key: cord-0007962-y93jzlvo authors: Mukhopadhyay, Subhankar; Plüddemann, Annette; Gordon, Siamon title: Macrophage Pattern Recognition Receptors in Immunity, Homeostasis and Self Tolerance date: 2009-12-29 journal: Target Pattern Recognition in Innate Immunity DOI: 10.1007/978-1-4419-0901-5_1 sha: 245c33aeb57537aa2cb1bd4c06012714278b733d doc_id: 7962 cord_uid: y93jzlvo Macrophages, a major component of innate immune defence, express a large repertoire of different classes of pattern recognition receptors and other surface antigens which determine the immunologic and homeostatic potential of these versatile cells. In the light of present knowledge of macrophage surface antigens, we discuss self versus nonself recognition, microbicidal effector functions and self tolerance in the innate immune system. The common basic fearures of any functional immune systems are: (i) ability to distinguish self tissues from microbial invaders (self vs nonself recognition), (ii) mount an appropriate effector response to kill or contain microbial infection, and perhaps most imponantly, (iii) spare the host tissues from potentially hazardous effector responses (self tolerance). All known immune systems, however primitive or advanced, show these three basic characteristics. 1 However, the ability ofthe immune system to recognize and respond to foreign materials or tolerate self components is not absolute; these functions operate robustly within a given range, as normal physiology, beyond which dysfunction leads to immune pathology. Susceptibility to infection, immunopathology and autoimmunity are probably extreme examples in a spectrum of immune failure. The molecular basis for immune recognition, response and tolerance is relatively well-studied in adaptive immunity of vertebrates, but such research was neglected in innate immunity until recently, despite the fact that most species rely solely on innate immunity to achieve these core immune functions. Innate immunity lacks most of the basic molecular machinery employed by the adaptive system such as somatically rearranged high affinity antigen receptors used by lymphocytes and thymic education ofT cells for central tolerance, indicating the presence of a fundamenrally different mechanism in innate immunity. The first major conceptual breakthrough came when Janeway proposed that cells of the innate immune system express a large repertoire of germ-line encoded receptors which recognize invariant molecular structures on pathogens, which are essential and unique to pathogens and not present in the host. He coined the term pathogen associated molecular patterns (PAMPs) for such molecular structures, recognised by pattern recognition receptors (PRR). PRRs are further subdivided into intracellular or cell surface molecules. Humoral PRRs generally recognise pathogens from various body fluids and form aggregates which are subsequently cleared by phagocytes. Apart from this opsonising ability they also have many immunomodulatory properties. Cell surface PRRs are either phagocytidendocytic or sensor in nature. Phagocytic receptors bind and internalise ligands directly and display temperature dependent, saturable and inhibitable ligand binding kinetics of classical receptors. On the other hand sensors do not bind or internalise ligand directly, but recognise PAMPs and induce a proinflammatory signalling cascade which leads to many antimicrobial effector responses. It is important to note that many intracellular PRRs are also sensing molecules. 4 A schematic diagram of different classes ofPRRs and selected examples are presented in Figure 1 . There is recent evidence that components of the cellular and humoral arms of the innate immune system collaborate to induce and maintain host defence. 5 . 6 Although amendments have been recently proposed to the original concept of pattern recognition, this remains fundamental to our present understanding ofinnate immunity. "Molecular patterns" are not restricted to pathogens, but are also expressed by commensals; it has been argued that microbial ligands should be characterised molecularly, in preference to introducing the term PAMp' 7 Although not clearly stated, it could be extrapolated from Janeway's proposal that self tolerance is achieved in innate immunity through "ignorance" as PRRs only recognize microbial molecules. This is in contrast to adaptive immunity where tolerance is achieved by "education". This theory of ignorance is challenged by recent observations that many PRRs recognize modified host molecules (generated during normal or aberrant metabolism) as well as naturally occurring host molecules, other than microbial structures. 8 It is conceivable that during evolution multipurpose PRRs were selected to recognize microbial molecules to counter infectious challenges, modified host molecules for clearing, homeostasis and natural host molecules for immunomodulation, thus minimizing the genetic resources invested in immunity. In this chapter we will discuss how PRRs differentially recognize microbial, modified host molecules as well as natural host molecules using examples from two major classes of PRRs, class A scavenger receptors and C type lectin families. We also speculate how tolerance is achieved in innate immunity. Inlracellwr -cyaolic NOD -lile receptors (NLR) Figure 2 . Different members of the class A scavenger receptor family. The scavenger receptor All II (SR-A), macrophage receptor with collgenous structure (MARCO) and scavenger receptor with C-type lectin-I/II (SRCL) all are three members ofthe class ASR family. Both SR-Aand SRCL have two functional isforms, where the C terminus of SR-AII and SRCL-II are truncated. SR-A was the first member identified in this family, subsequently MARCO and SRCL were included in this family due to their structural similarities with SR-A. SR-A is aType II trans-membrane glycoprotein which shows multi-domain protein structure with a short cytoplasmic tail, transmembrane region, followed by an extracellular spacer region, an a helical coiled coil region, a collagenous domain and a C terminal scavenger receptor cysteine-rich (SRCR) domain. Although MARCO and SRCL share a similar domain organization to that of SR-AI, the only differences are that MARCO lacks an a_helical coiled coil domain and possesses a longer collagenous domain; in the case of SRCL-I, the SRCR domain is replaced by aC-type lectin domai n. Functionally, all three receptors show overlapping ligand binding properties and contribute to varied functions. The scavenger receptors were functionally defmed by Brown and Goldstein for their ability to bind and internalise modified low density lipoprotein (mLOL) such as oxidised LOL (Ox-LOL), acetylated LOL (Ac-LOL), but not native LOL. 9 Subsequendy a variety ofartificial and natural polyanionic ligands including many micro-organisms and apoptotic cells were identified as ligands for SRs. After Brown and Goldstein's first proposal a large number of unrelated distinct gene products were identified which bind mLOL. Krieger and coUeagues classified these molecules (classes A-F) according to their similarities in multi-domain protein structure. lO Recendy several new molecules have been identified and cwo new classes (G and H) added to this list to accommodate novel structural features, totalling 8 independent structural classes of SR which possess common functional criteria.11 In this chapter we wiu restrict our discussion to class A SR family ( Fig. 2 and refer to Table 1 ). SR-A was the flISt molecule in this class to be cloned. Three alternatively spliced variants (SR-AI/II and III) of the same gene have been identified which are collectively called SR-A. Among these three splice variants SR-AIII is non functional and trapped in the endoplasmic reticulum. So far, no functional difference has been observed between SR-AI and II. SR-A is a Type II trimeric transmembrane glycoprotein molecule with a cytoplasmic tail, transmembrane region, followed by an extracellular spacer region, an a helical coiled coil region, a collagenous domain and a C terminal scavenger receptor cysteine-rich (SRCR) domain. The SRCR domain is absent in SR-AII and III. The collagenous domain is responsible for ligand binding, but the cytoplasmic tail is required for endocytosis and phagocytosis of ligand or adhesion to ligand-rich substrata.12 Macrophage receptor with collagenous structure (MARCO) and scavenger receptor with C type lectin I (SRCL-I) are the other two members of the class A SR family which share a similar domain organization to that of SR-AI. The only differences are that MARCO lacks an a helical coiled coil domain and possesses a longer collagenous domain; in the case of SRCL-I, the SRCR domain is replaced by a C-type lectin domain. It has been proposed that similarly to SR-AI, SRCL-I binds Ox-LDL through its collagenous region, but exhibits additional sugar binding properties through the C-We lectin domain. In contrast, MARCO may recognise ligands through its SRCR region. 13,1 The first evidence that SR-A can recognise nonself microbial components came with the observation that SR-A could bind the lipid-A portion of lipopolysaccharide (LPS) and lipoteichoic acid (LTA).15 Furthermore, different LTA structures showed differential specificity depending on their exposed negative charge available to SR-A. 16 Another bacterial component CpG DNA, has also been reported to be recognised by SR-A, but its immunostimulatory effect is independent of SR-A. 17 confirmed that SR-A mediated recognition of Neisseria mmingitidis is LPS-independent, indicating the presence of nonLPS ligands for SR-A. 22 Recently we have identified several surface proteins on N mmingitidis which are ligands for SR-A, providing evidence for unmodified protein ligands for SR-A (Peiser and Gordon submitted). As mentioned earlier, SR-A was first identified by its ability to bind mLDL. Subsequently, several other modified self molecules were identified as SR-A ligands which are generated during normal or aberrant metabolism. SR-A recognises~amyloid proteins, a hallmark of Alzheimer's disease, and contributes to the inflammatory nature of this disease by recruitment and adhesion of Mcjl. Similarly, SR-A contributes to inflammatory pathology by recognising advanced glycation end products (AGE) generated during diabetes. In contrast, SR-A contributes to phagocytosis of apoptotic cells inducing a profound anti-inflammatory response. 23 • 24 Fraser et al first described the presence of a natural ligand for SR-A in human and bovine serum which allows divalent cation-independent adhesion ofMcjl to tissue-culture plastic through SR_A. 25 Presently our group is involved in identifying the chemical nature and physiological role of this serum ligand. Similarly, another unidentified natural ligand for SR-A has been reported on activated B cells, but its physiological relevance is unknown. 26 Functional binding studies confirmed that SR-A and MARCO not only share very similar structural features, but also show similar ligand binding properties. Similarly to SR-A, MARCO also binds several Gram-positive and negative organisms or their isolated products such as LPS or CpG DNA.27 Infectious challenge with the lung pathogen Streptococcus pneumoniae confirmed that MARCO· I • mice display an impaired ability to clear pneumococcal infection, resulting in increased pulmonary inflammation and reduced survival, confirming a role ofMARCO in antibacterial protection. 28 Recently we have reponed that like SR-A, MARCO also recognises Neisseria independent of LPS. 29 Furthermore, we identified several Neisseria' surface proteins as potential nonLPS ligands for MARCO, distinct from those that bind SR-A (Mukhopadhyay & Gordon, unpublished observation). Other than microbial pathogens, MARCO also binds and protects the host from a range of nonself environmental pollutants such as TI0 2 and asbestos. 3o MARCO has been reported to bind modified self ligands such as Ox-LDL and Ac-LDL. MARCO expression is induced in murine atherosclerotic plaques, but its exact role in the pathogenesis of atherosclerosis remains to be determined. 31 The presence of natural or selfligand(s) for MARCO has been reponed on subsets ofsplenic marginal zone B cells. Blockade of this cell-cell interaction confirmed that it is critical for development and retention of the marginal zone microarchitecture in rodent spleen. 32 Similarly, MARCO· I • animals showed defects in splenic microarchitecture, with significant immunological consequences. 33 Uteroglobin related protein -1 (UGRP-I), a secreted protein expressed by lung clara cells, has been shown to be another endogenous ligand for MARCO. UGRP-I also binds to bacteria and therefore may act as an opsonin which increases MARCO-mediated clearance ofbacteria. 34 Recently cwo groups independently cloned a novel member of the class A SR family from a human placental eDNA library, designated as SRCL-I (scavenger receptor with C-type lectin) and CLP-I (Collectin from placenta-I), respectively. As mentioned earlier, this molecule differs from SR-AI by its C terminal C-type lectin domain in place of a SRCR domain. One group also identified a C terminal truncated form of this molecule which lacks the C-type lectin domain and displays a very similar structUre to that of SR-AII. These studies showed that SRCL-I transfectants bind Gram-positive and negative bacteria, as well as yeast and Ox-LDL in a polyanion sensitive manner. Fungal recognition by SRCL-I is not observed with other class A SR family molecules and possibly occurs through the lectin domain. 35 .36 The C-type lectin domain showed specificity for GalNac type glycoconjugates which is inhibitable by free GaiNac, L-o-fucose and o-galactose. SRCL-I has also been shown to bind T and Tn an!igens, cwo carcinoma associated autoantigens which display distinct modified glycosylation. 37 The C-type lectin receptor (CLR) family is made up of a wide range of receptors that are defined in part by their ability to bind carbohydrate molecules (Fig. 3 ).4 They can be divided into three groups, (1) the C-type lectins containing a single carbohydrate recognition domain (CRD), (2) the C-type leerins containing multiple CRDs and (3) the NK-like C-type lectin-like receptors (NKCL) which have a single CRD. The classical C-type lectins require calcium for binding, however the NKCL receptors differ from the other two groups in that their C-type lectin domains (CTLD) lack the residues involved in calcium binding. Members of the C-type leetins with a single CRD are Type II membrane receptors and include DC-51GN and Deetin-2. C-type lectins containing multiple CRDs are Type I membrane receptors and include the mannose receptor (MR), Endol80, DEC-205 and the phospholipase A2 receptorY The Type II membrane receptors termed NK-like C-type lectin-like receptors include Dectin-1, CD69 and LOX-l (reviewed in reE 4). Most of these receptors recognise both endogenous and exogenous molecules, self and nonself ligands. A few examples of CLRs and their binding propenies will be discussed in the following section. This group ofreceptors is made up ofDC-SIGN and related molecules. DC-SIGN (CD209) was originally described to be involved in the adhesion ofT-cells to dendritic cells via the intercellular adhesion molecule 3 (ICAM-3) and therefore the receptor was designated dendritic cell-specific lCAM-grabbing nonintegrin. 42 The receptor has since also been shown to playa role in DC migration via lCAM-2, a molecule that is highly expressed on vascular and lymphoid endothelium. 43 DC-SIGN is a terrarneric endocytic receptor consisting ofa single CTDL, a stalk region, a transmembrane domain and a cytoplasmic tail containing an internalisation moti£4 It generally recognises N-linked high mannose structures as well as fucose-containing glycans, but also discriminates between ligands on the basis ofsecondary binding sites. 44 The key to selective interaction with pathogens may be in the close proximity of the four CROs which bind closely spaced glycans, as clusters ofeither mannose-type or fucose-type ligands are not common in endogenous molecules. This receptor has been shown to be involved in the recognition of various pathogens including viruses such as HIV-l, HCMV'; Hepatitis C, Dengue and Ebola, as well as Myco~ rium tuberculosis, Candida albicans, Leishmania mtxicana, Htucobaeter pylori and Schistosoma manson; (Table 2) 52 Recently it has been shown that DCs interact with neutro~hils via DC-SIGN-mediated binding to the nonsialylated Lewis' antigen on Mac-l ofthese cells. 3Since activated neurrophils induce DC maturation which in turn triggers the T-cell response, this indicates that neurrophils may contribute to adaptive immune responses via their interaction with DCs, providing a cellular link between innate and adaptive immunity. The structure of these receptors includes an N-terminal cysteine-rich domain, a domain containing fibronectin Type II repeats, multiple extracellular CTLDs, a transmembrane domain and a short cytoplasmic tailY The best characterised receltor in this group is the mannose receptor (MR) (CD206). This receptor is a 180-kDa Ca +-dependent lectin that functions as an endocytic receptor and has been shown to bind bacteria, viruses and yeasts ( Table 2 ).54 MR specifically binds terminal mannose, fucose, N-acetylglucosarnine or glucose residues which allow it to distinguish nonselffrom selfas these moieties are commonly found on microorganisms, but not in terminal positions on mammalian cell surface oligosaccharides or serum glycoproteins. 55 On alveolar macrophages, for example, the mannose receptor has been identified as a pattern recognition receptor capable of NF-KB activation in response to the fungus Pntumocystis. 56 The ligand on Pneumocystis carinii mediating interaction with the mannose receptor was shown to be the major mannose-rich surface antigen complex termed glycoprotein A (gpA).57 This receptor has also been implicated in nonopsonic binding ofanother fsathogenic fungus, C albicans, most likely via mannose residues on the fungal surface. 58 . 9 The cysteine-rich domain has been shown to bind endogenous glycoproteins via their sulphated N-acetylgalaetosamine or galactose moieties 60 and this receptor has been implicated in the clearance of serum glycoproteins to maintain homeostasis. 61 On dendritic cells, the mannose receptor plays a role in binding to MUCl, an aberrantly glycosylated membrane protein that is highly expressed on tumour cells and is released into the circulation. 62 These receptors typically possess a single extracellular carbohydrate binding domain (CI1..D), a stalk region, a transmembrane domain and a cytoplasmic tail with or without signalling motifs. 4 Some receptors in this family contain cysteine residues in the stalk region which are involved in homo-or heterodimerization. Dectin-I is a small (~28 kDa) Type-II membrane receptor with a single extracellular C-type lectin-like domain and a cytoplasmic domain with a tyrosine-based activation motif. 63 .64 Carbohydrate recognition is independent of calcium. It recognises a variety of IJ-I ,3-linked and IJ-I,6-linked glucans and thus binds and promotes phagocytosis of yeasts such as Saccharomyces cerevisiae and C. albicans. 63 • 65 In alveolar macrophages, Dectin-l has been shown to bind the fungus P. carinii. 66 In contrast to the mannose receptor, it does not recognise monosaccharides or carbohydrates with different linkages. Dectin-l has also been shown to interact with an endogenous ligand on activated T-cells, although the identity of this ligand is as yet unknown. 67 SelfTolerance in Innate Immunity In recent years there has been significant progress in the field of innate recognition and antimicrobial host defence. However, our knowledge concerning induction of tolerance in the innate immune system is still rudimentary and the role of PRRs in tolerance induction is not clear. It is proposed that microbes express ligands for both phagocytic and sensing PRRs which simultaneously engage these two classes of receptors and induce full scale antimicrobial responses. However, phagocytic receptors possibly recognise natural or modified selfmolecules in the absence ofTLR stimulation, resulting in a tolerogenic outcome. Recognition of modified self molecules by phagocytic receptors can also lead to inflammatory responses such as recognition of mLDL or IJ amyloid protein by SR-A It is conceivable that in such aberrant metabolic conditions, TLR agonists are also produced which promote a dual signal through SR-A and TLR Other than PRR mediated recognition several other possible mechanisms for tolerance induction have been proposed in innate immunity. Our first mechanistic insight concerning tolerance induction in the innate system came from studies on activatory and inhibitory natural killer (NK) cell receptors. NK eells express a range ofITAM containing inhibitory receptors which recognise MHC class I molecules which are present in all nucleated cells of the body as a marker ofself, sparing them from killing. On the other hand, if MHC-I expression is absent or reduced, as in the case of viral infection or tumour cells, NK cells recognise them as foreign. However, "missing self' alone does not determine the target cell killing and virus-infected or tumour cells also express ligands for many activatory receptors present on NK cells, which initiate the killing machinery. Therefore absence of MHC-I as a self marker and presence of ligands for activatory NK cell receptors together act as a switch for cytotoxic activity ofNK cells. 88 Inhibitory receptor-mediated self tolerance is also observed in the Mep system. SIRP-a (CDIna) is a predominantly myeloid restricted molecule ofthe immunoglobulin superfamily (IGSF), whereas its ligand CD47 is more broadly expressed, including on myeloid cells. CD Ina contains three extracellular Ig-like domains; its intracellular domain contains several tyrosines and has been shown to interact with the tyrosine phosphatases SHPI and SHP2. This inhibits Mep activation, such as the response to growth factors or phagocytosis via Fc or complement receptors. Recently Oldenborg et al showed that CD4T'red blood cells are rapidly cleared by splenic red pulp Mep after infusion in wr animals. CD47 expression on wr RBC prevents such elimination by binding to the inhibitory molecule, CD Ina. Thus Mep rely on the presence or absence of CD47 to distinguish self from foreign. 89 CD200 and CD200R are both members of the IGSF and contain two Ig domains each in their extracellular region. CD200 has a very shon cytoplasmic domain and is unable to signal. In contrast, CD200R contains several tyrosine phosphorylation sites in its relatively longer cytoplasmic tail. CD200 is reponed to be expressed by a broad range ofcells including neurones, but not by myeloid cells. On the other hand CD200R expression is restricted to myeloid cells, particularly M$. Interaction between CD200 and CD200R induces an inhibitory signal through CD200R to M$.90 Knowledge ofthe physiologic relevance ofCD200-CD200R interaction in vivo came from studies ofCD200-1 -animals. NaIve CD200-Ianimals constitutively show some degree ofmyeloid expansion and M$ activation. However, CD200· 1 • animals show much faster disease progression and significandy more susceptibility to several autoimmune diseases, such as collagen induced experimental allergic encephalomyelitis (EAE), which is a mouse model for the human disease, multiple sclerosis. 91 In recent years our understanding has improved significandy about how innate PRRs recognise nonself, modified self and self molecules and how an appropriate inflammatory response is mounted against microbes. Our knowledge has grown, concerning how initial recognition by PRRs instructs the shape and nature of protective adaptive responses against microbes. However, knowledge is still sketchy about how discriminatory responses are induced against self and nonself molecules and how successful pathogens evade innate recognition and responses by PRRs. Future research should study the mechanistic differences between tolerance induction in innate and adaptive immunity. Why is autoimmunity predominandy associated with adaptive rather than innate immune responses? Does innate immunity instruct the regulatory functions of adaptive immunity? Recent advances in molecular and cellular biology make it possible to study new aspects of innate immunity and to understand the causes of many infectious and immune pathologies. 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The macrophage receptor MARCO The scavenger receptor MARCO is required for lung defense against pneumococcal pneumonia and inhaled particles an innate activation marker of macrophages, is a class A scavenger receptor for Neisseria meningitidis Role of the scavenger receptor MARCO in alveolar macrophage binding of unopsonized environmental particles Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone Defective microarchitecture of the spleen marginal zone and impaired response to a thymus-independent type 2 antigen in mice lacking scavenger receptors MARCO and SR-A Identification of uteroglobin-related protein 1 and macrophage scavenger receptor with collagenous structure as a lung-specific ligand-receptor pair Molecular cloning of a mouse scavenger receptor with Ctype lectin (SRCL)(I), a novel member of the scavenger receptor family The membrane-type collectin CL-Pl is a scavenger receptor on vascular endothelial cells SRCLlCL-PI recognizes GalNAc and a carcinoma-associated antigen, Tn antigen Class A scavenger receptors and the phagocytosis of apoptotic cells Characterization of recombinant soluble macrophage scavenger receptor MARCO Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages The mannose receptor family Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking Structural basis for distinct ligand-binding and targeting properties of the receptors DCSIGN and DC-SIGNR Curting edge: Carbohydrate profiling identifies new pathogens that interact with dendritic cell-specific ICAM-3-grabbing nonintegrin on dendritic cells Distinct functions of DC-SIGN and its homologues L-SIGN (DC-SIGNR) and mSIGNRl in pathogen recognition and immune regulation The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells A variant in the CD209 promoter is associated with severity of dengue disease A fatal attraction: Mycobacterium tuberculosis and HIV-l target DC-SIGN to escape immune surveillance Mycobacteria target DC-SIGN to suppress dendritic cell function Dendritic cells recognize tumor-specific glycosylation of carcinoembryonic antigen on colorectal cancer cells through dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegtin Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-l and DC-SIGN Normal host defense during systemic candidiasis in mannose receptor-deficient mice Charactetization of ligand binding to a carbohydrate-recognition domain of the macrophage mannose receptor Pneumocystis activates human alveolar macrophage NF-kappaB signaling through mannose receptors Pneumocystis carinii glycoprotein A binds macrophage mannose receptors Molecular characterization of the human macrophage mannose receptor: Demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-l cells Mechanisms of host defense against Candida species. I. Phagocytosis by monocytes and monocyte-derived rnacrophages A cysteine-rich domain of the "mannose" receptor mediates GalNAc-4-S04 binding Mannose receptor-mediated regulation of serum glycoprotein homeostasis The mechanism of unresponsiveness to circulating rumor antigen MUCI is a block in intracellular sorting and processing by dendritic cells Immune recognition: A new receptor for beta-glucans Characterization of beta-glucan recognition site on C-type lectin, dectin 1 Dectin-l and its role in the recognition of beta-glucans by macrophages Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-l beta-glucan receptor Identification of a novel, dendritic cell-associated molecule, dectin-l, by subtractive cDNA cloning The dendtitic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells Hepatitis C virus targets DC-SIGN and L-SIGN to escape lysosomal degradation DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus conidia by dendritic cells and macrophages The C-type lectin SIGN-Rl mediates uptake of the capsular polysaccharide of Streptococcus pneumoniae in the marginal zone of mouse spleen Herre Jet aI. The role of SIGNRI and the beta-g1ucan receptor (dectin-l) in the nonopsonic recognition of yeast by specific macrophages Marginal zone mactophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo Cell-specific g1ycoforms of sialoadhesin and CD45 are counter-receptors for the cysteine-rich domain of the mannose receptor Recognition of bacterial capsular polysaccharides and Iipopolysaccharides by the macrophage mannose receptor Endocytosis of lysosomal acid phosphatase; involvement of mannose receptor and effect of lectins Clearance of neutrophil-derived myeloperoxidase by the macrophage mannose receptor Involvement of the mannose receptor in infection of macrophages by influenza virus Diversity of receptors binding HIV on dendritic cell subsets Regulation of lutropin circulatoty half-life by the mannosel N-acetylgalactosamine-4-S04 receptor is critical for implantation in vivo Endo180 binds to the C-terminal region of type I collagen LOX-l supports adhesion of Gram-positive and Gram-negative bacteria LOX-I, the receptor for oxidized low-density lipoprotein identified from endothelial cells: Implications in endothelial dysfunction and atherosclerosis Conserved C-terminal residues within the lectin-like domain of LOX-l are essential for oxidized low-density-Iipoprotein binding Involvement of LOX-l in dendritic cell-mediated antigen cross-presentation Natural killer cell receptors Role of CD47 as a marker of self on red blood cells CD200 and membrane protein interactions in the control of myeloid cells Downregulation of the macrophage lineage through interaction with OX2 (CD200) Ligand recognition by antigen-presenting cell C-type lectin receptors