Showing papers in "Nature Reviews Immunology in 2008"
TL;DR: This Review suggests a new grouping of macrophages based on three different homeostatic activities — host defence, wound healing and immune regulation, and proposes that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation.
Abstract: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.
7,384 citations
TL;DR: The targets and mechanisms of M SC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches are discussed.
Abstract: Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.
3,142 citations
TL;DR: The hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate TReg-cell function is proposed.
Abstract: Regulatory T (T(Reg)) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that T(Reg) cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by T(Reg) cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for T(Reg)-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T(Reg)-cell function.
2,803 citations
TL;DR: New cellular and molecular mechanisms for the resolution of inflammation are presented, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins, which have anti-inflammatory and pro-resolution properties.
Abstract: Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins. These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence.
2,619 citations
TL;DR: Recent studies addressing the multifaceted roles of FcRs for IgG (FcγRs) in the immune system are discussed and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases are discussed.
Abstract: In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.
2,390 citations
TL;DR: This Review discusses four main effector pathways of the IFN-mediated antiviral response: the Mx GTPase pathway, the 2′,5′-oligoadenylate-synthetase-directed ribonuclease L pathways, the protein kinase R pathway and the ISG15 ubiquitin-like pathway.
Abstract: Since the discovery of interferons (IFNs), considerable progress has been made in describing the nature of the cytokines themselves, the signalling components that direct the cell response and their antiviral activities. Gene targeting studies have distinguished four main effector pathways of the IFN-mediated antiviral response: the Mx GTPase pathway, the 2',5'-oligoadenylate-synthetase-directed ribonuclease L pathway, the protein kinase R pathway and the ISG15 ubiquitin-like pathway. As discussed in this Review, these effector pathways individually block viral transcription, degrade viral RNA, inhibit translation and modify protein function to control all steps of viral replication. Ongoing research continues to expose additional activities for these effector proteins and has revealed unanticipated functions of the antiviral response.
1,927 citations
TL;DR: Current knowledge of cell death and repair processes in the host and their importance to host defence and disease pathogenesis has only been appreciated relatively recently is reviewed.
Abstract: When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes - that is, it is part of normal physiological processes - then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.
1,626 citations
TL;DR: The importance of using multiparameter flow cytometry to better understand the functional capacity of effector and memory T-cell responses, thereby enabling the development of preventative and therapeutic vaccine strategies for infections is highlighted.
Abstract: T cells mediate effector functions through a variety of mechanisms. Recently, multiparameter flow cytometry has allowed a simultaneous assessment of the phenotype and multiple effector functions of single T cells; the delineation of T cells into distinct functional populations defines the quality of the response. New evidence suggests that the quality of T-cell responses is crucial for determining the disease outcome to various infections. This Review highlights the importance of using multiparameter flow cytometry to better understand the functional capacity of effector and memory T-cell responses, thereby enabling the development of preventative and therapeutic vaccine strategies for infections.
1,483 citations
TL;DR: The roles of these B7 molecules in the dynamic interactions between tumours and the host immune system, including their expression, regulation and function in the tumour microenvironment are focused on.
Abstract: The B7 family consists of activating and inhibitory co-stimulatory molecules that positively and negatively regulate immune responses. Recent studies have shown that human and rodent cancer cells, and stromal cells and immune cells in the cancer microenvironment upregulate expression of inhibitory B7 molecules and that these contribute to tumour immune evasion. In this Review, we focus on the roles of these B7 molecules in the dynamic interactions between tumours and the host immune system, including their expression, regulation and function in the tumour microenvironment. We also discuss novel therapeutic strategies that target these inhibitory B7 molecules and their signalling pathways to treat human cancer.
1,411 citations
TL;DR: It is proposed that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies.
Abstract: Accumulating evidence indicates that the innate and adaptive immune systems make a crucial contribution to the antitumour effects of conventional chemotherapy-based and radiotherapy-based cancer treatments. Moreover, the molecular and cellular bases of the immunogenicity of cell death that is induced by cytotoxic agents are being progressively unravelled, challenging the guidelines that currently govern the development of anticancer drugs. Here, we review the immunological aspects of conventional cancer treatments and propose that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies.
1,352 citations
TL;DR: The current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, and the production of specific antibody isotypes and regulation of the immune response are presented.
Abstract: Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.
TL;DR: It is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations, which has important implications for the development of new therapies.
Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive airway diseases that involve chronic inflammation of the respiratory tract, but the type of inflammation is markedly different between these diseases, with different patterns of inflammatory cells and mediators being involved As described in this Review, these inflammatory profiles are largely determined by the involvement of different immune cells, which orchestrate the recruitment and activation of inflammatory cells that drive the distinct patterns of structural changes in these diseases However, it is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations This has important implications for the development of new therapies
TL;DR: This work focuses on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.
Abstract: A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.
TL;DR: The distinct biological features of CSFs offer opportunities for specific targeting, but with some associated risks, are described and the probable specific outcomes of targeting CSFs in vivo are discussed.
Abstract: Although they were originally defined as haematopoietic-cell growth factors, colony-stimulating factors (CSFs) have been shown to have additional functions by acting directly on mature myeloid cells. Recent data from animal models indicate that the depletion of CSFs has therapeutic benefit in many inflammatory and/or autoimmune conditions and as a result, early-phase clinical trials targeting granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor have now commenced. The distinct biological features of CSFs offer opportunities for specific targeting, but with some associated risks. Here, I describe these biological features, discuss the probable specific outcomes of targeting CSFs in vivo and highlight outstanding questions that need to be addressed.
TL;DR: This Review discusses new insights into the regulation of NF-κB, a key mediator of inducible transcription in the immune system, that have been identified and some of the known components have been assigned new roles.
Abstract: Research on the biological function of nuclear factor-kappaB (NF-kappaB), a key mediator of inducible transcription in the immune system, has traditionally focused on its role in the initiation of innate and adaptive immune responses. These studies have largely concentrated on the mechanisms of signalling that lead to NF-kappaB activation and on the positive role of NF-kappaB in both physiological immunity and pathological inflammation. More recently, there has been growing interest in the mechanisms that directly regulate the NF-kappaB transcriptional programmes. As a result, several new NF-kappaB regulatory components have been identified and some of the known components have been assigned new roles. In this Review, we discuss these new insights into the regulation of NF-kappaB.
TL;DR: This Review highlights recent insights into the molecular interactions that occur during sepsis and attempts to unravel the nature of the dysregulated immune response duringSepsis.
Abstract: Sepsis and sepsis-associated multi-organ failure are major challenges for scientists and clinicians and are a tremendous burden for health-care systems. Despite extensive basic research and clinical studies, the pathophysiology of sepsis is still poorly understood. We are now beginning to understand that sepsis is a heterogeneous, dynamic syndrome caused by imbalances in the 'inflammatory network'. In this Review, we highlight recent insights into the molecular interactions that occur during sepsis and attempt to unravel the nature of the dysregulated immune response during sepsis.
TL;DR: Several pDC receptors negatively regulate type I IFN responses by pDCs during viral infection and for normal homeostasis, which normally prevents pDC responses to them.
Abstract: Plasmacytoid dendritic cells (pDCs) are important mediators of antiviral immunity through their ability to produce large amounts of type I interferons (IFNs) on viral infection. This function of pDCs is linked to their expression of Toll-like receptor 7 (TLR7) and TLR9, which sense viral nucleic acids within the early endosomes. Exclusion of self nucleic acids from TLR-containing early endosomes normally prevents pDC responses to them. However, in some autoimmune diseases, self nucleic acids can be modified by host factors and gain entrance to pDC endosomes, where they activate TLR signalling. Several pDC receptors negatively regulate type I IFN responses by pDCs during viral infection and for normal homeostasis.
TL;DR: The current knowledge of the unique gene expression, cytokine-mediated regulation and transcriptional programming of TH17 cells is summarized, and the personal perspectives on the future studies that are required to elucidate this lineage in more detail are provided.
Abstract: Following activation, CD4+ T cells differentiate into different lineages of helper T (T(H)) cells that are characterized by distinct developmental regulation and biological functions. T(H)17 cells have recently been identified as a new lineage of effector T(H) cells, and they have been shown to be important in immune responses to infectious agents, as well as in various immune diseases. Over the past two to three years, there has been a rapid progress in our understanding of the differentiation programme of T(H)17 cells. Here, I summarize our current knowledge of the unique gene expression, cytokine-mediated regulation and transcriptional programming of T(H)17 cells, and provide my personal perspectives on the future studies that are required to elucidate this lineage in more detail.
TL;DR: A cardinal role for epithelial cells is identified in sampling the intestinal microenvironment, discriminating pathogenic and commensal microorganisms and influencing the function of antigen-presenting cells and lymphocytes.
Abstract: Mucosal surfaces such as the intestinal tract are continuously exposed to both potential pathogens and beneficial commensal microorganisms. This creates a requirement for a homeostatic balance between tolerance and immunity that represents a unique regulatory challenge to the mucosal immune system. Recent findings suggest that intestinal epithelial cells, although once considered a simple physical barrier, are a crucial cell lineage for maintaining intestinal immune homeostasis. This Review discusses recent findings that identify a cardinal role for epithelial cells in sampling the intestinal microenvironment, discriminating pathogenic and commensal microorganisms and influencing the function of antigen-presenting cells and lymphocytes.
TL;DR: Recent progress in uncovering the structures of IgE proteins and their complexes is reviewed, and the information that has emerged suggests new therapeutic directions for combating allergic disease.
Abstract: The spreading epidemic of allergies and asthma has heightened interest in IgE, the central player in the allergic response. The activity of IgE is associated with a network of proteins; prominent among these are its two principal receptors, FcepsilonRI (high-affinity Fc receptor for IgE) and CD23, as well as galectin-3 and several co-receptors for CD23, notably CD21 and various integrins. Here, we review recent progress in uncovering the structures of these proteins and their complexes, and in our understanding of how IgE exerts its effects and how its expression is regulated. The information that has emerged suggests new therapeutic directions for combating allergic disease.
TL;DR: This Review provides an overview of several important networks that sense and manage nutrients and discusses how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.
Abstract: The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.
TL;DR: Current understanding of the genetics and immunopathogenesis of Crohn's disease and ulcerative colitis is discussed, with comparative analyses of gene associations between these two inflammatory bowel diseases revealing common and unique mechanisms of their immunopathy.
Abstract: Genome-wide association studies efficiently and powerfully assay common genetic variation. The application of these studies to Crohn's disease has provided insight into the immunopathogenesis of this disease, implicating a role for genes of the innate and adaptive immune systems. In this Review, I discuss our current understanding of the genetics and immunopathogenesis of Crohn's disease and ulcerative colitis. Crohn's disease, but not ulcerative colitis, is associated with genetic variation in NOD2 and an autophagy gene, ATG16L1, both of which affect the intracellular processing of bacterial components. By contrast, variation in the gene encoding the interleukin-23 (IL-23) receptor subunit, as well as in the IL12B, STAT3 and NKX2-3 gene regions, is associated with both Crohn's disease and ulcerative colitis. Comparative analyses of gene associations between these two inflammatory bowel diseases reveal common and unique mechanisms of their immunopathogenesis.
TL;DR: It is crucial to address sex-based differences in disease pathogenesis and in the pharmacokinetics and pharmacodynamics of therapeutic medications to provide optimal disease management for both sexes.
Abstract: Despite accumulating evidence in support of sex-based differences in innate and adaptive immune responses, in the susceptibility to infectious diseases and in the prevalence of autoimmune diseases, health research and clinical practice do not address these distinctions, and most research studies of immune responses do not stratify by sex. X-linked genes, hormones and societal context are among the many factors that contribute to disparate immune responses in males and females. It is crucial to address sex-based differences in disease pathogenesis and in the pharmacokinetics and pharmacodynamics of therapeutic medications to provide optimal disease management for both sexes.
TL;DR: Recent data are described that reveal broader antiviral and antimicrobial activities of TRIM proteins and their involvement in the regulation of pathogen-recognition and transcriptional pathways in host defence is discussed.
Abstract: The superfamily of tripartite motif-containing (TRIM) proteins is conserved throughout the metazoan kingdom and has expanded rapidly during vertebrate evolution; there are now more than 60 TRIM proteins known in humans and mice. Many TRIM proteins are induced by type I and type II interferons, which are crucial for many aspects of resistance to pathogens, and several are known to be required for the restriction of infection by lentiviruses. In this Review, we describe recent data that reveal broader antiviral and antimicrobial activities of TRIM proteins and discuss their involvement in the regulation of pathogen-recognition and transcriptional pathways in host defence.
TL;DR: Recent advances in technology have allowed a more precise dissection of the phenotypes of GC B cells and the specific transcriptional programmes that are responsible for this phenotype and their implications for the pathogenesis of B-cell lymphomas are discussed.
Abstract: Over the past several years, studies on normal and malignant B cells have provided new insights into the unique physiology of the germinal centre (GC). In particular, advances in technology have allowed a more precise dissection of the phenotypes of GC B cells and the specific transcriptional programmes that are responsible for this phenotype. Furthermore, substantial progress has been made in the understanding of the mechanism controlling the exit of B cells from the GC and the decision to become a memory B cell or plasma cell. This Review focuses on these recent advances and discusses their implications for the pathogenesis of B-cell lymphomas.
TL;DR: New developments in the understanding of the biology of LCs and other langerin+ DCs are described and the challenges that remain in identifying the role of different DC subsets in tissue immunity are discussed.
Abstract: Langerhans cells (LCs) are a specialized subset of dendritic cells (DCs) that populate the epidermal layer of the skin Langerin is a lectin that serves as a valuable marker for LCs in mice and humans In recent years, new mouse models have led to the identification of other langerin(+) DC subsets that are not present in the epidermis, including a subset of DCs that is found in most non-lymphoid tissues In this Review we describe new developments in the understanding of the biology of LCs and other langerin(+) DCs and discuss the challenges that remain in identifying the role of different DC subsets in tissue immunity
TL;DR: The surprising contribution of granulocyte subsets and mast cells to early atherogenesis and subsequent plaque instability is highlighted, and the complex, double-edged role of monocyte, macrophage and dendritic-cell subsets through crosstalk with T cells and vascular progenitor cells is described.
Abstract: Chronic inflammation drives the development of atherosclerosis, and details regarding the involvement of different leukocyte subpopulations in the pathology of this disease have recently emerged. This Review highlights the surprising contribution of granulocyte subsets and mast cells to early atherogenesis and subsequent plaque instability, and describes the complex, double-edged role of monocyte, macrophage and dendritic-cell subsets through crosstalk with T cells and vascular progenitor cells. Improved understanding of the selective contributions of specific cell types to atherogenesis will pave the way for new targeted approaches to therapy.
TL;DR: Recent work that is beginning to identify factors responsible for intestinal conditioning of dendritic-cell function and the subsequent decision between tolerance and immunity in the intestine is reviewed.
Abstract: A delicate balance between tolerance to commensal bacteria and immunity to pathogens occurs in the intestine. Intestinal dendritic cells have a central role in maintaining this balance and, as described here, some of the molecular pathways involved have recently been resolved. A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease, coeliac disease and allergy. Dendritic cells, through their ability to orchestrate protective immunity and immune tolerance in the host, have a key role in shaping the intestinal immune response. The mechanisms through which dendritic cells can respond to environmental cues in the intestine and select appropriate immune responses have until recently been poorly understood. Here, we review recent work that is beginning to identify factors responsible for intestinal conditioning of dendritic-cell function and the subsequent decision between tolerance and immunity in the intestine.
TL;DR: Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.
Abstract: Recent studies have revealed that the TAM receptor protein tyrosine kinases — TYRO3, AXL and MER — have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.
TL;DR: The evidence that mast cells can have negative, as well as positive, immunomodulatory roles in vivo is reviewed, and it is proposed thatmast cells can both enhance and later suppress certain features of an immune response.
Abstract: Mast cells can promote inflammation and other tissue changes in IgE-associated allergic disorders, as well as in certain innate and adaptive immune responses that are thought to be independent of IgE. However, mast cells can also have anti-inflammatory and immunosuppressive functions. Here, we review the evidence that mast cells can have negative, as well as positive, immunomodulatory roles in vivo, and we propose that mast cells can both enhance and later suppress certain features of an immune response.