Toll样受体在先天性免疫反应中的作用

先天性免疫识别侵袭的微生物,引起宿主防御反应.然而,先天性免疫识别的分子机制还不清楚.最近,有人发现了Toll样受体家族(TLRs),并阐明了这些受体在微生物识别中的主要作用.TLR基因家族包括11个成员,也可能更多.每种引起TLR先天性免疫反应的微生物类型各不相同.先天性免疫的激活引起特定抗原获得性免疫的发展.因此,TLRs控制先天性免疫反应和获得性免疫反应.     

Roles of Toll-like receptors in innate immune responses

Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses.     

Genetic variations in toll-like receptor pathway genes influence asthma and atopy

Innate immunity is a pivotal defence system of higher organisms. Based on a limited number of receptors, it is capable of recognizing pathogens and to initiate immune responses. Major components of these innate immunity pathogen recognition receptors are the toll-like receptors (TLRs), a family of 11 in humans. They are all membrane bound and through dimerization and complex downstream signaling, TLRs elicit a variety of specific and profound effects. In recent years, the role of TLRs signaling was not only investigated in infection and inflammation but also in allergy. Fuelled by the hygiene hypothesis, which suggests that allergies develop because of a change in microbial exposure and associated immune signals early in life, it had been speculated that alterations in TLRs signaling could influence allergy development. Thus, TLR genes, genetic variations of these genes, and their association with asthma and other atopic diseases were investigated in recent years. This review provides an overview of TLR genetics in allergic diseases.     

Innate immunity: from lymphocyte mitogens to Toll-like receptors and back

Innate immunity, our inborn immediate defence mechanism, was thought for a long time to be non-specific and, consequently, research into innate mechanisms often took second place to research into adaptive immunity. In recent decades, however, the spotlight has shone on groundbreaking advances into mechanisms of innate immunity; from the hypothesis that mitogen receptors distinguish between 'self' and 'very-different-from-self' in the mid-1970s to the refining of the concept by Janeway in 1989, the identification of Toll-like molecules as mitogen receptors, and finally the cloning of the first mammalian Toll-like receptor (TLR) in 1997. We now know that innate immune activation has a role in the control of adaptive immune responses, and many more TLRs and their ligands have been characterised.     

蚯蚓与固有免疫

动物的免疫系统包括固有免疫和适应性免疫.固有免疫是指动物机体与生具有的抵御微生物或者外来异物侵袭的能力,包括组织屏障作用、细胞免疫作用和体液免疫作用.固有免疫细胞识别病原体表面的模式分子而活化,经特殊信号转导途径产生免疫效应.蚯蚓属无脊椎动物,其免疫系统缺乏免疫球蛋白,适应性免疫不发达,主要依赖固有免疫机制来抵御微生物的感染.     

Innate immunity to herpes simplex virus type 2

Herpes simplex virus type 2 (HSV-2) is responsible for most cases of genital herpes and also can cause fatal disseminated disease in perinatally infected newborns. Sexually transmitted infections initiate in the skin or mucosa and quickly spread into peripheral nerves to establish latency. Innate immunity, the first line of defense during both primary and recurrent infection, is essential during this period of acute infection to limit initial viral replication and to facilitate an appropriate adaptive immune response. The innate immune response consists of a complex multilayered system of mechanical and secreted defenses, immediate chemokine and IFN responses, and rapidly recruited cellular defenses. HSV has devised equally elaborate strategies to evade or interfere with innate immunity. This review summarizes our current understanding of the innate immune responses to HSV-2 and the mechanisms by which HSV-2 can overcome these barriers. Newly emerging links between products of innate responses and the development of adaptive immune responses are also discussed.     

Innate immune memory in mammals

Innate and adaptive immunity have evolved as sophisticated mechanisms of host defence against invading pathogens. Classically the properties attributed to innate immunity are its rapid pleiotropic response, and to adaptive immunity its specificity and ability to retain a long-term memory of past infections. It is now clear that innate immunity also contributes to raising a memory response upon pathogenic assault. In this review we will discuss the interaction between bacterial, viral, fungal and parasitic molecular patterns and innate immune cells in which a memory response is imposed, or has the potential to be imposed.     

Molecular mechanisms of innate immunity

All species require a rapid, systemic reply to pathogens in their environment. This response is known as the innate immune response and is characterized by de novo synthesis of mediators that directly or indirectly through phagocytosis remove and kill the pathogen. Innate immune responses have been preserved throughout evolution and have been studied in detail in organisms from the fruit fly Drosophila melanogaster to humans. In my laboratory, studies performed during the past 25 yr have focused on defining the molecular basis of innate immune responses to microbial pathogens. Specifically, we have used bacterial endotoxin (lipopolysaccharide) as a model stimulus to define how the innate immune system recognizes products of microbial pathogens and initiates responses to remove and/or kill such organisms. Such studies also serve as models to understand more fully the mechanisms underlying a serious human disease known as septic shock. This article discusses septic shock and its relationship to innate immunity.     

Innate immunity in experimental SIV infection and vaccination

Innate immunity represents the first line of defence to pathogens besides the physical barrier and seems to play a role in protection against HIV/SIV infection and disease progression. High production of beta-chemokines and CD8+ T cell anti-viral factors in naive as well as in vaccinated macaques has been associated with complete or partial protection against SIV infection indicating that genetic or environmental factors may influence their production. This innate immunity may help in generating HIV/SIV-specific responses upon the first exposure to HIV/SIV. SIV subunit vaccines given by the targeted iliac lymph node route have been shown to induce an increased production of CD8+ T cell suppressor factors and beta-chemokines. Only a few vaccine studies have focused on enhancing the innate immune response against HIV/SIV. The use of unmethylated CpG motifs, HSP and GM-CSF as adjuvants in SIV vaccines has been shown to induce production of HIV/SIV-inhibiting cytokines and beta-chemokines, which seem to be important in modulating and steering the adaptive immune responses. HSP has also been shown to induce gammadelta+ T cells, which contribute to the innate immunity. More knowledge about the interplay between the innate and adaptive immune responses is important to develop new HIV/SIV vaccine strategies.     

Innate immunity in allergy

Innate immune system quickly responds to invasion of microbes and foreign substances through the extracellular and intracellular sensing receptors, which recognize distinctive molecular and structural patterns. The recognition of innate immune receptors leads to the induction of inflammatory and adaptive immune responses by activating downstream signaling pathways. Allergy is an immune‐related disease and results from a hypersensitive immune response to harmless substances in the environment. However, less is known about the activation of innate immunity during exposure to allergens. New insights into the innate immune system by sensors and their signaling cascades provide us with more important clues and a framework for understanding allergy disorders. In this review, we will focus on recent advances in the innate immune sensing system.     

Toll-like receptors and innate immunity

The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses, and play a major role in innate immunity. However, TLRs recognize pathogens either on the cell surface or in the lysosome/endosome compartment. Recently, cytoplasmic PRRs have been identified to detect pathogens that have invaded cytosols. In this review, we focus on the functions of PRRs in innate immunity and their downstream signaling cascades.     

Translating Inhibitory Fc Receptor Biology into Novel Therapeutic Approaches

Innate and adaptive immune responses represent well balanced reactions aimed at resolving microbial infections without causing major collateral damage to the host. Disturbances in this system either due to enhanced activating or decreased inhibitory signaling pathways may lead to excessive immune activation resulting in tissue damage, the induction of autoimmune disease and/or chronic inflammation. On the molecular level this balance is achieved by the integration of inhibitory and activating signals, which are delivered by pairs of activating and inhibitory cell surface receptors expressed on innate and adaptive immune cells. The regulation of immunoglobulin G activity through cellular Fc receptors is a prime example for this type of regulation. This is not only relevant for the regulation of antibody-mediated effector functions through innate immune effector cells but also for the regulation of B cell activation and antibody production itself.     

Innate immunity in vertebrates: an overview

Innate immunity is a semi‐specific and widely distributed form of immunity, which represents the first line of defence against pathogens. This type of immunity is critical to maintain homeostasis and prevent microbe invasion, eliminating a great variety of pathogens and contributing with the activation of the adaptive immune response. The components of innate immunity include physical and chemical barriers, humoral and cell‐mediated components, which are present in all jawed vertebrates. The understanding of innate defence mechanisms in non‐mammalian vertebrates is the key to comprehend the general picture of vertebrate innate immunity and its evolutionary history. This is also essential for the identification of new molecules with applications in immunopharmacology and immunotherapy. In this review, we describe and discuss the main elements of vertebrate innate immunity, presenting core findings in this field and identifying areas that need further investigation.     

The innate immune system and HIV pathogenesis

Innate immunity represents the first line of defense against microbial infections. The innate immune system is activated by conserved structures present on most pathogens and profoundly regulates subsequent adaptive immune responses. HIV is notorious for evading and disrupting the immune system. Although HIV directly targets and gradually destroys the adaptive immunity, it has become clear that the virus also perturbs the components of the innate immune system. In this paper, we review the role of two innate lymphocyte subsets, natural killer and natural killer T cells, that are disrupted during HIV infection.     

Innate immune functions of microglia isolated from human glioma patients

Background  

Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM).     

Innate immune sensing of retroviral infection via Toll-like receptor 7 occurs upon viral entry

Innate immune sensors are required for induction of pathogen-specific immune responses. Retroviruses are notorious for their ability to evade immune defenses and establish long-term persistence in susceptible hosts. However, some infected animals are able to develop efficient virus-specific immune responses, and thus can be employed for identification of critical innate virus-sensing mechanisms. With mice from two inbred strains that control retroviruses via adaptive immune mechanisms, we found that of all steps in viral replication, the ability to enter?the host cell was sufficient to induce antivirus humoral immune responses. Virus sensing occurred in endosomes via a MyD88-Toll-like receptor 7-dependent mechanism and stimulated virus-neutralizing immunity independently of type I interferons. Thus, efficient adaptive immunity to retroviruses is induced in?vivo by innate sensing of the early stages of retroviral infection.     

Regulatory T cells and innate immune regulation in tumor immunity

Innate and adaptive immunity play important roles in immunosurveillance and tumor destruction. However, increasing evidence suggests that tumor-infiltrating immune cells may have a dual function: inhibiting or promoting tumor growth and progression. Although regulatory T (Treg) cells induce immune tolerance by suppressing host immune responses against self- or nonself-antigens, thus playing critical roles in preventing autoimmune diseases, they might inhibit antitumor immunity and promote tumor growth. Recent studies demonstrate that elevated proportions of Treg cells are present in various types of cancers and suppress antitumor immunity. Furthermore, tumor-specific Treg cells can inhibit immune responses only when they are exposed to antigens presented by tumor cells. Therefore, Treg cells at tumor sites have detrimental effects on immunotherapy directed to cancer. This review will discuss recent progress in innate immunity, Treg cells, and their regulation through Toll-like receptor (TLR) signaling. It was generally thought that TLR-mediated recognition of specific structures of invading pathogens initiate innate and adaptive immune responses through dendritic cells. New evidence suggests that TLR signaling may directly regulate the suppressive function of Treg cells. Linking TLR signaling to the functional control of Treg cells opens intriguing opportunities to manipulate TLR signaling to control both innate and adaptive immunity against cancer.An erratum to this article can be found at     

IRAK-4--a shared NF-kappaB activator in innate and acquired immunity

The human body is protected against external pathogens by two immune systems: innate and acquired immunities. Whereas innate immunity exhibits immediate responses to external pathogens by recognizing pathogen-associated molecular patterns (PAMPs), adaptive immunity uses T cells to recognize and defend against pathogens by developing effector cells, antibodies and memory cells. Although each system seems to possess distinct activation mechanisms, interleukin-1 receptor-associated kinase (IRAK)-4 is essential for NF-kappaB activation in Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. This implies possible crosstalk between innate and acquired immunities, and evolutionary development that resulted in the use of innate signaling molecules by the acquired immune system. Here, we discuss the impact of these evolutionarily conserved molecules on innate and acquired immunity, and their potential as drug targets for the simultaneous modulation of both immunities.     

Complexities of targeting innate immunity to treat infection

Innate immunity is an ancient form of host defence that is activated rapidly to enable, through a multiplicity of effector mechanisms, defence against a broad spectrum of microbial threats. From this perspective, innate immunity has desirable characteristics of a therapy against infections, and, as a consequence, the innate immune system has become a major target for the development of therapeutics to control inflammation and immune defences. Although advances in the field have come at a furious pace, and several companies are advancing the first Toll-like receptor-based drugs, there remain many unanswered questions about innate immunity and maintaining balance in the immune response. Indeed, innate immunity represents an enormously complex network of molecules, pathways and interactions, controlled by multiple positive and negative regulatory proteins, which are starting to be evaluated in more depth using systems biology approaches. However, accompanying the protective mechanisms is the production of pro-inflammatory cytokines such that, if excessive amplification of innate immunity occurs, there is the potential for such syndromes as sepsis and chronic inflammation.