The innate immune system in transplantation

The vertebrate innate immune system consists of inflammatory cells and soluble mediators that comprise the first line of defense against microbial infection and, importantly, trigger antigen-specific T and B cell responses that lead to lasting immunity. The molecular mechanisms responsible for microbial non-self recognition by the innate immune system have been elucidated for a large number of pathogens. How the innate immune system recognizes non-microbial non-self, such as organ transplants, is less clear. In this review, we approach this question by describing the principal mechanisms of non-self, or ‘damaged’ self, recognition by the innate immune system (pattern recognition receptors, the missing self theory, and the danger hypothesis) and discussing whether and how these mechanisms apply to allograft rejection.     

Identification and analysis of Toll-related genes in the domesticated silkworm, Bombyx mori

Silkworm (Bombyx mori), a model system for Lepidoptera, has contributed enormously to the study of insect immunology especially in humoral immunity. But little is known about the molecular mechanism of immune response in the silkworm. Toll receptors are a group of evolutionarily ancient proteins, which play a crucial role in the innate immunity of both insects and vertebrates. In human, Toll-like receptors (TLRs) are the typical pattern recognition receptors for different kinds of pathogen molecules. Toll-related receptors in Drosophila, however, were thought to function as cytokine receptors in immune response and embryogenesis. We have identified 11 putative Toll-related receptors and two Toll analogs in the silkworm genome. Phylogenetic analysis of insect Toll family and human TLRs showed that BmTolls is grouped with Drosophila Tolls and Anopheles Tolls. These putative proteins are typical transmembrane receptors flanked by the extracellular leucine-rich repeat (LRR) domain and the cytoplasmic TIR domain. Structural prediction of the TIR domain alignment found five stranded sheets and five helices, which are alternatingly joined. Microarray data indicated that BmToll and BmToll-2 were expressed with remarkable enrichment in the ovary, suggesting that they might play a role in the embryogenesis. However, the enriched expression of BmToll-2 and -4 in the midgut suggested that the proteins they encode may be involved in immune defense. Testis-specific expression of BmToll-10 and -11 and BmToLK-2 implies that these may be involved in sex-specific biological functions. The RT-PCR results indicated that 10 genes were induced or suppressed with different degrees after their immune system was challenged by different invaders. Expression profiles of BmTolls and BmToLKs reported here provide insight into their role in innate immunity and development.     

Hemocytes from the tobacco hornworm Manduca sexta have distinct functions in phagocytosis of foreign particles and self dead cells

Phagocytosis is an important innate immune response against microbial infections and an effective mechanism to eliminate apoptotic cells. In vertebrates, phagocytes such as macrophages and dendritic cells are involved in phagocytosis. We demonstrate here that insect hemocytes have distinct functions in phagocytosis of foreign particles and self dead cells. Plasmatocytes from the tobacco hornworm Manduca sexta were major hemocytes involved in phagocytosis of non-self microsphere beads, whereas granulocytes were apparently the only hemocytes that phagocytose self dead cells. We also showed that M. sexta immulectin-2, a pattern recognition receptor that protects larvae from bacterial infection, has an opsonic activity in phagocytosis. Immulectin-2 bound to the surface of granulocytes from the na?ve larvae, but more immulectin-2 bound to plasmatocytes when larvae were injected with microsphere beads. Coupling of immulectin-2 onto microsphere beads enhanced in vitro phagocytosis of the beads. Our results suggest that insect hemocytes can have specialized functions similar to vertebrate phagocytes in phagocytosis, and pattern recognition receptors may function as opsonins to enhance phagocytosis.     

Divergent roles for C-type lectins expressed by cells of the innate immune system

In recent years there has been increasing interest in the diversity and function of carbohydrates present on a range of endogenous mammalian glycoproteins and pathogen surfaces. It is clear that carbohydrate structures are not merely structural components of the molecules which bear them but are, in many instances, a source of information to be decoded by biological systems including the immune system. Macrophages and other antigen presenting cells express a variety of pattern recognition molecules which allow discrimination between self and non-self ligands and are well known for their ability to recognise and internalise foreign antigens. The role of carbohydrates as molecular determinants of self/non-self has been recognised for many years and a family of proteins known as the C-type lectins are implicated as the main players in carbohydrate recognition within the immune system. More recently, C-type lectin receptors which bind ligands other than carbohydrates have been identified, and there are additional receptors which bind both carbohydrate and non-carbohydrate ligands. In this review article we seek to shed light on the varied roles of this family of receptors, particularly those receptors expressed by antigen presenting cells and those with known ligands. We also review more recent data on several members of this family.     

Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity

Host cells trigger signals for innate immune responses upon recognition of conserved structures in microbial pathogens. Nucleic acids, which are critical components for inheriting genetic information in all species including pathogens, are key structures sensed by the innate immune system. The corresponding receptors for foreign nucleic acids include members of Toll-like receptors, RIG-I-like receptors, and intracellular DNA sensors. While nucleic acid recognition by these receptors is required for host defense against the pathogen, there is a potential risk to the host of self-nucleic acids recognition, thus precipitating autoimmune and autoinflammatory diseases. In this review, we discuss the roles of nucleic acid-sensing receptors in guarding against pathogen invasion, discriminating between self and non-self, and contributing to autoimmunity and autoinflammatory diseases.     

Role of scavenger receptors in dendritic cell function

Dendritic cells (DCs), the most potent of the antigen-presenting cells, are crucial in initiating and shaping innate and adaptive immune responses. DCs discriminate unmodified self antigens from non-self and altered/modified self antigens via a large family of receptors called pattern-recognition receptors, which include Toll-like receptors and scavenger receptors (SRs). Recent findings underscore the critical role of SRs on DCs in pathogen clearance, atherosclerosis, apoptotic cell recognition, diesel exhaust particle recognition, etc. These new findings present SRs as an unexplored therapeutic target that warrants further basic and applied research, and have implications for vaccine development. This review highlights recent insights into the emerging role of these receptors in DC-mediated immune responses.     

NOD蛋白与肺部疾病

天然免疫系统通过识别模式识别受体(patternrecognition receptors,PRR)介导的病原相关分子模式(pathogen-associated molecular patterns,PAMP)是抗微生物宿主防御的第1道防线,在机体感染早期发挥重要的保护性作用。在近来的研究中证实除Toll样受体(toll-like receptors,TLRs)     

Pattern recognition receptors in the immune response against dying cells

Pattern recognition receptors (PRR), immune sensors that discriminate self from non-self, link innate to adaptive immunity. PRR are involved in microbe internalization by phagocytes (soluble PRR and endocytic receptors) and/or cell activation (signaling PRR). PRR also recognize dying cells (i.e. modified self). Apoptotic cell recognition involves soluble bridging molecules (e.g. pentraxins) and endocytic receptors (e.g. scavenger receptors, the CD91-calreticulin complex). Apoptotic cells induce an immunosuppressive signal, avoiding the initiation of an autoimmune response. By contrast, necrotic cells, via the release of stimulatory molecules [heat shock protein (HSP), high-mobility group box 1 protein (HMGB1)], activate immune cells. This review summarizes the PRR involved in the recognition of dying cells and the consequences on the outcome of the immune response directed against dying cell antigens.     

Molecular diversity at the plant-pathogen interface

Plants have evolved a robust innate immune system that exhibits striking similarities as well as significant differences with various metazoan innate immune systems. For example, plants are capable of perceiving pathogen-associated molecular patterns through pattern recognition receptors that bear structural similarities to animal Toll-like receptors. In addition, plants have evolved a second surveillance system based on cytoplasmic "NB-LRR" proteins (nucleotide-binding, leucine-rich repeat) that are structurally similar to animal nucleotide-binding and oligomerization domain (NOD)-like receptors. Plant NB-LRR proteins do not detect PAMPs; rather, they perceive effector proteins that pathogens secrete into plant cells to promote virulence. This review summarizes the current state of knowledge about the molecular functionality and evolution of these immune surveillance genes.     

C1q and its growing family

C1q is the target recognition protein of the classical complement pathway and a major connecting link between innate and acquired immunity. As a charge pattern recognition molecule of innate immunity, C1q can engage a broad range of self and non-self ligands via its heterotrimeric globular (gC1q) domain and thus trigger the classical pathway. The trimeric gC1q signature domain has been identified in a variety of non-complement proteins that can be grouped together as a C1q family. The X-ray crystal structures of the gC1q domain of a few members of the C1q family reveal a compact jelly-roll beta-sandwich fold similar to that of the multifunctional tumor necrosis factor (TNF) ligand family, hence the C1q and TNF superfamily. This review is an update on the structural and functional aspects of the gC1q domain of human C1q. We also mention the diverse range of proteins that utilize a gC1q domain in order to reflect on its importance as a versatile scaffold to support a variety of functions.     

Sensing herpes: more than toll

To launch an effective antiviral immune response, cells must recognize the virus, activate a cytokine response, and initiate inflammatory processes. Herpes simplex virus 1 (HSV-1) and HSV-2 are nuclear-replicating viruses composed of a double-stranded DNA genome plus glycoproteins that are incorporated into a lipid bilayer envelope that surrounds an icosahedral capsid. Several novel receptors that mediate innate recognition of HSV and that activate the innate immune response have been identified in recent years. The host-virus interactions that lead to type I interferon (IFN), type III IFN, and cytokine production include cellular recognition of viral envelope and structural proteins, recognition of viral genomic DNA and recognition of virus-derived double-stranded RNAs. Such RNAs can interact with cellular pattern-recognition receptors, including Toll-like receptors and a number of cytoplasmic and nuclear receptors for virus DNA and virus-derived RNAs. In this review, I present a systematic overview of innate cellular recognition of HSV infection that leads to immune activation, and I discuss the implications of the known cell-host interactions. In addition, I discuss the use of innate stimulation to improve anti-HSV treatment and vaccine response and I discuss future research aims.     

Immunotherapeutic potential of CpG oligodeoxynucleotides in veterinary species

Abstract

Innate immunity plays a critical role in host defense against infectious diseases by discriminating between self and infectious non-self. The recognition of infectious non-self involves germ-line encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). The PAMPs are the components of pathogenic microbes which include not only the cell wall constituents but also the unmethylated 2′-deoxy-ribo-cytosine-phosphate-guanosine (CpG) motifs. These CpG motifs present within bacterial and viral DNA are recognized by toll-like receptor 9 (TLR9), and signaling by this receptor triggers a proinflammatory cytokine response which, in turn, influences both innate and adaptive immune responses. The activation of TLR9 with synthetic CpG oligodeoxynucleotides (ODNs) induces powerful Th1-like immune responses. It has been shown to provide protection against infectious diseases, allergy and cancer in laboratory animal models and some domestic animal species. With better understanding of the basic biology and immune mechanisms, it would be possible to exploit the potential of CpG motifs for animal welfare. The research developments in the area of CpG and TLR9 and the potential applications in animal health have been reviewed in this article.     

肽聚糖识别蛋白

天然免疫系统通过一系列高度保守的模式识别受体识别病原体相关分子模式.肽聚糖识别蛋白家族是重要的模式识别受体,从昆虫到人类均高度保守,可识别肽聚糖和含肽聚糖的细菌,在天然免疫和获得性免疫应答中发挥重要的识别和调节功能.     

Galectins in innate immunity: dual functions of host soluble β-galactoside-binding lectins as damage-associated molecular patterns (DAMPs) and as receptors for pathogen-associated molecular patterns (PAMPs)

Summary:  The glycocalyx is a glycan layer found on the surfaces of host cells as well as microorganisms and enveloped virus. Its thickness may easily exceed 50 nm. The glycocalyx does not only serve as a physical protective barrier but also contains various structurally different glycans, which provide cell- or microorganism-specific 'glycoinformation'. This information is decoded by host glycan-binding proteins, lectins. The roles of lectins in innate immunity are well established, as exemplified by collectins, dectin-1, and dendritic cell (DC)-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). These mammalian lectins are synthesized in the secretory pathway and presented on the cell surface to bind to specific glycan 'epitopes'. As they recognize non-self glycans presented by microorganisms, they can be considered as receptors for pathogen-associated molecular patterns (PAMPs), i.e. pattern recognition receptors (PRRs). One notable exception is the galectin family. Galectins are synthesized and stored in the cytoplasm, but upon infection-initiated tissue damage and/or following prolonged infection, cytosolic galectins are either passively released by dying cells or actively secreted by inflammatory activated cells through a non-classical pathway, the 'leaderless' secretory pathway. Once exported, galectins act as PRR, as well as immunomodulators (or cytokine-like modulators) in the innate response to some infectious diseases. As galectins are dominantly found in the lesions where pathogen-initiated tissue damage signals appear, this lectin family is also considered as potential damage-associated molecular pattern (DAMP) candidates that orchestrate innate immune responses alongside the PAMP system.     

Invertebrate Immunity: Another Viewpoint

All vertebrates and invertebrates manifest self/non-self recognition. Any attempt to answer the question of adaptive significance of recognition must take into account the universality of receptor-mediated responses. These may take two forms: (1) rearranging, clonally distributed antigen-specific receptors that distinguish in the broadest sense between self and non-self, and non-self A from non-self B, latecomers on the evolutionary scene; (2) pattern recognition receptors, the earliest to evolve and still around, necessitating the requirement for induced second signals in T- and B-cell activation. Either strategy need not force upon invertebrates the organization, structure and adaptive functions of vertebrate immune systems. Thus, we can freely delve into the unique aspects of the primitive immune mechanisms of invertebrates. In contrast, using the opposite strategy which is still problematic, i.e. linking invertebrate and vertebrate defence, seems to give us an approach to universality that might eventually reveal homologous kinship.     

哺乳动物固有免疫中肽聚糖识别蛋白研究进展

肽聚糖识别蛋白(PGRPs或PGLYRPs)是重要的识别细菌肽聚糖的模式识别受体之一,且从昆虫到哺乳动物高度保守.哺乳动物有4个PGRPs,它们分别表达于不同的细胞/组织.PGLYRP1、PGLYRP3和PGLYRP4具有抑杀细菌,而PGLYRP2水解肽聚糖的特性,最新研究表明PGLYRP2还具有促炎症的特性,其促炎症...     

On the origins of adaptive immunity: innate immune receptors join the tale

Among members of the Ig superfamily (IgSF), antigen receptors have the unique capacity to rearrange their variable domains, thereby creating an extensive repertoire for antigen recognition. It is assumed that antigen receptors evolved from a non-rearranging IgSF member by insertion of a transposable element. Although the nature of this predecessor is unknown, two multigene families of innate immune receptors that bear a close structural resemblance to antigen receptor chains have been identified in mammals and bony fish, respectively: signal-regulatory proteins (SIRPs) and novel immune-type receptors (NITRs). Members of both families encode V-set Ig domains with a typical antigen receptor-like joining (J) motif and possess the potential to signal through immunoreceptor tyrosine-based inhibition motifs (ITIMs) or immunoreceptor tyrosine-based activation motifs (ITAMs). By analogy to the T-cell receptor (TCR) and certain innate receptors [e.g. killer cell inhibitory receptors (KIRs)] that recognize MHC molecules, SIRP members regulate immune function by interaction with broadly expressed 'self' ligands. We propose the existence of an evolutionary and functional link between innate and adaptive immune receptors that sheds light on the nature of the antigen receptor predecessor(s).     

Pulmonary innate immune proteins and receptors that interact with gram-positive bacterial ligands

The two major gram-positive bacterial (GPB) ligands are peptidoglycan (PGN) and lipoteichoic acid (LTA). These polymeric LTA and highly organized PGN contain repeating carbohydrate moieties, which are potential targets for pattern recognition molecules. The major pattern recognition proteins and receptors, which bind GPB, either have a lectin, PGN recognition, collagen or leucine-rich repeat (LRR) domain. The soluble innate immune proteins (IIPs) that bind to PGN and LTA include pulmonary collectins surfactant-associated proteins (SP-) A and D, lectin-like pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP), and sCD14. Membrane-anchored lectin or lectin-like group members include macrophage mannose receptor (MR), complement receptor 3 (CR3, or Mac-1, or integrin CD11b/CD18), scavenger receptor A (SRCL-1), lectin-like oxidized LDL receptor 1 (LOX-1), and GPI-anchored CD14. Although Toll-like receptor (TLR) 2 and 4, and CD14 contain extracellular LRR domains, only TLRs have a cytoplasmic domain for signal transduction. Three of the four recently discovered human PGN recognition proteins (PGRP) have a transmembrane domain, and hence, considered as true receptors for GPB. Since lysozyme is the only known pulmonary enzyme that can lyse bacterial cell wall PGN, other innate immune molecules appear to be responsible for signalling and enhancing the clearance of GPB infection from the lung. Interestingly, pulmonary collectins bind not only to GPB ligands but also to the receptors, CD14 and TLR, and antigen processing cells such as dentritic cells. These complex interactions appear to play major roles in linking innate and adaptive immunity, and maintaining a pathogen-free lung with minimal, or no inflammation.