IFN signaling, are also found highly expressed in the early stage of BA. Thisreview examines the known components of innate immunity involved in BA and outlinesthe potential role of the innate immune system, in cooperation with adaptive immunity, inthe pathogenesis of BA.
Innate immunity against HIV: a priority target for HIV prevention research
Persephone Borrow, Robin J Shattock, Annapurna Vyakarnam, EUROPRISE Working Group
Retrovirology , 2010, DOI: 10.1186/1742-4690-7-84
Abstract: Increasing evidence suggests that innate responses are key determinants of the outcome of HIV infection, influencing critical events in the earliest stages of infection including the efficiency of mucosal HIV transmission, establishment of initial foci of infection and local virus replication/spread as well as virus dissemination, the ensuing acute burst of viral replication, and the persisting viral load established. They also impact on the subsequent level of ongoing viral replication and rate of disease progression. Modulation of innate immunity thus has the potential to constitute a powerful effector strategy to complement traditional approaches to HIV prophylaxis and therapy. Importantly, there is increasing evidence to suggest that many arms of the innate response play both protective and pathogenic roles in HIV infection. Consequently, understanding the contributions made by components of the host innate response to HIV acquisition/spread versus control is a critical pre-requisite for the employment of innate immunity in vaccine or microbicide design, so that appropriate responses can be targeted for up- or down-modulation. There is also an important need to understand the mechanisms via which innate responses are triggered and mediate their activity, and to define the structure-function relationships of individual innate factors, so that they can be selectively exploited or inhibited. Finally, strategies for achieving modulation of innate functions need to be developed and subjected to rigorous testing to ensure that they achieve the desired level of protection without stimulation of immunopathological effects. Priority areas are identified where there are opportunities to accelerate the translation of recent gains in understanding of innate immunity into the design of improved or novel vaccine and microbicide strategies against HIV infection.Rational approaches to HIV vaccine design have so far focused principally on the induction of virus-specific antibody
The Emerging Role of TLR and Innate Immunity in Cardiovascular Disease  [PDF]
Rolf Spirig,Janice Tsui,Sidney Shaw
Cardiology Research and Practice , 2012, DOI: 10.1155/2012/181394
Abstract: Cardiovascular disease is a complex disorder involving multiple pathophysiological processes, several of which involve activation of toll-like receptors (TLRs) of the innate immune system. As sentinels of innate immunity TLRs are nonclonally germline-encoded molecular pattern recognition receptors that recognize exogenous as well as tissue-derived molecular dangers signals promoting inflammation. In addition to their expression in immune cells, TLRs are found in other tissues and cell types including cardiomyocytes, endothelial and vascular smooth muscle cells. TLRs are differentially regulated in various cell types by several cardiovascular risk factors such as hypercholesterolemia, hyperlipidemia, and hyperglycemia and may represent a key mechanism linking chronic inflammation, cardiovascular disease progression, and activation of the immune system. Modulation of TLR signaling by specific TLR agonists or antagonists, alone or in combination, may be a useful therapeutic approach to treat various cardiovascular inflammatory conditions such as atherosclerosis, peripheral arterial disease, secondary microvascular complications of diabetes, autoimmune disease, and ischemia reperfusion injury. In this paper we discuss recent developments and current evidence for the role of TLR in cardiovascular disease as well as the therapeutic potential of various compounds on inhibition of TLR-mediated inflammatory responses. 1. Introduction: Innate Immunity and Toll-Like Receptors (TLRs) Historically the immune system has been divided into the innate and the adaptive immune system. Neutrophils, eosinophils, basophils, mast cells, monocytes, macrophages, dendritic cells (DCs), NK cells, NK-T cells, γδ T cells, and B-1 cells are considered to be cellular members of the innate immune system which can be activated by signaling through TLR. In addition, endothelial cells may form part of this system since they also possess antigen-presenting capabilities and therefore immune regulation properties apart from their function as a barrier between tissue and blood [1]. A year after the discovery of the role of drosophila Toll protein in the host defense against fungal infection [2], a mammalian homologue was identified, referred to as TLR4 [3]. Since then, 13 members of the TLR family have been identified in mammals, ten in humans, and twelve in mice. Mice do not express TLR10 but do express TLR11, TLR12, and TLR13 [4]. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11 are displayed on the cell surface while TLR3, TLR7, TLR8, and TLR9 are localized intracellularly. TLRs are distributed
Expression and Putative Function of Innate Immunity Genes under in situ Conditions in the Symbiotic Hydrothermal Vent Tubeworm Ridgeia piscesae  [PDF]
Spencer V. Nyholm, Pengfei Song, Jeanne Dang, Corey Bunce, Peter R. Girguis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038267
Abstract: The relationships between hydrothermal vent tubeworms and sulfide-oxidizing bacteria have served as model associations for understanding chemoautotrophy and endosymbiosis. Numerous studies have focused on the physiological and biochemical adaptations that enable these symbioses to sustain some of the highest recorded carbon fixation rates ever measured. However, far fewer studies have explored the molecular mechanisms underlying the regulation of host and symbiont interactions, specifically those mediated by the innate immune system of the host. To that end, we conducted a series of studies where we maintained the tubeworm, Ridgeia piscesae, in high-pressure aquaria and examined global and quantitative changes in gene expression via high-throughput transcriptomics and quantitative real-time PCR (qPCR). We analyzed over 32,000 full-length expressed sequence tags as well as 26 Mb of transcript sequences from the trophosome (the organ that houses the endosymbiotic bacteria) and the plume (the gas exchange organ in contact with the free-living microbial community). R. piscesae maintained under conditions that promote chemoautotrophy expressed a number of putative cell signaling and innate immunity genes, including pattern recognition receptors (PRRs), often associated with recognizing microbe-associated molecular patterns (MAMPs). Eighteen genes involved with innate immunity, cell signaling, cell stress and metabolite exchange were further analyzed using qPCR. PRRs, including five peptidoglycan recognition proteins and a Toll-like receptor, were expressed significantly higher in the trophosome compared to the plume. Although PRRs are often associated with mediating host responses to infection by pathogens, the differences in expression between the plume and trophosome also implicate similar mechanisms of microbial recognition in interactions between the host and symbiont. We posit that regulation of this association involves a molecular “dialogue” between the partners that includes interactions between the host’s innate immune system and the symbiont.
Modulation of Innate Antigen-Presenting Cell Function by Pre-patent Schistosome Infection  [PDF]
Christine E. Ferragine,Colleen D. Walls,Stephen J. Davies
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002136
Abstract: Schistosomes are intravascular helminths that infect over 200 million people worldwide. Deposition of eggs by adult schistosomes stimulates Th2 responses to egg antigens and induces granulomatous pathology that is a hallmark of schistosome infection. Paradoxically, schistosomes require host immune function for their development and reproduction and for egress of parasite eggs from the host. To identify potential mechanisms by which immune cells might influence parasite development prior to the onset of egg production, we assessed immune function in mice infected with developing schistosomes. We found that pre-patent schistosome infection is associated with a loss of T cell responsiveness to other antigens and is due to a diminution in the ability of innate antigen-presenting cells to stimulate T cells. Diminution of stimulatory capacity by schistosome worms specifically affected CD11b+ cells and did not require concomitant adaptive responses. We could not find evidence for production of a diffusible inhibitor of T cells by innate cells from infected mice. Rather, inhibition of T cell responsiveness by accessory cells required cell contact and only occurred when cells from infected mice outnumbered competent APCs by more than 3:1. Finally, we show that loss of T cell stimulatory capacity may in part be due to suppression of IL-12 expression during pre-patent schistosome infection. Modulation of CD4+ T cell and APC function may be an aspect of host immune exploitation by schistosomes, as both cell types influence parasite development during pre-patent schistosome infection.
HTLV-1 and Innate Immunity  [PDF]
Chloé Journo,Renaud Mahieux
Viruses , 2011, DOI: 10.3390/v3081374
Abstract: Innate immunity plays a critical role in the host response to a viral infection. The innate response has two main functions. First, it triggers effector mechanisms that restrict the infection. Second, it primes development of the adaptive response, which completes the elimination of the pathogen or of infected cells. In vivo, HTLV-1 infects T lymphocytes that participate in adaptive immunity but also monocytes and dendritic cells that are major players in innate immunity. Herein, we will review the interplay between HTLV-1 and innate immunity. Particular emphasis is put on HTLV-1-induced alteration of type-I interferon (IFN-I) function. In vitro, the viral Tax protein plays a significant role in the alteration of IFN synthesis and signaling. Despite this, IFN-I/AZT treatment of Adult T?cell Leukemia/Lymphoma (ATLL) patients leads to complete remission. We will discuss a model in which exogenous IFN-I could act both on the microenvironment of the T-cells to protect them from infection, and also on infected cells when combined with other drugs that lead to Tax down-regulation/degradation.
Human Herpesviruses-encoded dUTPases: A Family of Proteins that Modulate Dendritic Cell Function and Innate Immunity  [PDF]
Maria Eugenia Ariza,Marshall V. Williams
Frontiers in Microbiology , 2014, DOI: 10.3389/fmicb.2014.00504
Abstract: We have previously shown that Epstein-Barr virus (EBV)-encoded dUTPase can modulate innate immune responses through the activation of TLR2 and NF-kappaB signaling. However, whether this novel immune function of the dUTPase is specific for EBV or a common property of the Herpesviridae family is not known. In this study, we demonstrate that the purified viral dUTPases encoded by herpes simplex virus type 2 (HSV-2), human herpesvirus 6A (HHV-6A), human herpesvirus 8 (HHV-8) and varicella-zoster virus (VZV) differentially activated NF-kappaB through ligation of TLR2/TLR1 heterodimers. Furthermore, activation of NF-kappaB by the viral dUTPases was inhibited by anti-TLR2 blocking antibodies (Abs) and the over-expression of dominant negative constructs of TLR2, lacking the TIR domain, and MyD88 in human embryonic kidney 293 cells expressing TLR2/TLR1. In addition, treatment of human dendritic cells and PBMCs with the herpesviruses-encoded dUTPases from HSV-2, HHV-6A, HHV-8 and VZV resulted in the secretion of the inflammatory cytokines IL-1 beta, IL-6, IL-8, IL-12, TNF-alpha, IL-10 and IFN-gamma. Interestingly, blocking experiments revealed that the anti-TLR2 Ab significantly reduced the secretion of cytokines by the various herpesviruses-encoded dUTPases (p<0.05). To our knowledge, this is the first report demonstrating that a nonstructural protein encoded by herpesviruses HHV-6A, HHV-8, VZV and to a lesser extent HSV-2 is a pathogen-associated molecular pattern. Our results reveal a novel function of the virus-encoded dUTPases, which may be important to the pathophysiology of diseases caused by these viruses. More importantly, this study demonstrates that the immunomodulatory functions of dUTPases are a common property of the Herpesviridae family and thus, the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by these herpesviruses.
Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis  [PDF]
Sarah T.A. Roord, Evelien Zonneveld-Huijssoon, Tho Le, Gisella Puga Yung, Eva Koffeman, Arash Ronaghy, Negar Ghahramani, Paola Lanza, Rosario Billetta, Berent J. Prakken, Salvatore Albani
PLOS ONE , 2006, DOI: 10.1371/journal.pone.0000087
Abstract: Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation.
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