Showing papers in "Nature Reviews Immunology in 2005"
TL;DR: Recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues.
Abstract: Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
4,861 citations
TL;DR: It is anticipated that an increased understanding of the contributions of these recently identified pathways will advance current thinking about how interferons work.
Abstract: Interferons are cytokines that have antiviral, antiproliferative and immunomodulatory effects. Because of these important properties, in the past two decades, major research efforts have been undertaken to understand the signalling mechanisms through which these cytokines induce their effects. Since the original discovery of the classical JAK (Janus activated kinase)-STAT (signal transducer and activator of transcription) pathway of signalling, it has become clear that the coordination and cooperation of multiple distinct signalling cascades - including the mitogen-activated protein kinase p38 cascade and the phosphatidylinositol 3-kinase cascade - are required for the generation of responses to interferons. It is anticipated that an increased understanding of the contributions of these recently identified pathways will advance our current thinking about how interferons work.
2,912 citations
TL;DR: The hypothesis is put forward that activation of nuclear factor-κB by the classical, IKK-β (inhibitor-of-NF-β kinase-β)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.
Abstract: There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.
2,746 citations
TL;DR: These features of HMGB1 are discussed and recent advances that have led to the preclinical development of therapeutics that modulateHMGB1 release and activity are summarized.
Abstract: High-mobility group box 1 protein (HMGB1), which previously was thought to function only as a nuclear factor that enhances transcription, was recently discovered to be a crucial cytokine that mediates the response to infection, injury and inflammation. These observations have led to the emergence of a new field in immunology that is focused on understanding the mechanisms of HMGB1 release, its biological activities and its pathological effects in sepsis, arthritis, cancer and other diseases. Here, we discuss these features of HMGB1 and summarize recent advances that have led to the preclinical development of therapeutics that modulate HMGB1 release and activity.
2,318 citations
TL;DR: PNI researchers have used animal and human models to learn how the immune system communicates bidirectionally with the central nervous and endocrine systems and how these interactions impact on health.
Abstract: Folk wisdom has long suggested that stressful events take a toll on health. The field of psychoneuroimmunology (PNI) is now providing key mechanistic evidence about the ways in which stressors--and the negative emotions that they generate--can be translated into physiological changes. PNI researchers have used animal and human models to learn how the immune system communicates bidirectionally with the central nervous and endocrine systems and how these interactions impact on health.
1,845 citations
TL;DR: The spleen enables it to remove older erythrocytes from the circulation and leads to the efficient removal of blood-borne microorganisms and cellular debris, which makes it the most important organ for antibacterial and antifungal immune reactivity.
Abstract: The spleen combines the innate and adaptive immune system in a uniquely organized way. The structure of the spleen enables it to remove older erythrocytes from the circulation and leads to the efficient removal of blood-borne microorganisms and cellular debris. This function, in combination with a highly organized lymphoid compartment, makes the spleen the most important organ for antibacterial and antifungal immune reactivity. A better understanding of the function of this complex organ has been gained from recent studies, as outlined in this Review article.
1,823 citations
TL;DR: This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions.
Abstract: L-Arginine is an essential amino acid for birds and young mammals, and it is a conditionally essential amino acid for adult mammals, as it is important in situations in which requirements exceed production, such as pregnancy. Recent findings indicate that increased metabolism of L-arginine by myeloid cells can result in the impairment of lymphocyte responses to antigen during immune responses and tumour growth. Two enzymes that compete for L-arginine as a substrate - arginase and nitric-oxide synthase - are crucial components of this lymphocyte-suppression pathway, and the metabolic products of these enzymes are important moderators of T-cell function. This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions.
1,564 citations
TL;DR: This review assesses recent advances in the understanding of viral hepatitis, contrasts mechanisms of virus–host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.
Abstract: More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies. NECROINFLAMMATORY A state in which there is morphological evidence of infiltration of inflammatory cells and necrosis of parenchymal
1,547 citations
TL;DR: The various negative regulatory mechanisms that have evolved to attenuate TLR signalling to maintain this immunological balance are discussed.
Abstract: Toll-like receptors (TLRs) are involved in host defence against invading pathogens, functioning as primary sensors of microbial products and activating signalling pathways that induce the expression of immune and pro-inflammatory genes. However, TLRs have also been implicated in several immune-mediated and inflammatory diseases. As the immune system needs to constantly strike a balance between activation and inhibition to avoid detrimental and inappropriate inflammatory responses, TLR signalling must be tightly regulated. Here, we discuss the various negative regulatory mechanisms that have evolved to attenuate TLR signalling to maintain this immunological balance.
1,501 citations
TL;DR: This Review focuses on the recent advances in the understanding of the regulation, mechanism of action and functions of NFAT proteins in T cells.
Abstract: Since the discovery of the first nuclear factor of activated T cells (NFAT) protein more than a decade ago, the NFAT family of transcription factors has grown to include five members. It has also become clear that NFAT proteins have crucial roles in the development and function of the immune system. In T cells, NFAT proteins not only regulate activation but also are involved in the control of thymocyte development, T-cell differentiation and self-tolerance. The functional versatility of NFAT proteins can be explained by their complex mechanism of regulation and their ability to integrate calcium signalling with other signalling pathways. This Review focuses on the recent advances in our understanding of the regulation, mechanism of action and functions of NFAT proteins in T cells.
1,398 citations
TL;DR: The immunogenicity of antigens delivered by dendritic cells has now been shown in patients with cancer, and a better understanding of how dendrites regulate immune responses will allow us to better exploit these cells to induce effective antitumour immunity.
Abstract: Mouse studies have shown that the immune system can reject tumours, and the identification of tumour antigens that can be recognized by human T cells has facilitated the development of immunotherapy protocols. Vaccines against cancer aim to induce tumour-specific effector T cells that can reduce the tumour mass, as well as tumour-specific memory T cells that can control tumour relapse. Owing to their capacity to regulate T-cell immunity, dendritic cells are increasingly used as adjuvants for vaccination, and the immunogenicity of antigens delivered by dendritic cells has now been shown in patients with cancer. A better understanding of how dendritic cells regulate immune responses will allow us to better exploit these cells to induce effective antitumour immunity.
TL;DR: In this paper, the interplay between KIR and MHC class I polymorphisms has facilitated human survival in the presence of epidemic infections and has influenced both reproduction and population growth.
Abstract: MHC class I molecules are ligands for the killer-cell immunoglobulin-like receptors (KIRs), which are expressed by natural killer cells and T cells. The interactions between these molecules contribute to both innate and adaptive immunity. KIRs and MHC class I molecules are encoded by unlinked polymorphic gene families that distinguish all but the most related individuals. Combinations of MHC class I and KIR variants influence resistance to infections, susceptibility to autoimmune diseases and complications of pregnancy, as well as outcome after haematopoietic stem-cell transplantation. Such correlations raise the possibility that interplay between KIR and MHC class I polymorphisms has facilitated human survival in the presence of epidemic infections and has influenced both reproduction and population growth.
TL;DR: Gaining a better understanding of the crosstalk between dendritic cells and lymphatic vessels during the migration of d endritic cells to lymph nodes is essential for future advances in manipulating dendrite-cell migration as a means to fine-tune immune responses in clinical settings.
Abstract: Antigen-presenting dendritic cells often acquire foreign antigens in peripheral tissues such as the skin. Optimal encounter with naive T cells for the presentation of these antigens requires that the dendritic cells migrate to draining lymph nodes through lymphatic vessels. In this article, we review important aspects of what is known about dendritic-cell trafficking into and through lymphatic vessels to lymph nodes. We present these findings in the context of information about lymphatic-vessel biology. Gaining a better understanding of the crosstalk between dendritic cells and lymphatic vessels during the migration of dendritic cells to lymph nodes is essential for future advances in manipulating dendritic-cell migration as a means to fine-tune immune responses in clinical settings.
TL;DR: The studies that are being carried out to determine the respective contributions of infection, and monocyte and macrophage activation, to disease progression are discussed.
Abstract: HIV-associated dementia (HAD) is an important complication of the central nervous system in patients who are infected with HIV-1. Although the incidence of HAD has markedly decreased since it has become possible to effectively control viral replication in the blood by administering highly active antiretroviral therapy, a less severe form of HAD, comprising a milder cognitive and motor disorder, is now potentially a serious problem. Brain macrophages and microglia are the key cell types that are infected by HIV-1 in the central nervous system, and they are likely to mediate the neurodegeneration seen in patients with HAD; however, the precise pathogenesis of this neurodegeneration is still unclear. Here, we discuss the studies that are being carried out to determine the respective contributions of infection, and monocyte and macrophage activation, to disease progression.
TL;DR: There is now extensive evidence to support the direct involvement of interleukin-1 in the neuronal injury that occurs in both acute and chronic neurodegenerative disorders, and a rationale for targeting the interleuko-1 system as a therapeutic strategy is provided.
Abstract: Interleukin-1 is a pro-inflammatory cytokine that has numerous biological effects, including activation of many inflammatory processes (through activation of T cells, for example), induction of expression of acute-phase proteins, an important function in neuroimmune responses and direct effects on the brain itself. There is now extensive evidence to support the direct involvement of interleukin-1 in the neuronal injury that occurs in both acute and chronic neurodegenerative disorders. This article discusses the key evidence of a role for interleukin-1 in acute neurodegeneration - for example, stroke and brain trauma - and provides a rationale for targeting the interleukin-1 system as a therapeutic strategy.
TL;DR: The structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses are reviewed.
Abstract: Because the lungs function as the body's gas-exchange organ, they are inevitably exposed to air that is contaminated with pathogens, allergens and pollutants. Host-defence mechanisms within the lungs must facilitate clearance of inhaled pathogens and particles while minimizing an inflammatory response that could damage the thin, delicate gas-exchanging epithelium. Pulmonary surfactant is a complex of lipids and proteins that enhances pathogen clearance and regulates adaptive and innate immune-cell functions. In this article, I review the structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses.
TL;DR: It is now recognized that the ability of IL-23 to stimulate a unique T-cell subset to produce IL-17 has a dominant role in autoimmune inflammation and IL-27 has a role in limiting the intensity and duration of adaptive immune responses.
Abstract: Understanding the factors that influence T helper 1 (T(H)1)- and T(H)2-cell responses has been one of the main focuses of immunology for almost 20 years Whereas the central role of interleukin-12 (IL-12) in the generation of T(H)1 cells has long been appreciated, subsequent studies indicated that IL-23 and IL-27, two cytokines that are closely related to IL-12, also regulate T(H)1-cell responses However, as discussed in this article, it is now recognized that the ability of IL-23 to stimulate a unique T-cell subset to produce IL-17 has a dominant role in autoimmune inflammation By contrast, IL-27 has a role in limiting the intensity and duration of adaptive immune responses
TL;DR: This review focuses on the terminal differentiation of B cells into plasma cells, including the different subsets of B cell that become plasma cells), the mechanism of regulation of this transition, the transcription factors that control each developmental stage and the characteristics of long-lived plasma cells.
Abstract: Plasma cells are the terminally differentiated, non-dividing effector cells of the B-cell lineage. They are cellular factories devoted to the task of synthesizing and secreting thousands of molecules of clonospecific antibody each second. To respond to microbial pathogens with the necessary specificity and rapidity, B cells are exquisitely regulated with respect to both development in the bone marrow and activation in the periphery. This review focuses on the terminal differentiation of B cells into plasma cells, including the different subsets of B cells that become plasma cells, the mechanism of regulation of this transition, the transcription factors that control each developmental stage and the characteristics of long-lived plasma cells.
TL;DR: This Review describes how T cells actively acquire metabolic substrates from their environment to meet these energy demands and respond appropriately to pathogens.
Abstract: Ligation of antigen receptors at the surface of lymphocytes initiates a transcriptional and translational response that is required for cellular proliferation and effector function. By contrast, co-stimulatory-molecule ligation contributes to the immune response by allowing the uptake and utilization of extracellular nutrients to provide energy for cellular proliferation and effector functions. Growth factors also potentiate the ability of lymphocytes to metabolically switch between resting and proliferative states. Lymphocytes that do not receive these signals fail to increase their metabolism to meet the higher bioenergetic demands of cell growth and are either deleted or rendered unresponsive to mitogenic signals. In this Review, we describe how T cells actively acquire metabolic substrates from their environment to meet these energy demands and respond appropriately to pathogens.
TL;DR: Recent results that indicate that S1P and its receptors are required for the emigration of thymocytes from the thymus, the trafficking of lymphocytes in secondary lymphoid organs and the migration of B cells into splenic follicles are discussed.
Abstract: Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that transmits signals through a family of G-protein-coupled receptors to control cellular differentiation and survival, as well as the vital functions of several types of immune cell In this Review article, we discuss recent results that indicate that S1P and its receptors are required for the emigration of thymocytes from the thymus, the trafficking of lymphocytes in secondary lymphoid organs and the migration of B cells into splenic follicles In an autocrine manner, through interactions with different G-protein-coupled receptors, S1P also enhances optimal mast-cell migration and release of pro-inflammatory mediators in allergic reactions S1P–S1P-receptor regulatory systems might therefore be novel targets for the therapy of diverse immunological diseases
TL;DR: The evidence that regulatory T-cell function might be impaired in allergic and asthmatic disease and that certain therapeutic regimens might function, at least in part, to promote regulatoryT-cell generation is discussed.
Abstract: Allergic diseases are caused by aberrant T-helper-2 immune responses in susceptible individuals. Both naturally occurring CD4(+)CD25(+) regulatory T cells and inducible populations of antigen-specific interleukin-10-secreting regulatory T cells inhibit these inappropriate immune responses in experimental models. This article discusses the evidence that regulatory T-cell function might be impaired in allergic and asthmatic disease and that certain therapeutic regimens might function, at least in part, to promote regulatory T-cell generation. Current research strategies seek to exploit these observations to improve the generation of allergen-specific regulatory T-cell populations with the potential to provide the safe and long-term alleviation of disease symptoms.
TL;DR: A wealth of information indicates that marijuana-derived cannabinoids have immunosuppressive and anti-inflammatory properties, and on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.
Abstract: In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated. Recent studies in animal models and in humans have produced promising results for the treatment of various disorders — such as obesity, cancer, and spasticity and tremor due to neuropathology — with drugs based on marijuana-derived cannabinoids. Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.
TL;DR: This review describes BH3-only proteins, a pro-apoptotic subgroup of the BCL-2 family, and their role in the development and function of the immune system.
Abstract: Programmed cell death--also known as apoptosis--has a crucial role in the immune system of mammals and other animals. It removes useless cells and potentially dangerous cells, including lymphocytes, and is involved in killing pathogen-infected or damaged cells. Defects in this process have been found to cause or contribute to diseases of the immune system, including immunodeficiency, autoimmunity, lymphoma and leukaemia. This review describes BH3-only proteins, a pro-apoptotic subgroup of the BCL-2 family, and their role in the development and function of the immune system.
TL;DR: This Review article addresses the innate and adaptive immune mechanisms elicited during malaria that either cause or prevent disease and fatalities, and it considers the implications for vaccine design.
Abstract: Malaria is possibly the most serious infectious disease of humans, infecting 5-10% of the world's population, with 300-600 million clinical cases and more than 2 million deaths annually. Adaptive immune responses in the host limit the clinical impact of infection and provide partial, but incomplete, protection against pathogen replication; however, these complex immunological reactions can contribute to disease and fatalities. So, appropriate regulation of immune responses to malaria lies at the heart of the host-parasite balance and has consequences for global public health. This Review article addresses the innate and adaptive immune mechanisms elicited during malaria that either cause or prevent disease and fatalities, and it considers the implications for vaccine design.
TL;DR: Owing to their distinct homing preferences and helper function, these T cells differ from T helper 1 and T helper 2 cells and have been denoted follicular B helper T cells.
Abstract: T-cell help for B cells is essential for high-affinity antibody responses and B-cell memory. Recently, the identity of a discrete follicular population of T cells that has a crucial role in this process has become clearer. Similar to primed CD4(+) T cells in the tonsils and memory CD4(+) T cells in the peripheral blood, this follicular population of T cells expresses CXC-chemokine receptor 5 (CXCR5). Owing to their distinct homing preferences and helper function, these T cells differ from T helper 1 and T helper 2 cells and have been denoted follicular B helper T cells. Here, we outline the central role of this subset in normal and pathological immune responses.
TL;DR: Current understanding of the immune response to infection with Chlamydia spp.
Abstract: Sexually transmitted Chlamydia trachomatis infections are a serious public-health problem. With more than 90 million new cases occurring annually, C. trachomatis is the most common cause of bacterial sexually transmitted disease worldwide. Recent progress in elucidating the immunobiology of Chlamydia muridarum infection of mice has helped to guide the interpretation of immunological findings in studies of human C. trachomatis infection and has led to the development of a common model of immunity. In this review, we describe our current understanding of the immune response to infection with Chlamydia spp. and how this information is improving the prospects for development of a vaccine against infection with C. trachomatis.
TL;DR: Recent studies have provided new insight into the pathways that control the regulation of integrin activity and the coordination of complex cellular functions, such as the homing of lymphocytes and the formation of an immunological synapse.
Abstract: Since the discovery that integrins at the surface of lymphocytes undergo dynamic changes in their adhesive activity after stimulation through the T-cell receptor or stimulation with chemokines, intensive research has been carried out in an attempt to clarify the signalling events that lead to the activation of integrins. Whereas structural studies have provided us with a vivid picture of the conformational flexibility of integrins, the signalling pathways that regulate these conformational changes (known as inside-out signalling) have been elusive. However, as I discuss here, recent studies have provided new insight into the pathways that control the regulation of integrin activity and the coordination of complex cellular functions, such as the homing of lymphocytes and the formation of an immunological synapse.
TL;DR: The tetraspanin web represents a new concept of molecular interactions in the immune system that tends to associate with each other, together with their partners, in membrane microdomains that provide a scaffold for the transmission of external stimuli to intracellular-signalling components.
Abstract: The tetraspanin web represents a new concept of molecular interactions in the immune system. Whereas most surface immune-modulating molecules involve receptor-ligand interactions, tetraspanins associate with partner proteins and facilitate their lateral positioning in the membrane. Moreover, the same tetraspanin molecule can associate with different proteins depending on the cell type. Most importantly, members of this family tend to associate with each other, together with their partners, in membrane microdomains that provide a scaffold for the transmission of external stimuli to intracellular-signalling components.
TL;DR: This Review discusses the emerging consensus about which models of clonal deletion are most physiological, and it reviews recent data that define the molecular mechanisms of central tolerance.
Abstract: In the past few years, there has been a flurry of discoveries and advancements in our understanding of how the thymus prepares T cells to exist at peace in normal healthy tissue: that is, to be self-tolerant. In the thymus, one of the main mechanisms of T-cell central tolerance is clonal deletion, although the selection of regulatory T cells is also important and is gaining enormous interest. In this Review, we discuss the emerging consensus about which models of clonal deletion are most physiological, and we review recent data that define the molecular mechanisms of central tolerance.
TL;DR: Dendritic cells, long recognized as key initiators of primary adaptive immunity, are now also seen as crucial regulators of aspects of innate immunity, in particular natural-killer-cell function.
Abstract: Immune responses are generally divided into innate and adaptive responses, and the efficacy of one is thought to be independent of the other. The regulation of immune responses, however, is complex, and accumulating evidence indicates that multiple interactions between immune effector cells are common and are crucial for the initiation, as well as the outcome, of these responses. Dendritic cells, long recognized as key initiators of primary adaptive immunity, are now also seen as crucial regulators of aspects of innate immunity, in particular natural-killer-cell function. Reciprocally, natural killer cells can influence the activity of dendritic cells. Here, we review recent exciting progress in this field, and we highlight the impact of this cellular crosstalk on the design of immune-based therapies for control of infection and cancer.