Showing papers in "Nature Reviews Immunology in 2010"
TL;DR: Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
Abstract: Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
2,491 citations
TL;DR: The triggers and receptor pathways that result in sterile inflammation and its impact on human health are reviewed.
Abstract: Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.
2,481 citations
TL;DR: Recent findings regarding human TReg cells are discussed, including the ontogeny and development of TReg cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by TRegcell subsets and factors that regulateTReg cell lineage commitment.
Abstract: Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells are potent mediators of dominant self tolerance in the periphery. But confusion as to the identity, stability and suppressive function of human T(Reg) cells has, to date, impeded the general therapeutic use of these cells. Recent studies have suggested that human T(Reg) cells are functionally and phenotypically diverse. Here we discuss recent findings regarding human T(Reg) cells, including the ontogeny and development of T(Reg) cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by T(Reg) cell subsets and factors that regulate T(Reg) cell lineage commitment. We discuss future studies that are needed for the successful therapeutic use of human T(Reg) cells.
2,134 citations
TL;DR: This Review discusses the approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy and focuses on vaccines that have all the properties of pathogens with the exception of causing disease.
Abstract: Researchers working on the development of vaccines face an inherent dilemma: to maximize immunogenicity without compromising safety and tolerability. Early vaccines often induced long-lived protective immune responses, but tolerability was a major problem. Newer vaccines have very few side effects but can be of limited immunogenicity. One way to tackle this problem is to design vaccines that have all the properties of pathogens with the exception of causing disease. Key features of pathogens that can be mimicked by vaccine delivery systems are their size, shape and surface molecule organization. In addition, pathogen-associated molecular patterns can be used to induce innate immune responses that promote adaptive immunity. In this Review, we discuss the approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy.
1,572 citations
TL;DR: The authors would like to include as an addendum the contribution of R. Stout and J. Suttles to the conceptual framework of macrophage plasticity that was mentioned in the Review.
Abstract: Nature Reviews Immunology 8, 958–969 (2008) The authors would like to include as an addendum the contribution of R. Stout and J. Suttles to the conceptual framework of macrophage plasticity that was mentioned in our Review. Their ideas on the ability of macrophages to change their functional phenotype in response to their tissue environment were previously published in two review articles (J.
1,523 citations
TL;DR: A model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS) is suggested.
Abstract: This Opinion article discusses the evidence for and the limitations of the three main models of inflammasome activation. The authors propose that the production of reactive oxygen species might be a common factor downstream of many types of inflammasome activator. The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. The NLRP3 inflammasome is activated by a wide range of danger signals that derive not only from microorganisms but also from metabolic dysregulation. It is unclear how these highly varied stress signals can be detected by a single inflammasome. In this Opinion article, we review the different signalling pathways that have been proposed to engage the NLRP3 inflammasome and suggest a model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS).
1,492 citations
TL;DR: Recent advances in understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated are discussed.
Abstract: Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression, and they function by repressing specific target genes at the post-transcriptional level. Now, studies of miRNAs are resolving some unsolved issues in immunology. Recent studies have shown that miRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. Furthermore, when miRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity; they have also been shown to be useful as diagnostic and prognostic indicators of disease type and severity. This Review discusses recent advances in our understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated.
1,443 citations
TL;DR: The many innate immune cell populations that are an early source of IL-17 in response to stress, injury or pathogens are explored.
Abstract: The cytokine interleukin-17 (IL-17) has received considerable attention since the discovery of a distinct CD4(+) T helper (T(H)) cell subset that produces it, known as the T(H)17 cell subset. Despite the fact that most of the recent literature describes IL-17 as a T cell-secreted cytokine, much of the IL-17 released during an inflammatory response is produced by innate immune cells. In this Review, we explore the many innate immune cell populations that are an early source of IL-17 in response to stress, injury or pathogens. These early sources have been shown to have a central role in the initiation of IL-17-dependent immune responses, even before the first CD4(+)T cell sees its cognate antigen and initiates the T(H)17 cell developmental programme.
1,316 citations
TL;DR: This Review provides an overview of both the long-established and more recently characterized members of the IL-1 family and their effects on immune cells, their involvement in human disease and disease models is discussed.
Abstract: Over recent years it has become increasingly clear that innate immune responses can shape the adaptive immune response. Among the most potent molecules of the innate immune system are the interleukin-1 (IL-1) family members. These evolutionarily ancient cytokines are made by and act on innate immune cells to influence their survival and function. In addition, they act directly on lymphocytes to reinforce certain adaptive immune responses. This Review provides an overview of both the long-established and more recently characterized members of the IL-1 family. In addition to their effects on immune cells, their involvement in human disease and disease models is discussed.
1,229 citations
TL;DR: The unique adaptations of the intestinal immune system that maintain homeostatic interactions with a diverse resident microbiota are discussed.
Abstract: Humans harbour nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of co-evolution have moulded this human-microorganism interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment. Although intestinal microorganisms carry out essential functions for their hosts, they pose a constant threat of invasion owing to their sheer numbers and the large intestinal surface area. In this Review, we discuss the unique adaptations of the intestinal immune system that maintain homeostatic interactions with a diverse resident microbiota.
1,227 citations
TL;DR: This work states that antibodies exhibit various immunomodulatory properties and, by directly activating or inhibiting molecules of the immune system, antibodies can promote the induction of antitumour immune responses and form the basis for new cancer treatment strategies.
Abstract: Antibodies are important therapeutic agents for cancer. Recently, it has become clear that antibodies possess several clinically relevant mechanisms of action. Many clinically useful antibodies can manipulate tumour-related signalling. In addition, antibodies exhibit various immunomodulatory properties and, by directly activating or inhibiting molecules of the immune system, antibodies can promote the induction of antitumour immune responses. These immunomodulatory properties can form the basis for new cancer treatment strategies.
TL;DR: Dysregulated TLR signalling by intestinal epithelial cells may explain how colonic bacteria and inflammation promote colorectal cancer.
Abstract: A single layer of epithelial cells lines the small and large intestines and functions as a barrier between commensal bacteria and the rest of the body. Ligation of Toll-like receptors (TLRs) on intestinal epithelial cells by bacterial products promotes epithelial cell proliferation, secretion of IgA into the gut lumen and expression of antimicrobial peptides. As described in this Review, this establishes a microorganism-induced programme of epithelial cell homeostasis and repair in the intestine. Dysregulation of this process can result in chronic inflammatory and over-exuberant repair responses, and it is associated with the development of colon cancer. Thus, dysregulated TLR signalling by intestinal epithelial cells may explain how colonic bacteria and inflammation promote colorectal cancer.
TL;DR: Current understanding of the diverse functions of SYK is summarized and how this is being translated for therapeutic purposes is summarized.
Abstract: Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9-BCL-10-MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematological malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.
TL;DR: This Review provides an overview of concepts, with a focus on macrophage death and defective apoptotic cell clearance, and discusses new therapeutic strategies designed to boost inflammation resolution in atherosclerosis.
Abstract: A key event in atherosclerosis is a maladaptive inflammatory response to subendothelial lipoproteins. A crucial aspect of this response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective clearance of apoptotic cells and promotion of inflammatory cell egress. Defects in these processes promote the progression of atherosclerotic lesions into dangerous plaques, which can trigger atherothrombotic vascular disease, the leading cause of death in industrialized societies. In this Review I provide an overview of these concepts, with a focus on macrophage death and defective apoptotic cell clearance, and discuss new therapeutic strategies designed to boost inflammation resolution in atherosclerosis.
TL;DR: The mechanisms involved in the intimate partnership of phagocytes during each progressive phase of the inflammatory response are highlighted and the potential therapeutic relevance of these interactions are highlighted.
Abstract: Neutrophils, monocytes and macrophages are closely related phagocytic cells that cooperate during the onset, progression and resolution of inflammation. This Review highlights the mechanisms involved in the intimate partnership of phagocytes during each progressive phase of the inflammatory response. We describe how tissue-resident macrophages recognize tissue damage to promote the recruitment of neutrophils and the mechanisms by which infiltrating neutrophils can then promote monocyte recruitment. Furthermore, we discuss the phagocyte-derived signals that abrogate neutrophil recruitment and how the uptake of apoptotic neutrophils by macrophages leads to termination of the inflammatory response. Finally, we highlight the potential therapeutic relevance of these interactions.
TL;DR: IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting TH2-type immune responses but can also promote the pathogenesis of asthma by expanding TH2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation.
Abstract: Interleukin-33 (IL-33), a newly described member of the IL-1 family, is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis. The IL-33 receptor, consisting of ST2 and IL-1 receptor accessory protein, is also widely expressed, particularly by T helper 2 (T(H)2) cells and mast cells. IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting T(H)2-type immune responses. However, IL-33 can also promote the pathogenesis of asthma by expanding T(H)2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation. Thus IL-33 could be a new target for therapeutic intervention across a range of diseases.
TL;DR: How key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibody with promise for greater clinical efficacy and safety is reviewed.
Abstract: The development of therapeutic antibodies has evolved over the past decade into a mainstay of therapeutic options for patients with autoimmune and inflammatory diseases. Substantial advances in understanding the biology of human diseases have been made and tremendous benefit to patients has been gained with the first generation of therapeutic antibodies. The lessons learnt from these antibodies have provided the foundation for the discovery and development of future therapeutic antibodies. Here we review how key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibodies with promise for greater clinical efficacy and safety.
TL;DR: The involvement of allergen- and parasite product-mediated activation of epithelial cells, basophils and dendritic cells and the functions of the cytokines interleukin-4 (IL-4), IL-25, IL-33 and thymic stromal lymphopoietin in the initiation and amplification of TH2-type immune responses in vivo are discussed.
Abstract: CD4+ T helper (TH) cells have crucial roles in orchestrating adaptive immune responses. TH2 cells control immunity to extracellular parasites and all forms of allergic inflammatory responses. Although we understand the initiation of the TH2-type response in tissue culture in great detail, much less is known about TH2 cell induction in vivo. Here we discuss the involvement of allergen- and parasite product-mediated activation of epithelial cells, basophils and dendritic cells and the functions of the cytokines interleukin-4 (IL-4), IL-25, IL-33 and thymic stromal lymphopoietin in the initiation and amplification of TH2-type immune responses in vivo.
TL;DR: The finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia.
Abstract: The early immune response to HIV-1 infection is likely to be an important factor in determining the clinical course of disease. Recent data indicate that the HIV-1 quasispecies that arise following a mucosal infection are usually derived from a single transmitted virus. Moreover, the finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia. Strong innate and adaptive immune responses occur subsequently but they are too late to eliminate the infection. In this Review, we discuss recent studies on the kinetics and quality of early immune responses to HIV-1 and their implications for developing a successful preventive HIV-1 vaccine.
TL;DR: Recent observations reveal the ability of γδ T cells to rapidly produce cytokines that regulate pathogen clearance, inflammation and tissue homeostasis in response to tissue stress, and insights are provided into how they acquire these properties.
Abstract: Gammadelta T cells have several innate cell-like features that allow their early activation following recognition of conserved stress-induced ligands. Here we review recent observations revealing the ability of gammadelta T cells to rapidly produce cytokines that regulate pathogen clearance, inflammation and tissue homeostasis in response to tissue stress. These studies provide insights into how they acquire these properties, through both developmental programming in the thymus and functional polarization in the periphery. Innate features of gammadelta T cells underlie their non-redundant role in several physiopathological contexts and are therefore being exploited in the design of new immunotherapeutic approaches.
TL;DR: In the version of the article initially published, the table in BOX 1 incorrectly listed IL-17RB as the receptor forIL-17E (also known as IL-25), the correct receptor should have been IL- 17RA–IL- 17RB.
Abstract: Nature Reviews Immunology 10, 479–489, (2010), doi:10.1038/nri2800; published online 18 June 2010; corrected online 25 June 2010 In the version of the article initially published, the table in BOX 1 incorrectly listed IL-17RB as the receptor for IL-17E (also known as IL-25). The correct receptor should have been IL-17RA–IL-17RB.
TL;DR: Recent studies using mast cell activators as effective vaccine adjuvants show the potential of harnessing these cells to confer protective immunity against microbial pathogens.
Abstract: Although mast cells were discovered more than a century ago, their functions beyond their role in allergic responses remained elusive until recently. However, there is a growing appreciation that an important physiological function of these cells is the recognition of pathogens and modulation of appropriate immune responses. Because of their ability to instantly release several pro-inflammatory mediators from intracellular stores and their location at the host-environment interface, mast cells have been shown to be crucial for optimal immune responses during infection. Mast cells seem to exert these effects by altering the inflammatory environment after detection of a pathogen and by mobilizing various immune cells to the site of infection and to draining lymph nodes. Interestingly, the character and timing of these responses can vary depending on the type of pathogen stimulus, location of pathogen recognition and sensitization state of the responding mast cells. Recent studies using mast cell activators as effective vaccine adjuvants show the potential of harnessing these cells to confer protective immunity against microbial pathogens.
TL;DR: Strategies to select the best therapeutic antigen targets, to optimize the structure of IgG antibodies and to design related or new structures with additional functions are discussed.
Abstract: Antibodies and related products are the fastest growing class of therapeutic agents. By analysing the regulatory approvals of IgG-based biotherapeutic agents in the past 10 years, we can gain insights into the successful strategies used by pharmaceutical companies so far to bring innovative drugs to the market. Many challenges will have to be faced in the next decade to bring more efficient and affordable antibody-based drugs to the clinic. Here, we discuss strategies to select the best therapeutic antigen targets, to optimize the structure of IgG antibodies and to design related or new structures with additional functions.
TL;DR: The hypothesis that blocking TGFβ-induced signalling in the tumour microenvironment enhances antitumour immunity and may be beneficial for cancer therapy is favoured.
Abstract: Transforming growth factor-beta (TGFbeta) is an immunosuppressive cytokine produced by tumour cells and immune cells that can polarize many components of the immune system. This Review covers the effects of TGFbeta on natural killer (NK) cells, dendritic cells, macrophages, neutrophils, CD8(+) and CD4(+) effector and regulatory T cells, and NKT cells in animal tumour models and in patients with cancer. Collectively, many recent studies favour the hypothesis that blocking TGFbeta-induced signalling in the tumour microenvironment enhances antitumour immunity and may be beneficial for cancer therapy. An overview of the current drugs and reagents available for inhibiting TGFbeta-induced signalling and their phase in clinical development is also provided.
TL;DR: Recent studies on the features of viral siRNAs and other virus-derived small RNAs from virus-infected fungi, plants, insects, nematodes and vertebrates are reviewed and the innate and adaptive properties of RNA-based antiviral immunity are discussed.
Abstract: In eukaryotic RNA-based antiviral immunity, viral double-stranded RNA is recognized as a pathogen-associated molecular pattern and processed into small interfering RNAs (siRNAs) by the host ribonuclease Dicer. After amplification by host RNA-dependent RNA polymerases in some cases, these virus-derived siRNAs guide specific antiviral immunity through RNA interference and related RNA silencing effector mechanisms. Here, I review recent studies on the features of viral siRNAs and other virus-derived small RNAs from virus-infected fungi, plants, insects, nematodes and vertebrates and discuss the innate and adaptive properties of RNA-based antiviral immunity.
TL;DR: In chronically inflamed tissues, aberrant ECM expression and fragments of the ECM that are derived from tissue-remodelling processes can influence immune cell activation and survival, thereby actively contributing to immune responses at these sites.
Abstract: The advent of in situ immunology and intravital analyses of leukocyte movement in tissues has drawn attention to the previously neglected extracellular matrix (ECM) and its role in modulating immune cell behaviour in inflamed tissues. The ECM exists in different biochemical and structural forms; both their individual components and three-dimensional ultrastructure impart specific signals to cells that modulate basic functions that are important for the early steps in inflammation, such as immune cell migration into inflamed tissues and immune cell differentiation. In chronically inflamed tissues, aberrant ECM expression and fragments of the ECM that are derived from tissue-remodelling processes can influence immune cell activation and survival, thereby actively contributing to immune responses at these sites.
TL;DR: Progress so far towards understanding the role of CD4+CD25+FOXP3+ TReg cells in human autoimmune diseases and the impact that this knowledge might have on the diagnosis and treatment of these diseases are summarized.
Abstract: A lack of regulatory T (T(Reg)) cells that express CD4, CD25 and forkhead box P3 (FOXP3) results in severe autoimmunity in both mice and humans. Since the discovery of T(Reg) cells, there has been intense investigation aimed at determining how they protect an organism from autoimmunity and whether defects in their number or function contribute to the development of autoimmunity in model systems. The next phase of investigation - that is, to define the role that defects in T(Reg) cells have in human autoimmunity - is now underway. This Review summarizes our progress so far towards understanding the role of CD4(+)CD25(+)FOXP3(+) T(Reg) cells in human autoimmune diseases and the impact that this knowledge might have on the diagnosis and treatment of these diseases.
TL;DR: The central role of liver APCs in the regulation of hepatic immune function is reviewed and how recent insights may be applied in strategies to target liver tolerance for disease therapy is considered.
Abstract: The demands that are imposed on the liver as a result of its function as a metabolic organ that extracts nutrients and clears gut-derived microbial products from the blood are met by a unique microanatomical and immunological environment. The inherent tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are mediated by parenchymal and non-parenchymal antigen-presenting cells (APCs), cell-autonomous molecular pathways and locally produced factors. Here, we review the central role of liver APCs in the regulation of hepatic immune function and also consider how recent insights may be applied in strategies to target liver tolerance for disease therapy.
TL;DR: Studies of the immunobiology of farm living point to activation and modulation of innate and adaptive immune responses by intense microbial exposures and possibly xenogeneic signals delivered before or soon after birth.
Abstract: Numerous epidemiological studies have shown that children who grow up on traditional farms are protected from asthma, hay fever and allergic sensitization. Early-life contact with livestock and their fodder, and consumption of unprocessed cow's milk have been identified as the most effective protective exposures. Studies of the immunobiology of farm living point to activation and modulation of innate and adaptive immune responses by intense microbial exposures and possibly xenogeneic signals delivered before or soon after birth.
TL;DR: It is suggested that improving the understanding of the intestinal microbiota has therapeutic implications, not only for intestinal immunopathologies but also for systemic immune diseases.
Abstract: The mammalian intestine is home to a complex community of trillions of bacteria that are engaged in a dynamic interaction with the host immune system. Determining the principles that govern host-microbiota relationships is the focus of intense research. Here, we describe how the intestinal microbiota is able to influence the balance between pro-inflammatory and regulatory responses and shape the host's immune system. We suggest that improving our understanding of the intestinal microbiota has therapeutic implications, not only for intestinal immunopathologies but also for systemic immune diseases.