Back to Multiple Sclerosis (MS)
Enhanced by
Neuroinformation
Toll-like Receptors Reviews: 2003
(53 References)
Akira, S. and H. Hemmi (2003). "Recognition of pathogen-associated molecular patterns by TLR family." Immunol Lett 85(2): 85-95.
Toll-like receptors (TLRs) are type I transmembrane proteins involved in innate immunity by recognizing microbial conserved structures. Recent studies have shown that TLR3 recognizes dsRNA, a viral product, whereas TLR9 recognizes unmethylated CpG motifs frequently found in the genome of bacteria and viruses, but not vertebrates. TLR7 recognizes small synthetic immune modifiers including imiquimod, R-848, loxoribine, and bropirimine, all of which are already applied or promising for clinical use against viral infections and cancers. Plasmacytoid dendritic cells express TLR7 and TLR9, and respond to TLR7 and TLR9 ligands by producing a large amount of interferon (IFN-alpha). These results indicate that TLR3, TLR7 and TLR9 may play an important role in detecting and combating viral infections.
Akira, S. (2003). "Mammalian Toll-like receptors." Curr Opin Immunol 15(1): 5-11.
Berche, P. (2003). "[Bacterial aggression]." Ann Pharm Fr 61(4): 270-5.
In all living species, the first line of defence against microbial aggressions is constituted by innate immunity. During Evolution, it appears in invertebrates and plants, long before adaptive immunity, which appears in vertebrate. Adaptive immunity induces acquired resistance against microorganisms through random somatic rearrangements of genes encoding immunoglobulins and T cell receptors, thus generating a high level of diversity of receptors (>10(9)) in response to microbial aggressions. Acquired resistance is not vertically transmitted and reflects the "infectious history" of every individual. In contrast, innate immunity relies on recognition of antigens by a small number of weakly specific receptors (>10(2)) designated Pattern-Recognition Receptors (PRR) and is vertically transmitted by germinal cells. The PRR are expressed on macrophages dendritic cells and B lymphocytes and recognize antigenic structures highly conserved in the living world, termed Pathogen-Associated Molecular Patterns (PAMP), as lipopolysaccharides peptidoglycanes and lipoteichoic acids. PRR are secreted (complement, lectins), or expressed at the cell surface of cells to induce endocytosis or signaling (Toll-like receptors or TLRs). The recognition of antigens induces an immediate inflammatory response and triggers adaptive immunity. Among secreted PRR, the system of complement plays a major role in the immediate inflammatory response, controlling infections by its major role in opsonization, chemotactism and activation of leucocytes. TLRs induce the inflammatory response against microorganisms through NF-kB, a cytoplasmic factor controlling transcription of many genes, including cytokines (TNF, INF, IL-1, IL-2, IL-8, IL-12.) and defensines. So, within few minutes following microbial aggression, the inflammatory response is rapidly triggered to destroy infectious agents and to generate a long-term memory against pathogens.
Beutler, B. (2003). "Science review: key inflammatory and stress pathways in critical illness - the central role of the Toll-like receptors." Crit Care 7(1): 39-46.
A pure reductionist approach can sometimes be used to solve an exceptionally complicated biologic problem, and sepsis is nothing if not complicated. A serious infection promptly leads to changes in many aspects of host physiology, including alterations in circulation, metabolism, renal, hepatic, and neuroendocrine function; all of these changes happen at once, and each influences one another. It is difficult to tease apart a problem of this sort, if only because the systems affected are so profoundly interactive. The key to understanding sepsis, insofar as we do understand it at present, was found in the use of genetic tools to study the very earliest events that take place at the interface of the pathogen and the host. The continued application of both forward and reverse genetic methods, in both mammals and insects, is steadily revealing the central biochemical events that occur during infection.
Beutler, B. and E. T. Rietschel (2003). "Innate immune sensing and its roots: the story of endotoxin." Nat Rev Immunol 3(2): 169-76.
How does the host sense pathogens? Our present concepts grew directly from longstanding efforts to understand infectious disease: how microbes harm the host, what molecules are sensed and, ultimately, the nature of the receptors that the host uses. The discovery of the host sensors--the Toll-like receptors--was rooted in chemical, biological and genetic analyses that centred on a bacterial poison, termed endotoxin.
Beutler, B. (2003). "Innate immune responses to microbial poisons: discovery and function of the Toll-like receptors." Annu Rev Pharmacol Toxicol 43: 609-28.
There are many circumstances under which a toxin exploits an endogenous receptor or another protein of host origin to work its untoward effects. In most instances, the receptor normally fulfills a function that has nothing to do with the toxin per se; that is, the toxin is not the "natural" ligand. The situation with endotoxin, however, is a remarkable one. The endotoxin receptor evolved to detect endotoxin. Why have mammals maintained a gene that can undermine their survival? The search for the endotoxin receptor answered this question and also revealed the essential function and biological strategy of the Toll-like receptors: principal sensors of the innate immune system.
Buentke, E. and A. Scheynius (2003). "Dendritic cells and fungi." Apmis 111(7-8): 789-96.
Fungi comprise a group of microorganisms that in the past 20 years has become increasingly important as a cause of human disease. Few fungi are professional but instead opportunistic pathogens, and some fungi can even act as allergens. Dendritic antigen-presenting cells function as a link between innate and adaptive immunity and are therefore important in recognition of pathogens. Effective defense requires the host to discriminate between different pathogens to induce an appropriate response. Signaling from different groups of microbes can be mediated via the Toll-like receptors (TLRs), leading to activation of conserved host defense signaling pathways that control the expression of a variety of immune response genes. Different dendritic cells (DCs) express different patterns of recognition molecules, which indicate that they are more or less efficient when responding to certain pathogens. DCs have an important role in the induction of cell-mediated immune responses to fungi, and the studies reviewed here show that fungi, or possibly fungi-derived factors, provide a powerful activation stimulus to DCs, resulting in DC maturation with upregulation of co-stimulatory molecules and production of cytokine patterns leading to different T cell responses. The possibility of using ex vivo-generated DCs as therapeutic tools for restoring anti-fungal immunity is a challenge for the future.
Dabbagh, K. and D. B. Lewis (2003). "Toll-like receptors and T-helper-1/T-helper-2 responses." Curr Opin Infect Dis 16(3): 199-204.
PURPOSE OF REVIEW: Toll-like receptors (TLRs) are a family of pattern recognition receptors that are activated by specific components of microbes and certain host molecules. They constitute the first line of defense against many pathogens and play a crucial role in the function of the innate immune system. Recently, TLRs were observed to influence the development of adaptive immune responses, presumably by activating antigen-presenting cells. This has important implications for our understanding of how the host tailors its immune response as a function of specific pathogen recognition. The present review discusses the recent studies that demonstrate the role of TLRs in the regulation of adaptive T-helper-1 (Th1) and Th2 responses, and the mechanisms by which the effects are carried out. RECENT FINDINGS: Most studies have focused on the role of TLRs and components of their signaling pathways in the control of Th1-type immune responses, and on the implications for their use as antimicrobial agents, such as adjuvants in vaccines, or to treat or prevent the Th2-type dominated immune responses seen in allergies. TLR-deficient mice have been described and used to come to these conclusions. Although controversial, there is also evidence that TLRs may be important for Th2-type responses, possibly by augmenting the overall maturity of dendritic cells. SUMMARY: A greater understanding of the processes by which TLRs regulate adaptive immunity may yield not only improved ways to treat infectious diseases but also new approaches to the treatment and prevention of allergic and certain autoimmune disorders.
Dantzer, R. and E. E. Wollman (2003). "[Relationships between the brain and the immune system]." J Soc Biol 197(2): 81-8.
The concept that the brain can modulate activity the immune system stems from the theory of stress. Recent advances in the study of the inter-relationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. Lymphoid organs are innervated by branches of the autonomic nervous system. Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions, including cell proliferation, chimiotactism and specific immune responses. Brain lesions and stressors can induce a number of changes in the functioning of the immune system. All these changes are not necessarily mediated by the neuroendocrine system. They can also be dependent on autonomic nerve function. The communication pathways that link the brain to the immune system are normally activated by signals from the immune system, and they serve to regulate immune responses. These signals originate from accessory immune cells such as monocytes and macrophages and they are represented mainly by proinflammatory cytokines. Proinflammatory cytokines produced at the periphery act on the brain via two major pathways: (1) a humoral pathway allowing pathogen specific molecular patterns to act on Toll-like receptors in those brain areas that are devoid of a functional blood-brain barrier, the so-called circumventricular areas; (2) a neural pathway, represented by the afferent nerves that innervate the bodily site of infection and injury. In both cases, peripherally produced cytokines induce the expression of brain cytokines that are produced by resident macrophages and microglial cells. These locally produced cytokines diffuse throughout the brain parenchyma to act on target brain areas so as to organise the central components of the host response to infection (fever, neuroendocrine activation, and sickness behavior).
Dunne, A. and L. A. O'Neill (2003). "The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense." Sci STKE 2003(171): re3.
The signal transduction pathways activated by the proinflammatory cytokine interleukin-1 (IL-1) have been the focus of much attention because of the important role that IL-1 plays in inflammatory diseases. A number of proteins have been described that participate in the post-receptor activation of the transcription factor nuclear factor kappaB (NF-kappaB), and stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK). It has also emerged that the type I IL-1 receptor (IL-1RI) is a member of an expanding receptor superfamily. These related receptors all have sequence similarity in their cytosolic regions. The family includes the Drosophila melanogaster protein Toll, the IL-18 receptor (IL-18R), and 10 Toll-like receptors (TLRs), TLR-1 to TLR-10, which bind to microbial products, activating host defense responses. Because of the similarity of IL-1RI to Toll, the conserved sequence in the cytosolic region of these proteins has been termed the Toll-IL-1 receptor (TIR) domain. The same proteins activated during signaling by IL-1RI also participate in signaling by other receptors with TIR domains. The receptor superfamily is evolutionarily conserved; members also occur in plants and insects, where they also function in host defense. The signaling proteins that are activated are also conserved across species. Differences are, however, starting to emerge in signaling pathways activated by different receptors. This receptor superfamily, therefore, represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses.
Elward, K. and P. Gasque (2003). ""Eat me" and "don't eat me" signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system." Mol Immunol 40(2-4): 85-94.
A full innate immune system (e.g. complement system, scavenger receptors, Toll-like receptors (TLR)) has been described in the CNS and is thought to be an extremely efficient army designed to fight against invading pathogens and toxic cell debris such as apoptotic cells and amyloid fibrils. The binding of soluble or secreted innate immune molecules on pathogen-associated molecular patterns (PAMPs) as well as apoptotic cell-associated molecular patterns (ACAMPs) provide several "eat me" signals to promote the safe disposal of the intruders by professional and amateur phagocytes. These patterns are deciphered by receptors (pattern recognition receptors, PRRs; e.g. CR3) that control phagocytosis and associated inflammatory response depending on the meaning of these signals. Importantly, in order to avoid excessive collateral damage of surrounding cells, it is increasingly evident that "don't eat me" signals (coined herein as self-associated molecular patterns, SAMPs; e.g. complement regulatory proteins, CD200) are of paramount importance to signal a robust anti-inflammatory response and promote tissue repair. Further knowledge of the innate immune response in the CNS will greatly help to delineate the novel therapeutic routes to protect from CNS inflammation and neurodegeneration.
Emonts, M., J. A. Hazelzet, et al. (2003). "Host genetic determinants of Neisseria meningitidis infections." Lancet Infect Dis 3(9): 565-77.
The clinical presentation of infections caused by Neisseria meningitidis is highly diverse. Some patients develop meningitis, and others present with sepsis or even septic shock. After invasion of the bloodstream by the bacteria, three main cascade pathways are activated. These are the complement system, the inflammatory response, and the coagulation and fibrinolysis pathway. These pathways do not act independently but are able to interact with each other. Genetic polymorphisms among components of these pathways have been shown to be involved in the susceptibility, severity, and outcome of meningococcal disease. We review knowledge of genetic variations associated with susceptibility to and severity of meningococcal infection. Complement deficiencies and defects in sensing or opsonophagocytic pathways, such as the rare Toll-like receptor 4 single nucleotide polymorphisms (SNPs) and combinations of inefficient variants of Fcgamma-receptors, seem to have the most important role in genetically established susceptibility. Effect on severity has repeatedly been reported for FcgammaRIIa and plasminogen activator inhibitor type 1 (PAI1) polymorphisms. Outcome effects have been confirmed for SNPs in properdin deficiencies, PAI1 and combination of the -511C/T SNP in interleukin 1beta, and the +2018C/T SNP in interleukin RN. Conflicting results are reported for the effect of the -308G/A promoter polymorphism in tumour necrosis factor (TNF) alpha. These differences may reflect discrepancies in group definitions between studies or the influence of additional SNPs in the TNFalpha promoter, which can form haplotypes representing different cytokine production capacity. For several SNPs, the potential effect on susceptibility, severity, or outcome has not yet been confirmed in an independent study.
Evans, J. T., C. W. Cluff, et al. (2003). "Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529." Expert Rev Vaccines 2(2): 219-29.
MPL (Corixa) adjuvant is a chemically modified derivative of lipopolysaccharide that displays greatly reduced toxicity while maintaining most of the immunostimulatory activity of lipopolysaccharide. MPL adjuvant has been used extensively in clinical trials as a component in prophylactic and therapeutic vaccines targeting infectious disease, cancer and allergies. With over 33,000 doses administered to date, MPL adjuvant has emerged as a safe and effective vaccine adjuvant. Recently, scientists at Corixa Corporation have developed a library of synthetic lipid A mimetics (aminoalkyl glucosaminide 4-phosphates) with demonstrated immunostimulatory properties. Similar to MPL adjuvant, these synthetic compounds signal through Toll-like receptor 4 to stimulate the innate immune system. One of these compounds, Ribi.529 (RC-529), has emerged as a leading adjuvant with a similar efficacy and safety profile to MPL adjuvant in both preclinical and clinical studies.
Fondevila, C., R. W. Busuttil, et al. (2003). "Hepatic ischemia/reperfusion injury--a fresh look." Exp Mol Pathol 74(2): 86-93.
Ischemia/reperfusion (I/R) injury is a multifactorial process that affects graft function after liver transplantation. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and ultimate organ failure. Increased experimental evidence has suggested that Kupffer cells and T cells mediate the activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase system is among the most critical of the cytoprotective mechanisms activated during cellular stress, exerting antioxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. Finally, the activation of toll-like receptors on Kupffer cells may play a fundamental role in exploring new therapeutic strategies based on the concept that hepatic I/R injury represents a case for a host "innate" immunity.
Fukao, T. and S. Koyasu (2003). "PI3K and negative regulation of TLR signaling." Trends Immunol 24(7): 358-63.
Excessive immune responses are detrimental to the host and negative feedback regulation is crucial for the maintenance of immune-system integrity. Recent studies have shown that phosphoinositide 3-kinase (PI3K) is an endogenous suppressor of interleukin-12 (IL-12) production triggered by Toll-like receptor (TLR) signaling and limits excessive Th1 polarization. Unlike IRAK-M (IL-1 receptor-associated kinase-M) and SOCS-1 (suppressor of cytokine signaling-1) that are induced by TLR signaling and function during the second or continuous exposure to stimulation, PI3K functions at the early phase of TLR signaling and modulates the magnitude of the primary activation. Thus, PI3K, IRAK-M and SOCS-1 have unique roles in the gate-keeping system, preventing excessive innate immune responses.
Geijtenbeek, T. B. and Y. van Kooyk (2003). "Pathogens target DC-SIGN to influence their fate DC-SIGN functions as a pathogen receptor with broad specificity." Apmis 111(7-8): 698-714.
Dendritic cells (DC) are vital in the defense against pathogens. To sense pathogens DC express pathogen recognition receptors such as toll-like receptors (TLR) and C-type lectins that recognize different fragments of pathogens, and subsequently activate or present pathogen fragments to T cells. It is now becoming evident that some pathogens subvert DC functions to escape immune surveillance. HIV-1 targets the DC-specific C-type lectin DC-SIGN to hijack DC for viral dissemination. HIV-1 binding to DC-SIGN protects HIV-1 from antigen processing and facilitates its transport to lymphoid tissues, where DC-SIGN promotes HIV-1 infection of T cells. Recent studies demonstrate that DC-SIGN is a more universal pathogen receptor that also recognizes Ebola, cytomegalovirus and mycobacteria. Mycobacterium tuberculosis targets DC-SIGN by a mechanism that is distinct from that of HIV-1, leading to inhibition of the immunostimulatory function of DC and pathogen survival. Thus, a better understanding of DC-SIGN-pathogen interactions and their effects on DC function is necessary to combat infections.
Gewirtz, A. T. (2003). "Intestinal epithelial toll-like receptors: to protect. And serve?" Curr Pharm Des 9(1): 1-5.
The innate immune system uses a series of pattern recognition receptors to detect the presence of pathogens thus allowing for rapid host defense responses to invading microbes. A key component of such receptors are the "toll-like receptors" (TLRs), which recognize a panel of microbial molecules that tend to be somewhat invariant, at least in select regions, thus permitting a relatively small number of receptors to recognize a large number of different microbes. Accordingly, this panel of TLRs bears little ability to distinguish between commensal and pathogenic microbes as such organisms generally bear far more structural similarities than differences between them. For the professional phagocytic cells classically considered to be the primary mediators of innate immunity such distinction between commensal and pathogenic microbes is not particularly important since any microbe that breaches the outer host defensive barriers to reach these phagocytes, whether doing so by a pathogen-specific or opportunistic mechanism, is likely potentially hazardous to its host. However, epithelial cells that line mucosal surfaces, thus being on the front line of host defense, also play an active role in innate immunity particularly by secreting chemokines and other immune mediators in response to pathogenic microbes. Epithelial cells have been reported to express several TLRs suggesting these receptors play a role in intestinal epithelial innate immune signaling pathways. However, since some mucosal surfaces such as the intestinal epithelium are normally densely colonized by a wide variety of microbes, the ability to distinguish the occasional pathogen from the sea of commensals presents an important challenge. This minireview considers the current findings regarding TLR expression in the intestinal epithelium and the role these receptors might serve in host defense.
Heine, H. and E. Lien (2003). "Toll-like receptors and their function in innate and adaptive immunity." Int Arch Allergy Immunol 130(3): 180-92.
Over the past 3 years our knowledge about how we sense the microbial world has been fundamentally changed. It has been known for decades that microbial products, such as lipopolysaccharide, lipoproteins, or peptidoglycan, have a profound activity on human cells. Whereas the structure of many different pathogenic microbial compounds has been extensively studied and characterized, the molecular basis of their recognition by the cells of the innate immune system remained elusive for a long time. It was Charles Janeway [Cold Spring Harb Symp Quant Biol 1989;54/1:1-13] who developed the idea of microbial structures forming pathogen-associated molecular patterns that would be recognized by pattern recognition receptors. The discovery of the family of Toll receptors in species as diverse as DROSOPHILA and humans, and the recognition of their role in distinguishing molecular patterns that are common to microorganisms have led to a renewed appreciation of the innate immune system. Moreover, it is now clear that the activation of the innate immune system through mammalian Toll-like receptors has also an instructive role for the responses of the adaptive immune response and, thus, may influence allergic diseases such as asthma.
Hertz, C. J. and R. L. Modlin (2003). "Role of toll-like receptors in response to bacterial infection." Contrib Microbiol 10: 149-63.
Holmgren, J., A. M. Harandi, et al. (2003). "Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA." Expert Rev Vaccines 2(2): 205-17.
The mucosal immune system consists of an integrated network of lymphoid cells that work in concert with innate host factors to promote host defence. Mucosal immunization can be used both to protect the mucosal surfaces against colonization and invasion by microbial pathogens and to provide a means for immunological treatment of selected autoimmune, allergic or infectious-immunopathological disorders through the induction of antigen-specific tolerance. The development of mucosal vaccines, whether for prevention of infectious diseases or for oral tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems. Significant progress has recently been made to generate partly or wholly detoxified derivatives of cholera toxin (including the completely nontoxic cholera toxin B subunit) and the closely related Escherichia coli heat-labile enterotoxin, with retained adjuvant activity. Cholera toxin B subunit is a protective component of a widely registered oral vaccine against cholera, and has proven to be a promising vector for either giving rise to anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. Promising advances have also recently been made in the design of efficient mucosal adjuvants based on bacterial DNA that contains CpG-motifs and various imidazoquinoline compounds binding to different Toll-like receptors on mucosal antigen-presenting cells.
Janssens, S. and R. Beyaert (2003). "Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members." Mol Cell 11(2): 293-302.
Interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for the proinflammatory cytokine interleukin-1 (IL-1) and was later implicated in signal transduction of other members of the Toll-like receptor (TLR)/IL-1 receptor (IL-1R) family. In the meantime, four different IRAK-like molecules have been identified: two active kinases, IRAK-1 and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. All IRAKs mediate activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways. Although earlier observations suggested that IRAKs have redundant functions, this hypothesis is now challenged by knockout studies. Furthermore, recent data imply a role for IRAK-1 in tumor necrosis factor receptor (TNFR) superfamily-induced signaling pathways as well. The scope of this review is to highlight the specific role of different IRAKs and to discuss several mechanisms that contribute to their activation and regulation.
Jiang, W. and D. S. Pisetsky (2003). "Enhancing immunogenicity by CpG DNA." Curr Opin Mol Ther 5(2): 180-5.
Bacterial DNA and oligonucleotides containing unmethylated CpG dinucleotides (CpG DNA) can stimulate immune responses and have potential for use as novel agents to enhance immunogenicity. CpG DNA can interact with toll-like receptor 9 and cause activation through a myeloid differentiation primary response gene (MyD88)-dependent signaling pathway. Due to its pattern of immune cell activation, CpG DNA can induce a cytokine milieu to promote T-helper cell responses and serve as an adjuvant. Furthermore, CpG DNA can provide protection against pathogens in animal models and has therapeutic applications in clinical settings such as in cancer and allergy.
Kaisho, T. and S. Akira (2003). "Regulation of dendritic cell function through Toll-like receptors." Curr Mol Med 3(4): 373-85.
Higher animals establish host defense by orchestrating innate and adaptive immunity. This is mediated by professional antigen presenting cells, i.e. dendritic cells (DCs). DCs can incorporate pathogens, produce a variety of cytokines, maturate, and present pathogen-derived peptides to T cells, thereby inducing T cell activation and differentiation. These responses are triggered by microbial recognition through type I transmembrane proteins, Toll-like receptors (TLRs) on DCs. TLRs consist of ten members and each TLR is involved in recognizing a variety of microorganism-derived molecular structures. TLR ligands include cell wall components, proteins, nucleic acids, and synthetic chemical compounds, all of which can activate DCs as immune adjuvants. Each TLR can activate DCs in a similar, but distinct manner. For example, TLRs can be divided into subgroups according to their type I interferon (IFN) inducing ability. TLR2 cannot induce IFN-alpha or IFN-beta, but TLR4 can lead to IFN-beta production. Meanwhile, TLR3, TLR7, and TLR9 can induce both IFN-alpha and IFN-beta. Recent evidences suggest that cytoplamic adapters for TLRs are especially crucial for this functional heterogeneity. Clarifying how DC function is regulated by TLRs should provide us with critical information for manipulating the host defense against a variety of diseases.
Kauffman, H. F. and S. van der Heide (2003). "Exposure, sensitization, and mechanisms of fungus-induced asthma." Curr Allergy Asthma Rep 3(5): 430-7.
Healthy individuals are continuously exposed to fungal biomass, which includes live and dead spores and fungal debris that is entrapped in the airways. In patients with asthma and/or atopy, exposure to fungal biomass might result in age-dependent sensitization and asthmatic reactions. Interaction with Toll-like receptors (TLRs) of the innate immune defense (alveolar macrophages and epithelial cells) and protease-activated receptors (PARs) determine the effectiveness of elimination of fungal material. The association of sensitization to Alternaria with severe asthma is discussed in relation to the age-dependent sensitization, rate of release of allergens from spores, and activity of its proteases. A model is described concerning the influence of polymorphic genes for airway hyperresponsiveness (AHR) and atopy, showing a cumulating influence on susceptibility for allergen-induced asthma, and explaining that fungus-induced airway obstruction is mainly associated with more severe asthma.
Kauffman, H. F. (2003). "Interaction of environmental allergens with airway epithelium as a key component of asthma." Curr Allergy Asthma Rep 3(2): 101-8.
Epithelial cells in the airway wall actively interact with environmental antigens/allergens, both in healthy individuals and patients with asthma. In patients with (allergic) asthma, the epithelium is abnormal, showing damaged structures and continuous activation similar to a repair phenotype cell. Epithelial cells bind allergens by a diversity of innate receptors, similar and in part identical to the Toll-like receptor family, which can induce the release of cytokines, chemokines, and growth factors. Protease-containing extracts (house dust mite, fungi) may additionally cause damage of the epithelial cell layer, thereby enhancing the repair phenotype of epithelial cells in patients with asthma. These interactions may result in facilitation of transport of allergens and enhanced presentation to the immune system (Th2-type response). The inflammatory response induces a second phase of Th2-type cytokines and cytotoxic products that will enhance growth factor-mediated airway remodeling, as is found in asthma. An understanding of the largely unknown innate responses of epithelial cells with environmental antigens/allergens may open new treatment modalities for asthma and other airway diseases.
Kiechl, S., C. J. Wiedermann, et al. (2003). "Toll-like receptor 4 and atherogenesis." Ann Med 35(3): 164-71.
Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in the innate immune response to various microorganisms and other exogenous and endogenous stress factors. Recently, evidence emerged that important inflammatory processes implicit in human atherogenesis are mediated in part via the TLR4/nuclear factor-kappaB pathway. Polymorphisms of TLR4, which attenuate receptor signalling, enhance the risk of acute severe infections but may have opposite effects on atherogenesis. The aim of this review is to critically discuss current experimental and epidemiological evidence for a role of TLR4 in atherogenesis and to highlight the main controversies and perspectives in this emerging field of vascular biology.
Lakhani, S. A. and C. W. Bogue (2003). "Toll-like receptor signaling in sepsis." Curr Opin Pediatr 15(3): 278-82.
Despite extensive research, bacterial sepsis and its associated systemic inflammation remain a major cause of morbidity and mortality in the pediatric intensive care unit. Advances in molecular biology, however, have improved our understanding of this disease process and have opened up new avenues of potential therapeutic approaches. One such exciting area has been the substantial and still growing evidence that the mammalian immune system uses a family of Toll-like receptors (TLRs) to generate a response to molecular patterns present on invading microorganisms. In particular, TLR4 is part of a recognition complex for bacterial lipopolysaccharide (LPS), thus raising the likelihood of its involvement in the inflammatory response to bacterial sepsis. This review highlights our understanding of the molecular biology of these receptors, focusing on the LPS response, and concluding with a summary of ongoing evaluation and potential therapeutic strategies for treating sepsis through blockade of TLR signaling.
Leadbetter, E. A., I. R. Rifkin, et al. (2003). "Toll-like receptors and activation of autoreactive B cells." Curr Dir Autoimmun 6: 105-22.
Miyake, K. (2003). "[Toll-like receptors and their roles in defense responses against infection]." Kansenshogaku Zasshi 77(7): 473-9.
Miyake, K. (2003). "Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2." Int Immunopharmacol 3(1): 119-28.
Adaptive immunity generally refers to the ability of lymphocytes to recognize microbial, viral and fungal proteins via T cell receptors and antibodies. More ancestral and widespread innate immune mechanisms include those responsible for recognition of microbial glycolipids. Lipopolysaccharide (LPS) is the best studied, and arguably one of the most important of bacterial products because of its role in innate immune responses and endotoxin-mediated sepsis. Converging studies in two independent fields have recently led to the identification of LPS recognition molecules utilized by mammalian cells. Toll-like receptor 4 (TLR4) was identified as a mammalian homologue of the Toll receptor, which recognized fungi in the Drosophila's immune system. Spontaneous and targeted mutations identified TLR4 as an LPS recognition molecule. Separate studies of a Radioprotective 105 (RP105) and MD-1 heterodimer expressed by cells led to the identification of MD-2 as a molecule associated with TLR4. Very recent in vivo studies have now revealed an essential contribution of MD-2 to LPS recognition. These findings further our understanding of protective, as well as detrimental innate immune mechanisms and may lead to new therapies for endotoxin shock.
Nagy, L. E. (2003). "Recent insights into the role of the innate immune system in the development of alcoholic liver disease." Exp Biol Med (Maywood) 228(8): 882-90.
The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of alcoholic liver disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of disease is by disrupting the signal transduction cascades mediating the innate immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogen-activated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of alcoholic liver disease.
O'Neill, L. A., K. A. Fitzgerald, et al. (2003). "The Toll-IL-1 receptor adaptor family grows to five members." Trends Immunol 24(6): 286-90.
Toll-like receptor (TLR) signal transduction is mediated by an adaptor protein termed MyD88. In the case of TLR2 and TLR4, another adaptor related to MyD88 called Mal also participates in signalling. Two recent papers have added a third adaptor to the family, called Toll-interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-beta (IFN-beta) (TRIF) or TIR-containing adaptor molecule-1 (TICAM-1), which is particularly important for IFN regulatory factor-3 (IRF-3) activation by antiviral TLR3. Two additional adaptors are present in humans, termed Trif-related adaptor molecule (TRAM) and sterile alpha and HEAT-Armadillo motifs (SARM). It is probable that differential use of adaptors will help explain the distinct pathways activated by TLRs during host defence.
O'Neill, L. A., A. Dunne, et al. (2003). "Mal and MyD88: adapter proteins involved in signal transduction by Toll-like receptors." J Endotoxin Res 9(1): 55-9.
Signal transduction processes activated by Toll-like receptors (TLRs) include the important transcription factor NF-kappaB and 2 MAP kinases, p38 and Jun N-terminal kinase. These signals ultimately give rise to increased expression of a multitude of pro-inflammatory proteins. Receptor-proximal proteins involved in signalling by all TLRs include the adapter MyD88, 3 IRAKs (IRAK-4, IRAK and IRAK-2), Tollip, Traf-6 and TAK-1. Differences between signals generated by TLRs are emerging, with both TLR4 and TLR2 signalling requiring an additional adapter termed MyD88-adapter-like (Mal; also known as TIRAP). MyD88 and Mal both have a homologous Toll/IL-1 receptor (TIR) domain although they differ in their N-termini, with MyD88 possessing a death domain. In addition, structural models reveal marked differences in surface charges which, when taken with surface charge differences between TLR2 and TLR4 TIR domains, may indicate that TLR4 but not TLR2 recruits Mal directly. Another difference is that Mal can become phosphorylated. Future studies on Mal will reveal specificities in signal transduction by different TLRs, which may ultimately provide molecular explanations for specificities in the innate immune response to infection.
Reis e Sousa, C., S. D. Diebold, et al. (2003). "Regulation of dendritic cell function by microbial stimuli." Pathol Biol (Paris) 51(2): 67-8.
Dendritic cells (DC) initiate T cell responses and produce cytokines and other molecules that can regulate the class adaptive immunity. It is increasingly clear that DC in vivo are in a "resting" state and require exogenous signals to transit into an "effector" state in which they can prime T cells. Much of this DC activation process appears to be regulated by infection. Exposure of murine DC to certain pathogens or their products triggers DC migration to T cell areas of secondary lymphoid tissues, improves MHC presentation and increases DC co-stimulatory potential. Pathogen recognition can also initiate cytokine production and/or condition DC to produce cytokines in response to subsequent T cell feedback signals delivered via CD40 and similar receptors. Recognition of pathogens by DC is largely dependent on Toll-like receptors (TLRs). Interestingly, mouse splenic CD8alpha+ and CDalpha-CD4- DC have the ability to produce either IL-12 p70 or IL-10 depending on the nature of the pathogen encountered. In contrast, CD4+ DC seem incapable of producing IL-12 p70. Thus, the nature of the pathogen can dictate the type of cytokine that is made by some DC subsets, allowing them to prime distinct types of immune responses. Overall, DC display significant plasticity in their ability to respond to infection and direct adaptive immunity.
Rivest, S. (2003). "Molecular insights on the cerebral innate immune system." Brain Behav Immun 17(1): 13-9.
All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.
Romics, L., Jr., G. Frendl, et al. (2003). "[Cellular and molecular changes of the liver in sepsis and in systemic inflammatory response syndrome (SIRS)]." Orv Hetil 144(11): 499-506.
This paper provides a review on the changes in the molecular and cellular level of the liver during sepsis and systemic immune response syndrome. The different function of the various liver cells and their mediators are analyzed. Dual role of nitric-oxide and carbon-monoxide are discussed followed by an overview about acute phase proteins and heat shock proteins in septic liver. A detailed description is presented on the role of the Toll-like receptors and their signaling pathways in the liver during sepsis and systemic immune response syndrome. Finally, the possible mechanisms leading to apoptosis of the liver cells are shown and the most recent therapeutical challenges are discussed.
Rothenfusser, S., E. Tuma, et al. (2003). "Recent advances in immunostimulatory CpG oligonucleotides." Curr Opin Mol Ther 5(2): 98-106.
The vertebrate immune system has evolved a mechanism to detect CpG motifs within microbial DNA (CpG DNA). Synthetic oligonucleotides containing CpG motifs (CpG ODNs) are potent immunomodulatory molecules and outstanding vaccine adjuvants. A number of recent findings have greatly improved our understanding of the biology of CpG DNA, and the immunological effects of CpG DNA are now recognized to be distinct in mouse and human. The plasmacytoid dendritic cell (PDC) was identified to play a pivotal role in mediating CpG-induced immune responses. So far, the B-cell is the only other immune cell subset in humans besides the PDC, equipped with the toll-like receptor-9 to detect CpG motifs. The information on these two prime CpG-sensitive cells has allowed the identification of novel CpG ODNs with distinct functional activity. Together with exciting contributions from animal studies, the way seems to be paved for the successful clinical development of this novel class of molecular therapeutics.
Sabroe, I., R. C. Read, et al. (2003). "Toll-like receptors in health and disease: complex questions remain." J Immunol 171(4): 1630-5.
Schwarz, K., T. Storni, et al. (2003). "Role of Toll-like receptors in costimulating cytotoxic T cell responses." Eur J Immunol 33(6): 1465-70.
Stimulation of Toll-like receptors (TLR) by pathogen-derived compounds leads to activation of APC, facilitating the induction of protective immunity. This phenomenon is the basis of most adjuvant formulations currently in development. Here, we tested the ability of TLR2, 3, 4, 5, 7 and 9 signaling to enhance CTL responses upon vaccination with virus-like particles. Stimulation of TLR2 and 4 failed to increase CTL responses, whereas ligands for TLR3, 5 and 7 exhibited moderate adjuvant function. In contrast, stimulation of TLR9 dramatically increased CTL responses, indicating that ligands for TLR9 are likely to be the most promising candidates for the development of novel adjuvant formulations for stimulating CTL responses.
Silverstein, R. and D. C. Johnson (2003). "Endogenous versus exogenous glucocorticoid responses to experimental bacterial sepsis." J Leukoc Biol 73(4): 417-27.
Although lack of adrenals dramatically reduces resistance against sepsis generally, the value of glucocorticoid levels above those normally produced by stress remains controversial. An early and long-held concept is that glucocorticoid protection against lipopolysaccharides in animal models is important. Supporting this concept, C3H/HeJ mice, lacking Toll-like receptor-4 (TLR-4), and consequently, endotoxin hyporesponsive, have recently been shown to be resistant to glucocorticoid protection against live Escherichia coli. Effective antibiotic intervention, as an additional parameter and with concomitant administration of glucocorticoid, not only allows for expected antibiotic protection but also for glucocorticoid protection against E. coli or Staphylococcus aureus of mice sensitized to tumor necrosis factor alpha, regardless of the status of the TLR-4 receptor. TLRs, including but not limited to TLR-2, may be involved in glucocorticoid protective efficacy against Gram-positive and Gram-negative sepsis. Overlapping and possibly endotoxin-independent signaling may become important considerations.
Someya, T., K. Sasaki, et al. (2003). "[The application of molecular biology to anti-endotoxin therapies]." Nippon Geka Gakkai Zasshi 104(7): 523-6.
Toll-like receptors (TLRs), recently identified on macrophages and dendritic cells in mammals, recognize a specific pattern of pathogen components, including endotoxins(lipopolysaccharide). Pathogen recognition by TLRs activates the innate immune system through the signaling pathway and provokes inflammatory responses, such as inducing the production of cytokines. Therefore the specific inhibition of the signaling pathway and the administration of excess inflammatory responses have useful potential in the management of sepsis syndrome. Currently, several monoclonal antibodies are applicable to the treatment of autoimmune diseases and cancer. On the other hand, immunotherapies against proinflammatory cytokines in septic shock have failed to demonstrate clinical benefit. In this review, we summarize recent views of novel therapeutic targets, provided from molecular biologic studies of gram-negative infection.
Strieter, R. M., J. A. Belperio, et al. (2003). "Host innate defenses in the lung: the role of cytokines." Curr Opin Infect Dis 16(3): 193-8.
PURPOSE OF REVIEW: The lung has a unique relationship with the environment. Through evolution the lung has developed strategies to defend itself from microbial invasion. As we encounter increasing multidrug-resistant microorganisms, we need to further our knowledge of innate defense systems in order to design novel strategies to deal with these microbes without inducing over-exuberant inflammation and lung injury. RECENT FINDINGS: The development of lung innate immunity requires microbial molecular pattern recognition by the recently described Toll like receptors, the release of early response cytokines that further activate the 'master switch', nuclear factor-kappaB, leading to amplified host defense to invading microbes. A balance of Type 1 and Type 2 cytokines modulates the intensity of innate immunity. Cytokines/chemokines orchestrate the polarization and transition of innate to adaptive immunity. SUMMARY: The elucidation of the pathways involved in innate immunity and factors controlling the transition to adaptive immunity will improve our understanding of the host response to infection and improve our ability to design new therapies for the treatment of infectious disease.
Sundquist, M., C. Johansson, et al. (2003). "Dendritic cells as inducers of antimicrobial immunity in vivo." Apmis 111(7-8): 715-24.
Models of infection have provided important insight into the function of dendritic cells (DC) in vivo. Several microbial products induce DC maturation via Toll-like receptors, a process that is crucial for the ability of DC to initiate adaptive immune responses. Splenic DC have also been shown to produce IL-12 during infection in vivo. This DC-derived IL-12 might be important to skew T cell responses towards Th1. Microbial infections also induce changes in the DC populations of lymphoid organs, often in a subset-specific manner, manifested as an accumulation and redistribution of DC. Furthermore, data are emerging pointing at an absolute requirement of DC in priming of naive T cells in vivo.
Takeda, K. and S. Akira (2003). "Toll receptors and pathogen resistance." Cell Microbiol 5(3): 143-53.
Toll receptors in insects, mammals and plants are key players that sense the invasion of pathogens. Toll-like receptors (TLRs) in mammals have been established to detect specific components of bacterial and fungal pathogens. Furthermore, recent evidence indicates that TLRs are involved in the recognition of viral invasion. Signalling pathways via TLRs originate from the conserved Toll/IL-1 receptor (TIR) domain. The TIR domain-containing MyD88 acts as a common adaptor that induces inflammatory cytokines; however, there exists a MyD88-independent pathway that induces type I IFNs in TLR4 and TLR3 signalling. Another TIR domain-containing adaptor, TIRAP/Mal has recently been shown to mediate the MyD88-dependent activation in the TLR4 and TLR2 signalling pathway. Thus, individual TLRs may have their own signalling systems that characterize their specific activities.
Takeda, K., T. Kaisho, et al. (2003). "Toll-like receptors." Annu Rev Immunol 21: 335-76.
The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.
Trinchieri, G. (2003). "Interleukin-12 and the regulation of innate resistance and adaptive immunity." Nat Rev Immunol 3(2): 133-46.
Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-gamma (IFN-gamma), favours the differentiation of T helper 1 (T(H)1) cells and forms a link between innate resistance and adaptive immunity. Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN. Recent data, however, argue against an absolute requirement for IL-12 for T(H)1 responses. Our understanding of the relative roles of IL-12 and other factors in T(H)1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process of IL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.
Tschopp, J., F. Martinon, et al. (2003). "NALPs: a novel protein family involved in inflammation." Nat Rev Mol Cell Biol 4(2): 95-104.
A newly discovered family of cytoplasmic proteins--the NALPs--has been implicated in the activation of caspase-1 by the Toll-like receptors (TLRs) during the cell's response to microbial infection. Like the structurally related apoptotic protease-activating factor-1 (APAF-1), which is responsible for the activation of caspase-9, the NALP1 protein forms a large, signal-induced multiprotein complex, the inflammasome, resulting in the activation of pro-inflammatory caspases.
Uhlmann, E. and J. Vollmer (2003). "Recent advances in the development of immunostimulatory oligonucleotides." Curr Opin Drug Discov Devel 6(2): 204-17.
Some immune cells recognize distinct molecular structures present in pathogens through specific pattern recognition receptors that are able to distinguish prokaryotic DNA from vertebrate DNA. The detection of invading microbial DNA is based on the recognition of unmethylated deoxycytidyl-deoxyguanosin dinucleotide (CpG) motifs. Synthetic oligonucleotides (ODNs) containing these CpG motifs are able to activate both innate and acquired immune responses through a signaling pathway involving Toll-like receptor 9 (TLR9). Depending on the sequence, length, as well as number and positions of CpG motifs in an ODN, distinct immunostimulatory profiles can be observed. These immunostimulatory profiles can be further modified and fine-tuned by appropriate chemical modifications, leading to preclinical and clinical development of CpG ODNs in cancer, allergy, asthma and infectious diseases
Underhill, D. M. (2003). "Toll-like receptors: networking for success." Eur J Immunol 33(7): 1767-75.
The innate immune system is essential for host defense and is responsible for early detection of potentially pathogenic microorganisms. Upon recognition of microbes by innate immune cells such as macrophages and dendritic cells, diverse signaling pathways are activated that combine to define inflammatory responses that direct sterilization of the threat and/or orchestrate development of the adaptive immune response. Innate immune signaling must be carefully controlled, and regulation comes in part from interactions between activating and inhibiting signaling receptors. Toll-like receptors (TLR) have recently emerged as key receptors responsible for recognizing specific conserved components of microbes including lipopolysaccharides from Gram-negative bacteria, CpG DNA, and flagellin. Full activation of inflammatory responses by TLR may require the assembly of receptor signaling complexes including other transmembrane proteins that may influence signal transduction. In addition to TLR, many additional receptors participate in innate recognition of microbes, and recent studies demonstrate strong interactions between signaling through these receptors and signaling through TLR. Useful models for these interacting signaling pathways are now emerging and should pave the way for understanding the molecular mechanisms that drive the rich diversity of inflammatory responses.
Van Amersfoort, E. S., T. J. Van Berkel, et al. (2003). "Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock." Clin Microbiol Rev 16(3): 379-414.
Bacterial sepsis and septic shock result from the overproduction of inflammatory mediators as a consequence of the interaction of the immune system with bacteria and bacterial wall constituents in the body. Bacterial cell wall constituents such as lipopolysaccharide, peptidoglycans, and lipoteichoic acid are particularly responsible for the deleterious effects of bacteria. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Within the circulation bacterial constituents interact with proteins such as plasma lipoproteins and lipopolysaccharide binding protein. The interaction of the bacterial constituents with receptors on the surface of mononuclear cells is mainly responsible for the induction of proinflammatory mediators by the bacterial constituents. The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail. In addition, the roles of a number of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described. Finally, the therapies for the treatment of bacterial sepsis and septic shock are discussed in relation to the action of the aforementioned receptors and proteins.
van Eden, W., A. Koets, et al. (2003). "Immunopotentiating heat shock proteins: negotiators between innate danger and control of autoimmunity." Vaccine 21(9-10): 897-901.
Heat shock proteins (hsps) are known to be immunodominant antigens of bacteria. Hsps are evolutionarily strongly conserved proteins present in all eukaryotic and prokaryotic cellular organisms and upregulated by several forms of stress. Despite (the paradigm of) self-tolerance, hsp-epitopes homologous to endogenous host hsp sequences have been implicated as T cell epitopes to endow crossreactive, hsp-specific T cells with the capacity to regulate inflammation, such as in experimentally induced autoimmune diseases. Such T cells were found to produce regulatory cytokines like IL10, in contrast to T cells induced with other conserved microbial proteins that are not upregulated by stress. Hsps have been implicated in immune regulation not only as upregulated targets of adaptive immunity during inflammatory stress, but recently also as triggering factors for innate immunity through activation via Toll-like receptors (TLRs).
van Kooyk, Y. and T. B. Geijtenbeek (2003). "DC-SIGN: escape mechanism for pathogens." Nat Rev Immunol 3(9): 697-709.
Dendritic cells (DCs) are crucial in the defence against pathogens. Invading pathogens are recognized by Toll-like receptors (TLRs) and receptors such as C-type lectins expressed on the surface of DCs. However, it is becoming evident that some pathogens, including viruses, such as HIV-1, and non-viral pathogens, such as Mycobacterium tuberculosis, subvert DC functions to escape immune surveillance by targeting the C-type lectin DC-SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin). Notably, these pathogens misuse DC-SIGN by distinct mechanisms that either circumvent antigen processing or alter TLR-mediated signalling, skewing T-cell responses. This implies that adaptation of pathogens to target DC-SIGN might support pathogen survival.
Werling, D. and T. W. Jungi (2003). "TOLL-like receptors linking innate and adaptive immune response." Vet Immunol Immunopathol 91(1): 1-12.
Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, which is mediated by B and T lymphocytes, recognises pathogens by rearranged high affinity receptors. However, the establishment of adaptive immunity is often not rapid enough to eradicate microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defense mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors (PRR). Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns (PAMP) to TLR induces the production of reactive oxygen and nitrogen intermediates (ROI and RNI), pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this review, we will summarize the discovery and the critical roles of the TLR family in host defense, briefly allude to signaling mechanisms mediating the response to TLR ligands, and will provide an update on current knowledge regarding the ligand specificity of these receptors and their role in immunity of domestic animals, particularly cattle.