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Curating the innate immunity interactome
David J Lynn, Calvin Chan, Misbah Naseer, Melissa Yau, Raymond Lo, Anastasia Sribnaia, Giselle Ring, Jaimmie Que, Kathleen Wee, Geoffrey L Winsor, Matthew R Laird, Karin Breuer, Amir K Foroushani, Fiona SL Brinkman, Robert EW Hancock
BMC Systems Biology , 2010, DOI: 10.1186/1752-0509-4-117
Abstract: Here, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response.In summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity.The immune system is traditionally divided into two different branches - the adaptive immune system, the arm of the immune system that mounts a specific response to foreign antigens, and the innate immune system. The importance of the innate immune response is now well recognised as the first, and perhaps even the most critical, line of defence against invading pathogens and there has been an explosion of interest in investigating it. Innate immunity is fast-acting by comparison to the adaptive response, which can take several days to respond, and furthermore, innate immunity instructs, regulates and shapes the subsequent adaptive response [1,2].Despite the lack of
libtissue - implementing innate immunity  [PDF]
Jamie Twycross,Uwe Aickelin
Computer Science , 2010,
Abstract: In a previous paper the authors argued the case for incorporating ideas from innate immunity into articficial immune systems (AISs) and presented an outline for a conceptual framework for such systems. A number of key general properties observed in the biological innate and adaptive immune systems were hughlighted, and how such properties might be instantiated in artificial systems was discussed in detail. The next logical step is to take these ideas and build a software system with which AISs with these properties can be implemented and experimentally evaluated. This paper reports on the results of that step - the libtissue system.
Experimenting with Innate Immunity  [PDF]
Jamie Twycross,Uwe Aickelin
Computer Science , 2010,
Abstract: In a previous paper the authors argued the case for incorporating ideas from innate immunity into artificial immune systems (AISs) and presented an outline for a conceptual framework for such systems. A number of key general properties observed in the biological innate and adaptive immune systems were highlighted, and how such properties might be instantiated in artificial systems was discussed in detail. The next logical step is to take these ideas and build a software system with which AISs with these properties can be implemented and experimentally evaluated. This paper reports on the results of that step - the libtissue system.
The complexity of Drosophila innate immunity  [PDF]
A Reumer,T Van Loy,L Schoofs
Invertebrate Survival Journal , 2010,
Abstract: Metazoans rely on efficient mechanisms to oppose infections caused by pathogens. The immediate and first-line defense mechanism(s) in metazoans, referred to as the innate immune system, is initiated upon recognition of microbial intruders by germline encoded receptors and is executed by a set of rapid effector mechanisms. Adaptive immunity is restricted to vertebrate species and it is controlled and assisted by the innate immune system.Interestingly, most of the basic signaling cascades that regulate the primeval innate defense mechanism(s) have been well conserved during evolution, for instance between humans and the fruit fly, Drosophila melanogaster. Being devoid of adaptive signaling and effector systems, Drosophila has become an established model system for studying pristine innate immune cascades and reactions. In general, an immune response is evoked when microorganisms pass the fruit fly’s physical barriers (e.g., cuticle, epithelial lining of gut and trachea), and it is mainly executed in the hemolymph, the equivalent of the mammalian blood. Innate immunity in the fruit fly consists of a phenoloxidase (PO) response, a cellular response (hemocytes), an antiviral response, and the NF-κB dependent production of antimicrobial peptides referred to as the humoral response. The JAK/STAT and Jun kinase signaling cascades are also implicated in the defence against pathogens.
Evolution of innate immunity
Cathy Holding
Genome Biology , 2004, DOI: 10.1186/gb-spotlight-20040709-01
Abstract: The discovery, by Zeev Pancer and Max D. Cooper at the University of Alabama at Birmingham, shows that evolutionarily diverse vertebrates have a similar fundamental strategy of somatic rearrangement of germline receptor units to combat infectious disease.The fundamentals are similar across species, but in jawed vertebrates, diversity is generated by joining gene segments in the immunoglobulin and T-cell receptor gene loci, while in the sea lamprey Petromyzon marinus (a jawless vertebrate), the Alabama team found a completely different set of molecules that mediate adaptive immunity - with a completely different molecular structure and molecular architecture."After more than 40 years of evidence of adaptive immunity in agnathans [jawless fish], we found the molecules," Pancer told us. "It's no wonder that for so many years it was a big mystery," he added, "because everyone until now more or less linked adaptive immunity with rearranging immunoglobulin genes, as it is from sharks up to man."Experts are uncertain whether the findings illustrate convergent evolution. Pancer believes that at the lamprey level, this is not yet convergent evolution but merely a continuation of the usage of a very ancient motif - the leucine rich repeat - that is conserved in man, invertebrates, and plants.Max D. Cooper, coauthor of the paper, also believes in the common ancestor idea. "I think the strategy of using the kind of building blocks like toll and toll-like receptors and other innate immune receptors was used by many different organisms, but with a single gene," Cooper told us.Cooper fully anticipates that the mechanism will be present in hagfish as well, and the authors had 'hints' that it will still be present going forward into the jawed vertebrates, although he did not know how far. "I would imagine that since every living thing on the planet uses this kind of building block, these leucine rich repeat sequences, for defense, that having the ability to vary them within an indiv
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.
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.
Towards a Conceptual Framework for Innate Immunity  [PDF]
Jamie Twycross,Uwe Aickelin
Computer Science , 2010,
Abstract: Innate immunity now occupies a central role in immunology. However, artificial immune system models have largely been inspired by adaptive not innate immunity. This paper reviews the biological principles and properties of innate immunity and, adopting a conceptual framework, asks how these can be incorporated into artificial models. The aim is to outline a meta-framework for models of innate immunity.
Biliary Innate Immunity: Function and Modulation  [PDF]
Kenichi Harada,Yasuni Nakanuma
Mediators of Inflammation , 2010, DOI: 10.1155/2010/373878
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). 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. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor- (PPAR ), is involved in the pathogenesis of cholangitis. Immunosuppression using PPAR ligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Moreover, the epithelial-mesenchymal transition (EMT) of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA. 1. Introduction Clarification of the molecular mechanisms of innate immunity and significance of innate immune responses to the pathogenesis of immune-mediated diseases as well as to the defense against infections has progressed steadily since the cloning of Tolls in drosophila and Toll-like receptors (TLRs) in mammals including humans [1, 2]. 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. Liver and extrahepatic bile ducts consisting of hepatocytes and biliary epithelial cells (BECs) are also exposed to microorganisms and their components originating from the intestines via portal blood and duodenum. In the gastrointestinal tract, TLRs expressed in intestinal epithelial cells may be involved in innate immunity to maintain mucosal homeostasis and also the development of enterocolitis by producing inflammatory molecules [3]. Similar processes using TLRs may operate in the biliary tree. Human bile is sterile under normal conditions, but bacterial components such as lipopolysaccharide (LPS),
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
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