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Showing papers in "Nature Reviews Immunology in 2004"


Journal ArticleDOI
TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

7,906 citations


Journal ArticleDOI
TL;DR: Professional phagocytes generate high levels of reactive oxygen species (ROS) using a superoxide-generating NADPH oxidase as part of their armoury of microbicidal mechanisms, leading to the concept that ROS are 'intentionally' generated in these cells with distinctive cellular functions related to innate immunity, signal transduction and modification of the extracellular matrix.
Abstract: Professional phagocytes generate high levels of reactive oxygen species (ROS) using a superoxide-generating NADPH oxidase as part of their armoury of microbicidal mechanisms. The multicomponent phagocyte oxidase (Phox), which has been well characterized over the past three decades, includes the catalytic subunit gp91phox. Lower levels of ROS are seen in non-phagocytic cells, but are usually thought to be 'accidental' byproducts of aerobic metabolism. The discovery of a family of superoxide-generating homologues of gp91phox has led to the concept that ROS are 'intentionally' generated in these cells with distinctive cellular functions related to innate immunity, signal transduction and modification of the extracellular matrix.

2,865 citations


Journal ArticleDOI
TL;DR: This review summarizes key recent developments and proposes a unifying model for the role of IDO in tolerance induction, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases.
Abstract: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.

2,184 citations


Journal ArticleDOI
TL;DR: Recent findings indicate that matrix metalloproteinases act on pro-inflammatory cytokines, chemokines and other proteins to regulate varied aspects of inflammation and immunity.
Abstract: As their name implies, matrix metalloproteinases are thought to be responsible for the turnover and degradation of the extracellular matrix. However, matrix degradation is neither the sole nor the main function of these proteinases. Indeed, as we discuss here, recent findings indicate that matrix metalloproteinases act on pro-inflammatory cytokines, chemokines and other proteins to regulate varied aspects of inflammation and immunity.

1,745 citations


Journal ArticleDOI
TL;DR: Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi.
Abstract: Fungal diseases represent an important paradigm in immunology, as they can result from either a lack of recognition by the immune system or overactivation of the inflammatory response. Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi. The fine line between these two research areas is central to our understanding of tissue homeostasis and its possible breakdown in fungal infections and diseases. Recent insights into immune responses to fungi suggest that functionally distinct mechanisms have evolved to achieve optimal host-fungus interactions in mammals.

1,528 citations


Journal ArticleDOI
TL;DR: In this article, the immunological mechanisms that initiate, sustain and suppress the fibrotic process were studied. But the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation.
Abstract: Tissue fibrosis (scarring) is a leading cause of morbidity and mortality. Current treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, target the inflammatory cascade, but they have been widely unsuccessful, largely because the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation. Several experimental models have recently been developed to dissect the molecular mechanisms of wound healing and fibrosis. It is hoped that by better understanding the immunological mechanisms that initiate, sustain and suppress the fibrotic process, we will achieve the elusive goal of targeted and effective therapeutics for fibroproliferative diseases.

1,466 citations


Journal ArticleDOI
TL;DR: The developing understanding of the far-reaching effects that the commensal flora have on mucosal and systemic immunity and their relevance to the effects of hygiene on human disease is described.
Abstract: Although we might shudder at the thought of billions of bacteria living in our lower intestine, we are colonized by these passengers shortly after birth. However, the relationship is mostly of mutual benefit, and they shape our immune system throughout life. Here, we describe our developing understanding of the far-reaching effects that the commensal flora have on mucosal and systemic immunity and their relevance to the effects of hygiene on human disease.

1,459 citations


Journal ArticleDOI
TL;DR: Several newly described co-inhibitory pathways in the B7–CD28 family are focused on, which control the priming, growth, differentiation and functional maturation of a T-cell response.
Abstract: Co-signalling molecules are cell-surface glycoproteins that can direct, modulate and fine-tune T-cell receptor (TCR) signals. On the basis of their functional outcome, co-signalling molecules can be divided into co-stimulators and co-inhibitors, which promote or suppress T-cell activation, respectively. By expression at the appropriate time and location, co-signalling molecules positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response. We are now beginning to understand the power of co-inhibitors in the context of lymphocyte homeostasis and the pathogenesis of human diseases. In this article, I focus on several newly described co-inhibitory pathways in the B7–CD28 family.

1,206 citations


Journal ArticleDOI
TL;DR: It is proposed that immune responses are initiated by pathogen-associated molecular patterns or by tissue-derived danger/alarm signals and these two groups of molecules might not be mutually exclusive.
Abstract: It is currently thought that immune responses are initiated by pathogen-associated molecular patterns or by tissue-derived danger/alarm signals. Here, we propose that these two groups of molecules might not be mutually exclusive. Many of them might be part of an evolutionarily ancient alert system in which the hydrophobic portions of biological molecules act, when exposed, as universal damage-associated molecular patterns to initiate repair, remodelling and immunity.

1,172 citations


Journal ArticleDOI
TL;DR: This perspective article seeks to clarify which cells fall under the NKT-cell umbrella, and which might be best considered as separate.
Abstract: Recent years have seen so-called natural killer T (NKT) cells emerge as important regulators of the immune response. The existence of NKT-cell subsets, and other types of T cell that resemble NKT cells, is an ongoing source of confusion in the literature. This perspective article seeks to clarify which cells fall under the NKT-cell umbrella, and which might be best considered as separate.

1,134 citations


Journal ArticleDOI
TL;DR: This article focuses on the functional consequences and recently described mechanisms of the dendritic-cell defects in cancer.
Abstract: The failure of the immune system to provide protection against tumour cells is an important immunological problem. It is now evident that inadequate function of the host immune system is one of the main mechanisms by which tumours escape from immune control, as well as an important factor that limits the success of cancer immunotherapy. In recent years, it has become increasingly clear that defects in dendritic cells have a crucial role in non-responsiveness to tumours. This article focuses on the functional consequences and recently described mechanisms of the dendritic-cell defects in cancer.

Journal ArticleDOI
TL;DR: Ongoing clinical studies indicate that CpG ODN use is safe in humans, and that they modulate the immune response to co-administered allergens and vaccines.
Abstract: Synthetic oligodeoxynucleotides (ODNs) that contain immunostimulatory CpG motifs trigger an immunomodulatory cascade that involves B and T cells, natural killer cells and professional antigen-presenting cells. The response to CpG ODNs skews the host's immune milieu in favour of T helper 1 (TH1)-cell responses and pro-inflammatory cytokine production — an effect that underlies their use as immunoprotective agents, vaccine adjuvants and anti-allergens. Preclinical studies provide evidence that CpG ODNs are effective for each of these uses. Ongoing clinical studies indicate that CpG ODN use is safe in humans, and that they modulate the immune response to co-administered allergens and vaccines.

Journal ArticleDOI
TL;DR: The instrumentation and considers the reagents, analysis and applications for this powerful, new extension of flow-cytometric technology.
Abstract: The increasing need for polychromatic approaches to flow cytometry, coupled with rapid technological advances, has pushed the frontiers of flow cytometry beyond 12-colour systems. Recent breakthroughs have allowed the design and implementation of instruments that measure 19 parameters (17 fluorescent colours and 2 physical parameters). This article describes the instrumentation and considers the reagents, analysis and applications for this powerful, new extension of flow-cytometric technology.

Journal ArticleDOI
TL;DR: This review focuses on the new understanding in mice and, where it is clear that related phenomena occur, in humans.
Abstract: The past decade has brought great strides in our understanding of adaptive immunity in neonatal mice. Although poor immune responses are commonly observed, it is now clear that mature function can be achieved by all arms of the adaptive immune system. An ever-increasing body of evidence indicates that the neonatal period of life is a unique developmental stage in which responses are highly plastic and dependent on the conditions of antigen exposure. This review focuses on our new understanding in mice and, where it is clear that related phenomena occur, in humans.

Journal ArticleDOI
TL;DR: The advances and controversy for a role of leptin in the pathophysiology of immune responses in several animal models of disease are reviewed.
Abstract: Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is sexually dimorphic — that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses.

Journal ArticleDOI
TL;DR: Findings suggest that T-cell immunity is readily elicited to various agents in the absence of IL-2 in vivo, and the action ofIL-2 on regulatory T cells and effector cells and the targeting of IL -2 and/or the IL-1 receptor in clinical settings are discussed.
Abstract: Interleukin-2 (IL-2) was identified based on its potent T-cell growth-factor activity and is widely considered to be a key cytokine in T-cell-dependent immune responses. However, the main non-redundant activity of this cytokine centres on the regulation of T-cell tolerance, and recent studies indicate that a failure in the production of CD4(+)CD25(+) regulatory T cells is the underlying cause of autoimmunity in the absence of IL-2. In marked contrast to the importance of IL-2 in peripheral T-cell tolerance, T-cell immunity is readily elicited to various agents in the absence of IL-2 in vivo. Here, we discuss these findings and, in particular, the action of IL-2 on regulatory T cells and effector cells, and the targeting of IL-2 and/or the IL-2 receptor in clinical settings.

Journal ArticleDOI
TL;DR: Studies of this intriguing immune-effector cell provide important insights into the complex mechanisms by which appropriate innate and acquired immune responses are initiated.
Abstract: Mast cells have mainly been studied in the setting of allergic disease, but the importance of mast cells for host defence against several pathogens has now been well established. The location of mast cells, which are found closely associated with blood vessels, allows them to have a crucial sentinel role in host defence. The mast cell has a unique 'armamentarium' of receptor systems and mediators for responding to pathogen-associated signals. Studies of this intriguing immune-effector cell provide important insights into the complex mechanisms by which appropriate innate and acquired immune responses are initiated.

Journal ArticleDOI
TL;DR: A torrent of studies characterizing the contributions of different cytokines, receptors, adaptors and effector molecules to resistance against infection with Listeria monocytogenes yield one of the most comprehensive pictures of the 'battle' between host and microorganism.
Abstract: Listeria monocytogenes is a Gram-positive bacterium that is often used to study the mammalian immune response to infection because it is easy to culture, is relatively safe to work with and causes a highly predictable infection in laboratory mice. The broad application of this mouse model has resulted in a torrent of studies characterizing the contributions of different cytokines, receptors, adaptors and effector molecules to resistance against infection with Listeria monocytogenes. These studies, which are yielding one of the most comprehensive pictures of the 'battle' between host and microorganism, are reviewed here.

Journal ArticleDOI
TL;DR: Similar to other aspects of immunity, their clonal expansion and survival depend on the activity of CD4+ T cells, although the mechanism(s) of 'help' for CTL responses is still debated.
Abstract: Cytotoxic T lymphocytes (CTLs) that express the CD8 co-receptor are the guided missiles of the immune system. They express clonally distributed receptors for foreign antigen, undergo marked proliferation in response to infection and kill any cell that expresses their target antigen. When an infection is cleared or brought under control, the progeny of these cytolytic effectors are retained as an essential component of immunological memory. As I discuss here, similar to other aspects of immunity, their clonal expansion and survival depend on the activity of CD4+ T cells, although the mechanism(s) of 'help' for CTL responses is still debated.

Journal ArticleDOI
TL;DR: The possibility that regulatory T cells can be both beneficial to the host, through limiting the immunopathology associated with anti-pathogen immune responses, and beneficial toThe pathogen, through subversion of the protective immune responses of the host is explored.
Abstract: Homeostasis in the immune system depends on a balance between the responses that control infection and tumour growth and the reciprocal responses that prevent inflammation and autoimmune diseases. It is now recognized that regulatory T cells have a crucial role in suppressing immune responses to self-antigens and in preventing autoimmune diseases. Evidence is also emerging that regulatory T cells control immune responses to bacteria, viruses, parasites and fungi. This article explores the possibility that regulatory T cells can be both beneficial to the host, through limiting the immunopathology associated with anti-pathogen immune responses, and beneficial to the pathogen, through subversion of the protective immune responses of the host.

Journal ArticleDOI
TL;DR: The interaction between the innate and adaptive immune systems in the skin as a model for immune function at epithelial-cell interfaces with the environment is discussed.
Abstract: The skin, as the primary interface between the body and the environment, provides the first line of defence against a broad array of microbial pathogens and trauma. In addition to its properties as a physical barrier, the skin has many active defence mechanisms. In this review, we discuss the interaction between the innate and adaptive immune systems in the skin as a model for immune function at epithelial-cell interfaces with the environment. How these mechanisms account for the robust nature of cutaneous immune surveillance and how their dysregulation drives the pathogenesis of inflammatory skin disorders and skin-based tumours are the subjects of this review.

Journal ArticleDOI
TL;DR: This review discusses the mechanisms for establishing and controlling the 'dialogue' between unresponsiveness and initiation of active immune defences in the gut.
Abstract: That we live with numerous bacteria in our gut without any adverse effects is a remarkable feat by the body's immune system, particularly considering the wealth of sensing and effector systems that are available to trigger inflammatory or innate immune responses to microbial intrusion So, a fine line seems to exist between the homeostatic balance maintained in the presence of commensal gut flora and the necessarily destructive response to bacterial pathogens that invade the gut mucosa This review discusses the mechanisms for establishing and controlling the 'dialogue' between unresponsiveness and initiation of active immune defences in the gut Si vis pacem, para bellum (If you wish for peace, prepare for war)

Journal ArticleDOI
TL;DR: A greater understanding of the differences between NALT and other organized lymphoid tissues, such as Peyer's patches, should facilitate the development of nasal vaccines.
Abstract: Recent studies indicate that the mechanism of nasopharynx-associated lymphoid tissue (NALT) organogenesis is different from that of other lymphoid tissues. NALT has an important role in the induction of mucosal immune responses, including the generation of T helper 1 and T helper 2 cells, and IgA-committed B cells. Moreover, intranasal immunization can lead to the induction of antigen-specific protective immunity in both the mucosal and systemic immune compartments. Therefore, a greater understanding of the differences between NALT and other organized lymphoid tissues, such as Peyer's patches, should facilitate the development of nasal vaccines.

Journal ArticleDOI
TL;DR: It is provocatively suggested that adult cancer results from rounds of disordered and unscheduled necrotic cell death, subsequent epithelial proliferation and the resulting suppressed immunity, rather than from a process that is dictated solely by cell growth.
Abstract: In children, cancer probably arises from a combination of inherited genetic mutations and genetic alterations that are acquired during the rapid cellular expansion that occurs during embryogenesis, and it is rarely associated with immune cell infiltrates. Conversely, in adults, cancer is frequently preceded by a long period of subclinical inflammatory disease and micronecrosis that provides a setting in which the epigenetic regulation of genes, cell death, cell proliferation and mutagenesis occurs. Here, we provocatively suggest that adult cancer results from rounds of disordered and unscheduled necrotic cell death, subsequent epithelial proliferation and the resulting suppressed immunity, rather than from a process that is dictated solely by cell growth. This paradigm shift regarding the development of cancer and this 'sixth sense' of the immune system indicates new strategies for cancer prevention and therapy.

Journal ArticleDOI
TL;DR: The potential for innate immune mechanisms directed against Plasmodium parasites both to contribute to protection from malaria and to modulate adaptive immune responses is considered.
Abstract: Malaria is a major cause of disease and death in tropical countries. A safe and effective vaccine is essential to achieve significant and sustained reductions in malaria-related morbidity and mortality. Driven by this need, research on the immunology of malaria has tended to focus on adaptive immunity. The potential for innate immune mechanisms to provide rapid protection against malaria has been largely neglected. On the basis of data from animal models, and clinical and epidemiological studies, this review considers the potential for innate immune mechanisms directed against Plasmodium parasites both to contribute to protection from malaria and to modulate adaptive immune responses.

Journal ArticleDOI
TL;DR: A powerful mechanism of vertebrate innate immunity has been discovered in the past year, in which APOBEC proteins inhibit retroviruses by deaminating cytosine residues in nascent retroviral cDNA, which might help to tip the balance in favour of cellular defences.
Abstract: A powerful mechanism of vertebrate innate immunity has been discovered in the past year, in which APOBEC proteins inhibit retroviruses by deaminating cytosine residues in nascent retroviral cDNA. To thwart this cellular defence, HIV encodes Vif, a small protein that mediates APOBEC degradation. Therefore, the balance between APOBECs and Vif might be a crucial determinant of the outcome of retroviral infection. Vertebrates have up to 11 different APOBEC proteins, with primates having the most. APOBEC proteins include AID, a probable DNA mutator that is responsible for immunoglobulin-gene diversification, and APOBEC1, an RNA editor with antiretroviral activities. This APOBEC abundance might help to tip the balance in favour of cellular defences.

Journal ArticleDOI
TL;DR: Several recent advances are focused on that address the required diversity for the generation of an optimal immune response in the thymus.
Abstract: In the thymus, a diverse and polymorphic T-cell repertoire is generated by random recombination of discrete T-cell receptor (TCR)-αβ gene segments. This repertoire is then shaped by intrathymic selection events to generate a peripheral T-cell pool of self-MHC restricted, non-autoaggressive T cells. It has long been postulated that some optimal level of TCR diversity allows efficient protection against pathogens. This article focuses on several recent advances that address the required diversity for the generation of an optimal immune response.

Journal ArticleDOI
TL;DR: The current knowledge of the mechanism of CSR is discussed, which seems to involve transcription-generated, higher-order RNA–DNA structures, specific DNA deamination and several DNA-repair pathways.
Abstract: Class-switch recombination (CSR) of immunoglobulin heavy chains is the genetic process by which a B cell switches from the production of IgM to the production of IgG, IgE or IgA. Although the general characteristics of CSR have been known for some time, the detailed molecular mechanism of this process is only now emerging. CSR is unique, in that it seems to involve transcription-generated, higher-order RNA–DNA structures, specific DNA deamination and several DNA-repair pathways. In this review, we discuss our current knowledge of the mechanism of CSR and highlight the important unanswered questions.

Journal ArticleDOI
TL;DR: The signals by which chemokines regulate the leukocyte-adhesion molecules that are essential for transendothelial migration are discussed, and the routes taken by monocytes and myeloid dendritic cells to reach their final destination are described.
Abstract: Because of their phagocytic activity and their ability to differentiate into antigen-presenting cells, monocytes participate in both innate and adaptive immune responses. They derive from bone-marrow progenitor cells, circulate in the blood as monocytes and differentiate into tissue macrophages or myeloid dendritic cells in the periphery. After activation by an antigenic challenge in the tissues, they can contribute to the local resolution of the injury or can migrate farther to secondary lymphoid organs. Recruitment of these cells from the blood to the tissue and from the tissue to the lymph nodes requires orchestrated adhesive interactions between leukocytes and the vascular or lymphatic endothelium. Here, we discuss the signals by which chemokines regulate the leukocyte-adhesion molecules that are essential for transendothelial migration, and we describe the routes taken by monocytes and myeloid dendritic cells to reach their final destination.

Journal ArticleDOI
TL;DR: The present understanding of how classical and new immunosuppressive agents interfere with dendritic cells development and function is reviewed to provide a rational basis for the selection of immunOSuppressive drugs in different clinical settings and for the generation of tolerogenic DCs in the laboratory.
Abstract: Immunosuppressive drugs have revolutionized organ transplantation and improved the therapeutic management of autoimmune diseases. The development of immunosuppressive drugs and understanding of their action traditionally has been focused on lymphocytes, but recent evidence indicates that these agents interfere with immune responses at the earliest stage, targeting key functions of dendritic cells (DCs). Here, we review our present understanding of how classical and new immunosuppressive agents interfere with DC development and function. This knowledge might provide a rational basis for the selection of immunosuppressive drugs in different clinical settings and for the generation of tolerogenic DCs in the laboratory.