On regulation of phagosome maturation and antigen presentation

Phagocytosis has essential functions in immunity. Here we highlight the presence of a subcellular level of self-non-self discrimination in dendritic cells that operates at the level of individual phagosomes. We discuss how engagement of Toll-like receptor signaling controls distinct programs of phagosome maturation. An inducible mode of phagosome maturation triggered by these receptors ensures the selection of microbial antigens for presentation by major histocompatibility class II molecules during the simultaneous phagocytosis of self and non-self.     

The regulation of phagosome maturation in Dictyostelium

Macropinocytosis (fluid uptake) and phagocytosis (particle uptake) are processes that result in the formation of intracellular membrane enclosed vacuoles termed macropinosomes and phagosomes, respectively. Macropinosomes and phagosomes are modified by fission and fusion reactions with the endo-lysosomal pathway that eventually transform these vacuoles into a lysosomal environment. Many human bacterial pathogens, including species of Mycobacteria, Legionella, and Chlamydia, are thought to survive by disrupting the normal membrane trafficking events that usually result in the formation of phago-lysosomes and death of the microorganism. In addition, a number of important pathogens facilitate homotypic phagosome fusion in order to generate an intracellular environment conducive for survival. A greater understanding of the regulation of phagosomal maturation and fusion will be critical in designing new therapies to treat infections caused by intracellular pathogens. The genetically tractable phagocyte, D. discoideum, has proven extremely useful in dissecting the signaling pathways regulating macropinocytosis, phagocytosis, phagosomal maturation and phagosome–phagosome fusion. A body of knowledge has accumulated and demonstrates important roles for Rab GTPases, the cytoskeleton, phosphoinositide metabolism and pH regulation in regulating phagosome maturation. This review will summarize the current state of knowledge.     

Toll-like receptors

The toll-like receptors are innate immunity receptors which recognise particular exogenous structures in the microorganisms pathogen associated molecular pattern (PAMP) and endogenous structures damage-associated molecular patterns (DAMP). Eleven TLR have been identified among human beings. These are danger receptors located in the cells of the immune system but also in other cells. Their primary function is the recognition of pathogens and the activation of the cell that holds them. It follows from it an action on the cells environment, inflammation cells and an activation of the adaptive immunity. The knowledge of the intracellular signalisation ways of the TLR has allowed us to understand the physiopathology of certain diseases. Thus, several works use the agonists of TLR to stimulate them: vaccines against infectious diseases, allergies and cancers. The antagonists are used to block the TLR in autoimmune and chronic inflammatory diseases. It is clear that the border between innate and adaptive immunity fades and that these two components of the immune response are closely related, thus opening up new prospects diagnostic and therapeutic procedures.     

Phosphatidylinositol 3-kinases and their roles in phagosome maturation

Phagosome maturation is a highly organized and sequential process that results in the formation of a microbicidal phagolysosome. This results in crucial contributions to innate and adaptive immunity through pathogen clearance and antigen presentation. Thus, it is important to understand the regulatory networks that control the extent and nature of phagosome maturation. PI3Ks are lipid kinases that catalyze the phosphorylation of the 3' position of the inositol ring. This enzyme family is divided into three classes based on structure and substrate preferences. Previously, only the class III PI3K, hVps34, was thought to contribute to phagosome maturation. Recent evidence, however, suggests important contributions by class I PI3Ks in bringing about the diverse phagosome maturation phenotypes. Class I PI3Ks have also been implicated in the activation of Rab GTPases that function in maturation, such as Rab14. In addition, recent studies have illuminated the overlap between phagosome maturation and autophagy, which itself is regulated by multiple classes of PI3K. Taken together, a picture of phagosome maturation is emerging in which multiple classes of PI3Ks are involved in modulating maturation phenotypes. This review summarizes the known contributions of PI3Ks to phagosome maturation. Special emphasis is placed on the impact of PI3Ks on different maturation outcomes stemming from the engagement of diverse phagocytic receptors and on Rab and Ca(2+) signaling cascades.     

Toll-like receptors and autoimmunity

The understanding of autoimmune diseases experienced an impressive boost since the Toll-like receptors (TLRs) have been identified as possible key players in autoimmune pathophysiology. Although these receptors recognize a variety of structures derived from viruses, bacteria and fungi leading to subsequent initiation of the relevant immune responses recent data support the idea that TLRs are crucial in the induction and perpetuation of certain autoimmune diseases, especially the systemic lupus erythematosus (SLE). In this review we will summarize recent data on involvement of TLRs in the development of autoimmune diseases. This review will focus on TLRs 7, 8 and 9 which were originally identified as receptors specific for bacterial and viral RNA/DNA, but more recent in vitro and in vivo studies have linked these receptors to the detection of host RNA, DNA, and RNA- or DNA-associated proteins in the context of autoimmunity.     

Toll样受体与肥胖

肥胖是目前威胁人类健康的一种代谢性疾病。Toll样受体是一类重要的模式识别受体,参与肥胖慢性低度炎症状态的形成,并影响机体的物质代谢,在肥胖的发生发展过程中发挥一定的作用。明确Toll样受体与肥胖的关系,探究其中的免疫学机制,将给肥胖的治疗提供新的作用靶点。本文就TLR2、3、4、5、6、9与肥胖之间的关系作一简要综述。     

Toll-like receptors and atherosclerosis

The identification of Toll-like receptors (TLRs) as key patten-recognition receptors of innate immunity has opened inquiries into previously unknown disease mechanisms. The ability of TLRs to detect a spectrum of pathogen-derived molecules defines their importance in innate immunity and provides a mechanistic link between infection and disease. Atherosclerosis is a chronic inflammatory disease where immune and metabolic factors interact to initiate and propagate arterial lesions. An understanding of TLRs in atherosclerosis could clarify the etiology of this complex process. Furthermore, the existence of host-derived endogenous TLR ligands may implicate TLR involvement in disease mechanisms beyond innate immunity, such as a role in homeostatic mechanisms to resolve injury. Our current knowledge of TLRs in atherosclerosis is discussed in this review with emphasis on experimental studies in atherosclerosis-susceptible mouse models. Highlights from studies of TLR involvement in other disease processes have demonstrated that TLR-dependent mechanisms probably parallel those found in atherosclerosis, some of which could be important in mitigating atherosclerotic injury. Finally, an appreciation of the pro- and anti-atherosclerotic mechanisms of TLR activation over the entire lifetime of an organism will provide clues to the role of TLRs in both health and disease.     

Toll样受体与急性胰腺炎

急性胰腺炎（AP）是一个临床常见的疾病,在大多数病人是一个良性自限的病程,称为水肿性胰腺炎。而如果病情恶化,伴发胰腺的坏死,炎症细胞因子的活化,从而导致多器官功能衰竭,则称为坏死性胰腺炎。迄今为止,其详细的发病机理是不清楚的。作为固有免疫重要部分的Toll样受体（TLR）在胰腺炎过程中起重要的作用,但也有人提出异议。     

Toll-like receptors and the eye

PURPOSE OF REVIEW: This review will describe the structure, expression/distribution and functional activity of Toll-like receptors, in particular in the ocular structures. It will also discuss innate and adaptive immune responses, by exploring the possible modulation/regulation of innate and adaptive immunity by Toll-like receptors, in view of recent findings observed in the ocular surface. RECENT FINDINGS: Current knowledge indicates that Toll-like receptors represent essential elements in host defence against pathogens, a prerequisite to the induction of adaptive immune responses. The expression/distribution of Toll-like receptors in the healthy eye highlights the possible function of Toll-like receptors in both innate and adaptive responses during pathological conditions of the ocular surface. SUMMARY: Recent findings have greatly increased the knowledge of the possible role of Toll-like receptors in innate and adaptive immune responses. Toll-like receptors seem to play different roles in a wide range of activities of the immune system, and might represent an exclusive link between innate and adaptive responses under pathological conditions. Recent studies in ophthalmology have highlighted the role of Toll-like receptors in infections (keratitis) as well as in allergic states of the ocular surface. This review thus describes the relationship between Toll-like receptors and the main immune/structural cells taking part in inflammatory disorders. Understanding the complex mechanisms underlying Toll-like receptor localization and function will provide additional data that might help devise novel therapeutic approaches involving Toll-like receptors and their agonists, in an attempt to modulate the biased immune system.     

TLRs与同种异型移植排斥

Toll样受体(Toll-like receptors,TLRs)是一类在机体识别、清除入侵病原微生物免疫过程中起重要作用的受体.除此之外,新近的研究表明TLRs还参与同种异型移植过程中的排斥反应.本文就TLRs的这一进展进行了综述,内容包括TLRs的结构、功能和信号通路,TLRs与无菌性炎症,以及TLRs与皮肤、内脏移植排斥.     

Toll样受体与抗真菌免疫

Toll样受体（TLR）是固有免疫系统中特异的I型跨膜蛋白,能广泛识别细菌、真菌及病毒等表面保守的病原相关分子模式（PAMP）,传导炎症信号,介导多种生物学效应,是联系固有免疫和适应性免疫的桥梁。已证实TLR能够通过识别真菌表面某些PAMP,激活巨噬细胞和中性粒细胞的吞噬作用并释放各种炎性细胞因子,从而起到抗真菌作用。对TLR进一步深入研究将有可能为真菌感染性疾病的免疫治疗提供新的思路。     

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 and acquired immunity

Toll-like receptors are a family of pattern recognition receptors (PRRs) that evolved to detect microbial infection. These receptors recognize conserved molecular products derived from different classes of microorganisms, including Gram-positive and -negative bacteria, fungi, protozoa and viruses. Following recognition of ligands TLRs initiate signaling events that result in acute innate responses. In addition, TLRs are responsible for initiation of adaptive immune responses against pathogen-derived antigens primarily through triggering dendritic cell activation. Control of adaptive immunity by TLRs is a complex phenomenon and much needs to be understood about how different TLRs tailor the outcome of adaptive immune responses to the advantage of the host. Although TLRs have evolved to induce protective immune responses, under some circumstances, activation of these receptors may lead to autoimmune diseases.     

Toll样受体家族与肥胖性高血压

在许多发达国家中,约75%-80% 的高血压患者有不同程度肥胖,65% -75%的原发性高血压患者同时合并有肥胖.随着社会的发展,中国的肥胖性高血压(obesity-related hypertension)患病率也在逐年上升［1-3］.肥胖性高血压为多因疾病,对肥胖性高血压机制的相关研究已成为热点,其形成机制可能涉及胰岛素抵抗、血清脂联素、高瘦素血症、交感系统活化、肾素-血管紧张素系统(renin-angiotensin system, RAS)、凝血因子改变,炎症、内皮功能障碍等,但尚未达成广泛共识［4, 5］.现在越来越多的研究表明,Toll样受体家族（Toll-like receptors,TLRs）与其形成密切相关.深入探讨此种受体的作用,将为肥胖性高血压的治疗提供新的思路.     

Severe sepsis and Toll-like receptors

Severe sepsis dominates the mortality of non-cardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops. Severe sepsis may be a consequence of an inappropriately excessive response or inadequate endogenous negative feedback. Therapies targeting these pathways are currently being evaluated. Alternatively, in clinical scenarios such as compensatory anti-inflammatory response syndrome, chronic viral sepsis or inadequate vaccine function, TLR signalling may be inadequate. TLR agonists may augment the innate response and are being investigated.     

Toll-like receptors and innate antiviral responses

Toll-like receptors (TLRs) have a unique and important role in detecting the presence of pathogenic infection. TLRs can recognize conserved structures from a wide variety of microorganisms, such as bacteria, mycobacteria, spirochetes and yeast. However, they are generally not thought to play a major role in viral infection. Several reports have now identified distinct viral ligands for the TLRs, and evidence is accumulating for a functional role of the TLRs in mediating antiviral effector mechanisms.