先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展.特别是在关于模式识别受体的发现和功能研究方面.模式识别受体能识别病原相关的分子模式.先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活.如果没有先天免疫,后天获得性免疫的功能会变得很微弱.Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展.特别是在关于模式识别受体的发现和功能研究方面.模式识别受体能识别病原相关的分子模式.先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活.如果没有先天免疫,后天获得性免疫的功能会变得很微弱.Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展。特别是在关于模式识别受体的发现和功能研究方面。模式识别受体能识别病原相关的分子模式。先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活。如果没有先天免疫,后天获得性免疫的功能会变得很微弱。Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体。激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达。所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗。     

Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells

The innate immune system deploys a variety of pattern-recognition receptors (PRRs) which include Toll-like receptors (TLRs), RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors to detect the invasion of pathogens and initiate protective responses. The intercellular and intracellular orchestration of signals from different PRRs, their endogenous or microbial ligands and accessory molecules determine the stimulatory or inhibitory responses. Progressing over the last two decades, considerable research on the molecular mechanisms underlying host–pathogen interactions has led to a paradigm shift of our understanding of TLR signaling in the innate immune system. Given that a significant amount of evidence implicates TLRs in the pathogenesis of immune diseases and cancer, and their activation occurs early in the inflammatory cascade, they are attractive targets for novel therapeutic agents. In this review, we discuss the recent advances in TLR signaling cross talks and the mechanism of pathogen recognition with special emphasis on the role of TLRs in tumor immunity and TLR-targeted therapeutics.     

Pattern recognition receptors

Immunity is based on self/nonself discrimination. In vertebrates, two major systems, innate and adaptive immune systems, constitute host defense against invading microbes. Adaptive immunity is characterized by specific immune responses through B- or T-cell antigen receptors that are generated by somatic recombination, whereas nonspecific responses to microbes had been accentuated in innate immunity. However, the discovery of pattern recognition receptors (PRRs) that are encoded in the germ-line, including Toll-like receptors, RIG-I-like receptors, NOD-like receptors and AIM2-like receptors, advanced our understanding of a mechanism for innate immune recognition. These types of PRR recognize pathogen- or damage-associated molecular patterns (PAMPs or DAMPs) during infection or tissue damage, and commonly evoke the downstream gene induction programme, such as expression of type I interferons, inflammatory cytokines and chemokines. Dysregulation of PRR-triggered signal activation leads to pathologic inflammatory responses. In this regard, it has been shown that many of "autoinflammatory diseases", recently defined clinical entity, have putatively causative mutations in the genes that encode PRRs or their signaling mediators. In this review article, we describe recent overview of PRRs as innate sensors and update knowledge of "autoinflammatory diseases" particularly by focusing on their association with innate signaling.     

The microbiome and cytosolic innate immune receptors

The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune-mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host-environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide-binding domain, leucine-rich repeat-containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)–like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid-inducible gene-I (RIG-I)–like receptors (RLRs), cyclic GMP-AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host-microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.     

Pattern recognition receptors: sentinels in innate immunity and targets of new vaccine adjuvants

The innate immune system plays an essential role in the host's first line of defense against microbial invasion, and involves the recognition of distinct pathogen-associated molecular patterns by pattern recognition receptors (PRRs). Activation of PRRs triggers cell signaling leading to the production of proinflammatory cytokines, chemokines and Type 1 interferons, and the induction of antimicrobial and inflammatory responses. These innate responses are also responsible for instructing the development of an appropriate pathogen-specific adaptive immune response. In this review, the focus is on different classes of PRRs that have been identified, including Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and the retinoic acid-inducible gene-I-like receptors, and their importance in host defense against infection. The role of PRR cooperation in generating optimal immune responses required for protective immunity and the potential of targeting PRRs in the development of a new generation of vaccine adjuvants is also discussed.     

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.     

Toll-like receptors in innate immunity

Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.     

Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins

Pattern-recognition receptors (PRRs) detect molecular signatures of microbes and initiate immune responses to infection. Prototypical PRRs such as Toll-like receptors (TLRs) signal via a conserved pathway to induce innate response genes. In contrast, the signaling pathways engaged by other classes of putative PRRs remain ill defined. Here, we demonstrate that the beta-glucan receptor Dectin-1, a yeast binding C type lectin known to synergize with TLR2 to induce TNF alpha and IL-12, can also promote synthesis of IL-2 and IL-10 through phosphorylation of the membrane proximal tyrosine in the cytoplasmic domain and recruitment of Syk kinase. syk-/- dendritic cells (DCs) do not make IL-10 or IL-2 upon yeast stimulation but produce IL-12, indicating that the Dectin-1/Syk and Dectin-1/TLR2 pathways can operate independently. These results identify a novel signaling pathway involved in pattern recognition by C type lectins and suggest a potential role for Syk kinase in regulation of innate immunity.     

Toll样受体2和Toll样受体4在免疫应答衣原体感染中的作用

衣原体是重要的人类病原体,其能够导致多种疾病的发生.由衣原体引起的许多人类疾病被认为是免疫病理学介导的.已经证明Toll样受体(TLRs)是多种病原体感染的主要模式识别受体( PRRs),在起始固有免疫应答,建立适应性免疫应答中发挥着重要作用.在TLR家族中,TLR2和TLR4与衣原体感染的相关性研究备受关注,在识别衣原体感染、调节宿主的早期免疫应答、炎症反应和病理形成中执行着关键性的作用.研究TLR2和TLR4在免疫应答衣原体感染中的作用可以更好地理解TLRs介导的分子免疫机制,可能有助于研发免疫治疗的分子靶标,最终有效预防、控制衣原体感染引起的疾病.     

Innate signaling and regulation of Dendritic cell immunity

Dendritic cells are crucial in pathogen recognition and induction of specific immune responses to eliminate pathogens from the infected host. Host recognition of invading microorganisms relies on evolutionarily conserved, germline-encoded pattern-recognition receptors (PRRs) that are expressed by DCs. The best-characterized PRR family comprises the Toll-like receptors (TLRs) that recognize bacteria or viruses. In addition to TLRs, intracellular Nod-like receptors and the membrane-associated C-type lectins (CLRs) function as PRRs. Many of these innate receptors also have an important function in natural host homeostatic responses, such as the maintenance of gut homeostasis. Clearly, more indications are hinting at a fine-tuning of immune responses by a concerted action of these PRRs on the recognition of pathogen components and the consequent signalling events that are created. It is becoming increasingly clear that these PRRs can initiate specific signalling events that modulate the production of inflammatory cytokines, phagocytosis, intracellular routing of antigen, release of oxidative species and DC maturation and the subsequent development of adaptive immunity. Notably, members within one family of PRRs can trigger opposite signalling features, indicating that the ultimate outcome of pathogen-induced immune responses depends on the pathogen signature and the collective PRRs involved.     

Toll-like receptors: networking for success

The innate immune system is essential for host defense and is responsible for early detection of potentially pathogenic microorganisms. Upon recognition of microbes by innate immune cells such as macrophages and dendritic cells, diverse signaling pathways are activated that combine to define inflammatory responses that direct sterilization of the threat and/or orchestrate development of the adaptive immune response. Innate immune signaling must be carefully controlled, and regulation comes in part from interactions between activating and inhibiting signaling receptors. Toll-like receptors (TLR) have recently emerged as key receptors responsible for recognizing specific conserved components of microbes including lipopolysaccharides from Gram-negative bacteria, CpG DNA, and flagellin. Full activation of inflammatory responses by TLR may require the assembly of receptor signaling complexes including other transmembrane proteins that may influence signal transduction. In addition to TLR, many additional receptors participate in innate recognition of microbes, and recent studies demonstrate strong interactions between signaling through these receptors and signaling through TLR. Useful models for these interacting signaling pathways are now emerging and should pave the way for understanding the molecular mechanisms that drive the rich diversity of inflammatory responses.     

Intracellular Roles of Microbial Aminotransferases: Overlap Enzymes Across Different Biochemical Pathways

Microbial challenges to the host initiate an array of defense processes through the activation of innate and adaptive immunity. Innate immunity consists of sensors or pattern-recognition receptors (PRRs) that are expressed on immune and non-immune cells and sense conserved pathogen-derived molecules or pathogen-associated molecular patterns (PAMPs) in various compartments of the host cells. Recognition of the PAMPs by PRRs triggers antimicrobial effector responses via the induction of proinflammatory cytokines and type I IFNs. Several families of PRRs, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and DNA sensors and their respective PAMPs have been well studied in innate immunity and host defense. Here, we review the recent findings on bacterial recognition by TLRs and NLRs and the signaling pathways activated by these sensors.     

Highlights of the advances in basic immunology in 2011

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells.     

Toll-like receptor]

Toll-like receptors (TLRs) have been revealed to recognize specific patterns of microbial components. Recognition of microbial components by TLRs initiates signal transduction pathways, triggering expression of genes, which products control innate immune responses and further instruct development of antigen-specific acquired immunity. TIR domain-containing adaptors, such as MyD88, TIRAP, TRIF, and TRAM, play pivotal roles in TLR signaling pathways. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. TLR-mediated activation of innate immunity, when in excess, leads to immune disorders such as inflammatory bowel diseases. Therefore, several mechanisms that negatively control TLR signaling pathways and thereby prevent overactivation of innate immunity have been elucidated. Nuclear IkappaB proteins, such as Bcl-3 and IkappaBNS, have been revealed to be responsible for this process, by differentially inhibiting TLR-dependent cytokine production.     

The Emerging Role of the Receptor for Advanced Glycation End Products on Innate Immunity

Cells from innate immune system are activated by the engagement of germ-line encoded pattern-recognition receptors (PRRs) in response to the microbial insult. These receptors are able to recognize either the presence of highly conserved microbial components called pathogen-associated molecular patterns or endogenous danger-associated molecular patterns. These danger signals are recognized by different types of (PRRs), including the receptor for advanced glycation end products. This new PRR share both ligands and intracellular signaling with Toll-like receptors and thus may cooperate with each other as essential partners to strength inflammatory response. This review summarizes recent advances in understanding the promiscuity of this receptor as well as its role in the context of innate immunity by triggering an inflammatory response when innate immune cells detect infection or tissue injury.     

Direct and indirect role of Toll-like receptors in T cell mediated immunity

Toll-like receptors (TLR) are pathogen-associated molecular patterns (PAMPs) recognition receptors that playan important role in protective immunity against infection and inflammation.They act as central integrators ofa wide variety of signals,responding to diverse agonists of microbial products.Stimulation of Toll-like receptorsby microbial products leads to signaling pathways that activate not only innate,but also adaptive immunity byAPC dependent or independent mechanisms.Recent evidence revealed that TLR signals played a determiningrole in the skewing of na(?)ve T cells towards either Th1 or Th2 responses.Activation of Toll-like receptors alsodirectly or indirectly influences regulatory T cell functions.Therefore,TLRs are required in both immuneactivation and immune regulation.Study of TLRs has significantly enhanced our understanding of innate andadaptive immune responses and provides novel therapeutic approaches against infectious and inflammatorydiseases.Cellular & Molecular Immunology.2004;1(4):239-246.