Introduction

The increased attention focussed on the natural immune response over the past decade has markedly expanded our knowledge regarding the number of the mediators and range of their functions, and has renewed interest and discussion on issues associated with the natural immune system including the evolutionary pressure for the development of the system and its relationship with the adaptive response.

The natural immune system has long been considered a first line of defence against invading pathogens. The mediators are widely distributed in mammalian tissues and systemically in the circulation. They are preformed and ready to act or are rapidly inducible. Activation of the natural immune system implies a recognition event followed by a sequence of events aimed at destroying an invader or alternatively maintaining the integrity of the organism. Our awareness has increased regarding the multiplicity of receptors contributing to recognition, their structures, their redundancy, the use of facilitating or amplifying, intermediary molecules (opsonins, LBP) to reach the threshold of interaction for functional activation. The receptors which contribute to the innate response include secreted molecules in blood and lymph which act as bridging molecules between the effector cell and the target for phagocytosis, cell surface receptors for pathogens leading to phagocytosis and cell surface receptors which lead to signalling and induction of proinflammatory cytokines.

The dual concepts of pathogen-associated molecular patterns (PAMPs), invariant structures associated with essential microbial functions, which act as the main targets of the innate response against pathogens, and their non-clonal, germline-specified pattern-recognition receptors (PRRs), developed by Janeway and Medzhitov [1^1], have provided a productive framework for discussing the induction of natural immune responses, particularly against microbial pathogens. Their view of natural immune strategies for recognition encompassed recognition of "microbial nonself ' and Kârre's 'recognition of missing self' [3,5], This was extended with the addition of "induced or altered self'[6], The first strategy distinguishes between "infectious non-self' and "non-infectious self' through recognition of conserved metabolic products unique to microbes leading to activation of the innate immune system. The second acknowledged the benefit of self-recognition and this was coupled to inhibitory signalling pathways, so that when "markers of normal self'are not recognized on an abnormal cell, activation would occur. The last strategy was considered to end in apoptosis through a " cell-autonomous mechanism" or as the result of a signal from another cell, following recognition of markers of infection or cell transformation [6J. In addition, markers on apoptotic cells can trigger clearance mechanisms of the innate immune response. An alternate view proposed by Matsinger suggests that pattern recognition receptors react in response to 'danger' recognized as self-antigens exposed upon cell destruction through necrotic cell death [7], Berczi's concept of homotopes and their receptors [8,9], with homotopes being highly conserved homologous or cross-reactive epitopes which may also be expressed on self tissue, suggests an additional contribution from self-recognition in the evolutionary development and conservation of natural immune reactivity. This thinking is also evident in the description of antigen presenting cell (APC) dual-specific pattern recognition receptors which recognize both endogenous and exogenous ligands suggesting their participation in normal tissue functions and in defence mechanisms [10J.

2. ACTIVATION RECEPTORS/ AND THEIR LIGANDS

Recognition molecules contributing to the initiation of activation of the natural immune system arc widely distributed for pervasive surveillance of the organism, with their presence detected on cell surfaces, in cells (in granules or in cytoplasm, for example HSP), or on soluble mediators. In contrast with the receptors of the adaptive immune response, they are highly conserved in evolution, originate from the germline, do not require clonal expansion, do not tend toward somatic mutation and are generally of weak affinity. Proteins of many different structural gene families contribute to this function [11,12] suggesting the essential nature of natural immunity.

2.1. Lectins

Lectins have long been implicated in cell aggregation. Three molecular strategies contribute to cell adhesion in prokaryotic and eukaryotic systems. Cell surface molecules can bind through homophilic or heterophilic interactions, or through the linking action of a multivalent, soluble molecule. Our knowledge of the diversity of lectins participating in natural immune responses has increased markedly in the last 15 years [13], However, x-ray crystallographic studies have also revealed surprising evidence of tertiary structure evolutionary convergence among some lectins [reviewed in 13],

Collectins, are oligomers of a cysteine-rich region and a collagen-like domain joined through a neck region to a C-type lectin carbohydrate-recognition domain (CRD), present in plasma and on mucosa surfaces [14]. For example serum mannose-binding lectin (MBL) which binds man-nose and N-acetyl-glucosamine [15] consists of three polypeptide chains with globular heads wound into triplets which oligomerize and exhibit structural and functional similarities with Clq and IgM [16]. MBL produced in the liver can activate complement through MBL-associated serine proteases, MASPs, splitting C4 and C2, and similar to the classical pathway, leading to the non-specific covalent binding of the intermediary molecule C3b which increases phagocytosis of the MBL target. MBL is opsonic for bacteria but can also bind an endogenous epitope on CD45RO of immature murine thymocytes [17]. This provides evidence for homotopes and links MBL-recognized PAMPs with carbohydrate expression on the leukocyte common antigen (LCA), CD45. Since this epitope was expressed on a lymphocyte subpopulation during a transient stage of maturation, mannose-binding lectins of the innate immune system, MBL or possibly the homologous cell surface DEC-205 of thymic DCs may contribute to a physiological process, the selective maturation of thymocytes [reviewed in 17]. Conversely, considering that CD45 has been identified in hagfish [18] and is a negative regulator of JAKs-dependent signalling by cytokines [19] which includes, the innate system cytokines, IL-6, 11-10 and IL-15, it has been argued that CD45 plays a crucial role in innate immunity [reviewed in 18]. Surfactant proteins S and D (SP-A and SP-D) are collectins found coating pulmonary epithelial cells and in the gastrointestinal tract [20]. They aggregate pathogens reducing their infectivity and increase their phagocytosis via SP-specific receptors on phagocytes [reviewed in 14,21].

Selectins are membrane glycoproteins, a subfamily of C-type lectins bearing a C-type domain, an epidermal growth factor receptor-like domain and variable numbers of complement regulatory protein-like domains [13]. They include the murine lymph node homing receptor (L-selectin), the endothelial-leukocyte adhesion molecule (E-selectin) and the platelet granule membrane protein-140 (P-selectin). They exhibit approximately 50% homology in their C-type lectin domains and possess fairly similar saccharide specificities and functions [13]. They participate in cell trafficking and contribute to the recruitment of neutrophils to inflammatory sites.

Macrophage mannose-binding receptors contribute to the phagocytosis of bacteria. They consist of twelve domains, eight of which are C-type lectins with the carbohydrate-binding activity detected between the fourth and the eighth domains [22]. The cysteine-rich (CR) domain has been identified as a lectin [23].

2.1.2. Natural killer (NK) cell transmembrane receptors

The Ly49 C-type lectins are a family of MHC-class I-specific receptors. The Ly49D and LY49H members are activating receptors for murine NK cells. LY49H binds ml 57 produced by murine cytomegalovirus (MCMV) which has ben shown by protein structural prediction studies to be similar to class I MHC with similarities to H-2M3, MICA and CD Id non-classical MHC class I molecules [24], However, in another strain of mice, ml57 binds the inhibitory MHC-specific Ly49I receptor arguing that ml57 binding to Ly49H may have evolved as a defence against MCMV [24],

NKG2 C-type lectin-like family member NKG2D, is considered the most widely expressed NK receptor and a potent activator of natural immune responses [11], In humans it is present on NK cells, CD8+ T cells and intraepithelial lymphocyte (IEL) yS T cells, and recognizes, through protein-protein interactions, molecules distantly related in sequence to MHC-class I which are upregulated in response to stress, oncogenic transformation or virus infection. These include the non-classical MHC class I molecules MIC-A and MIC-B [25] , which exhibit a limited distribution on the surface of normal cells including, mainly epithelial cells, the epithelial lining of the gastrointestinal tract and the thymic cortex, and fibroblasts [24,26,27]. However, MICA is also induced on anti-CD3- or anti-CD28- plus PMA-activated T cells [28,29], and on IFN-a-stimulated dendritic cells [30], suggesting that MICA is a marker of activated cells. Expression of MICA on the epithelium of the gastrointestinal tract, cells which undergo continued rapid renewal during life [31], is consistent with this thinking. In addition, the demonstration of heat shock elements defined by HSP70 in the promoter regions of MICA and MICB [32], link expression of these nonclassical class I molecules to situations where HSPs are expressed. Heat shock proteins (HSPs) 27, 60, 70 and 90 are constitutively expressed inside all cells under normal physiological conditions [reviewed in 33]. They act as intracellular molecular chaperones for the proper assembly, folding, translocation and degradation of proteins. Their differential cellular and subcellular expression in human decidua and placenta during pregnancy [33] and the presence of HSP70 mRNA in human fetal membranes [34] raise questions regarding whether MICA or MICB, which exhibit heat shock elements defined by HSP70 in their promoter regions [32] may also be induced in this metabolically active tissue providing targets for cells bearing NKG2 receptors to participate in morphological development or control of the pregnancy. This is supported by the requirement for the major heat shock transcriptional factor HSF1 for extra-embryonic development beginning at mid-gestation and for postnatal growth in mice coupled with the failure to detect changes in basal HSP levels associated with extra-embryonic abnormalities in HFS1 -deficient mice, suggesting the activation of non-HSP genes [35]. Could activation of these genes lead to expression of MICA and/or MICB ?

Murine NKG2D recognize molecules with weak homology to MHC class I including the retanoic acid early inducible 1 protein family Rael and the H60 family of dominant histocompatibility antigens of BALB/c mice. They are detected on tumour but not normal cells and interestingly, H60 is also expressed at low levels on activated lymphoblasts and at high levels on the thymocytes of BALB/c [24], Human NKG2D also binds ULBPs or binding proteins for human cytomegalovirus UL16 glycoprotein [24], The MHC-binding surfaces of NKG2D and other C-type lectin MHC-binding NK receptors to date appear to be relatively flat consistent with their protein-binding capacity and they are missing the Ca++ binding residues [25].

The NKR-P1 family of C-type lectin receptors in mice includes NK1.1 which is expressed on NK and T cells and is implicated in NK cell activation. However, some NKR-P1 bear ITIMs and are considered to exert an inhibitory function on NK cell activation [36].

2.1.3. Galectins (S-Type Lectins)

Galectins are a growing and widely distributed family of structurally-related lectins which bind [3-galactoside and are considered master regulators of immune cell homeostasis [37]. Their specificity including that of the ubiquitously expressed N-acetyl-lactosamine-binding lectins, is conserved through evolution in their carbohydrate-recognition domains (CRDs) [38,39]. Genomic studies of galectin-like domains suggest that the galectin gene family may have originated at or before the development of multicellularity [39]. Galectins in the main, are soluble proteins, synthesized in the cytosol and are secreted through a non-classical mechanism. They are not endocytic receptors; however, their binding to cell surface molecules regulates the inflammatory response. Expression of the core 2(3-1,6-N-acetylglucosaminyltransferase (C2GnT) which is developmentally regulated and increased after T cell activation, has been proposed as the basis of T cell susceptibility to galectin-1 induced cell-cycle arrest and/or apoptosis during development in the thymus and in the periphery after activation [38], In contrast, galectin-3 is considered an amplifier of the inflammatory response. As an extracellular molecule galectin activated cells including monocytes, macrophages, neutrophils, mast cells and basophils [reviewed in 37,40], and as an intracellular molecule provided a critical role in phagocytosis by macrophages [40], Galectin-3 was first identified as a cell surface antigen Mac-2 on thioglycolate-elicited macrophages and then as a glycoform-specific IgE-binding protein (epsilon bp/Mac-2), exhibits two independent sites for LPS, a C-terminal carbohydrate-binding site inhibitable by lactose and an N-terminal site which bound LPS from (3-galactoside-negative bacterium [41 ]. Galectin-3 is also able to aggregate and cross-link ligands, extending its functional capacity. Thus, galectin-3 and its ligands appear to fulfil the definition of a homotope/homotope receptor system, binding both exogenous microbial epitopes and endogenous epitopes, through its carbohydrate-binding site.

2.1.4. The Pentraxins

C-reactive protein (CRP) and serum amyloid P component (SAP) are acute phase proteins (APP) which exhibit calcium-dependent binding to several different molecules and pathogens. They are members of the ancient family of pentraxins which are composed of five identical segments joined to form a five sided doughnut structure. CRP exhibits high affinity binding to phosphorylcholine expressed on microbes, oxidized phospholipids and apoptotic host cells [42,43], Through a different site CRP binds galactans and galactose phosphates [44], CRP acts as an opsonin indirectly through activation of complement. It has been reported to act directly as an opsonin by reacting with Fc receptors on phagocytic cells; however, recent experiments have not confirmed this [reviewed in 45], SAP has a preference for binding phosphoethanolamine and activates complement.

2.1.5. Ficolins

Ficolins are oligomers, somewhat similar to collectins, of a cysteine-rich region, a collagen-like domain attached through a neck structure to a carbohydrate-binding fibrinogen-like domain found in plasma and on mucosa surfaces [14,15]. Serum ficolins bind N-acetyl-glucosamine (GlcNAc) with human serum L-ficolin/35 (ficolin L) and H-ficolin (Hakata antigen) reported to activate complement through MASPs.

2.1.6. Scavenger receptors (SRs)

SRs are transmembrane receptors detected on macrophages, dendritic cells and some epithelial cells [46] which internalize modified low-density lipoproteins and phagocytose apoptotic cells, microorganisms and their products [46]. These structurally heterogeneous receptors include molecules with C-type lectin, collagenous, cysteine-rich or other domains, arguing for diverse mechanisms in the binding of their diverse ligands including the polyanionic targets of the collagenous domains.

2.2. The Ig superfamily (IgSF)

IgSF genes encode the most common domain type in the human proteome [reviewed in 47], a clear indicator of its importance. The IgSF codes for a broad spectrum of molecules which exert diverse functions such as cell-cell recognition and adhesion, recognition of soluble molecules and specific antigen recognition. Most Fc receptors (FcRs) function as multichain receptors with the a chain, which recognizes the Fc portion of immunoglobulins being itself a member of the IgSF. Recent identification of Fc receptor homologs in humans [reviewed in 47], holds a promise of unveiling additional activating receptors of natural immunity.

2.2.1. Fc Receptors

FcyRI (CD64), bears three IgSF domains and is constitutively expressed on monocytes and macrophages [reviewed in 48,49], The murine FcyRI is the high affinity receptor for T-depend-ent IgG2a but also the low affinity receptor for complexed IgG^ [50], Since IgG3 is the first IgG class produced in mice, is T-independent with the class switch from IgM promoted by INF-y produced largely from NK cells, recognizes primarily carbohydrates and antigens with repeating epitopes and tends towards self-aggregation [reviewed in 50], activation of APCs, macrophages and some DCs, through antigen-bound IgG^ interaction with their FcyRIs would contribute to innate responses and provide a link with the adaptive response by presenting for T cells, antigens from T-independent immune complexes [50,51], Production of human IgG2 is considered to be relatively T-cell independent [reviewed in 52] so that low affinity interactions through FcyRIs may contribute similarly to innate and adaptive responses in humans. FcyRIs have been induced by INF-y on human PMNs where they participated in ADCC and induction on human CD34+ stem cell-derived mast cells lead to degranulation and cytokine release upon receptor aggregation [reviewed in 51].

FcyRII (CD32), a transmembrane molecule bears two IgSF domains and occurs in several isoforms, with some or all detected on human monocytes, macrophages, PMNs, platelets and B cells [reviewed in 48]. This is a low affinity IgG receptor, binding polymeric or aggregated IgG, with a low capacity for binding IgG2. Thus, this FcR should also contribute to innate and adaptive responses. Since binding of the T-independent IgG2 is lowest for FcyRI and FcyRII, as the adaptive response proceeds and T-dependent IgGs are produced they should compete more efficiently leading to an increasingly antigen-specific expansion and effector phase of the response.

FcyRIII (CD 16) bears two IgSF domains and occurs in a transmembrane form in man and mouse and also a GPI-linked form in humans [reviewed in 48], In humans, the transmembrane form is expressed on NK cells, macrophages and mast cells with the GPI-linked form on neutrophils. In mice the transmembrane form is expressed on NK cells, macrophages and neutrophils. FcyRI is a low-affinity receptor for aggregated IgG with the transmembrane form mediating phagocytosis and ADCC. The GPI-linked form on neutrophils appears to bind without any subsequent function or signal.

FcR-bearing APCs, bind and phagocytose antibody coated antigens. Additional effector cells: NK cells, mast cells, eosinophils and basophils, are stimulated through their Fc receptors to release their stored mediators leading to ADCC.

2.2.2. NK transmembrane receptors

IgSF activation receptors identified on NK cells include KIR2DS2, a short cytoplasmic tailed member of the Ig-like killing inhibitory receptors of the killer-cell Ig-like receptor (KIR) family which binds MHC-class-I [53], and NKp46, NKp44 and NKp30, receptors which do not bind classical or nonclassical MHC-I [11,25,54],

2.2.3. Trem (triggering receptor expressed selectively in myeloid cells)

Trem family receptors are transmembrane glycoproteins with a single extracellular immu-noglobulin-like domain differentially expressed on myeloid cells [24,55,56], TREMs signal through the ITAM-containing KARAP/DAP12 signalling adapter proteins upon exposure of TREM-bearing cells to bacteria or fungi. However, it is not clear whether the ligands are of microbial or host origin. Trem-1 activates neutrophils and monocytes/macrophages and amplifies TLR-initiated responses. Trems are distantly related to the novel Ig-like stimulatory receptor of NK cells NKp44 which signals through the same adapter proteins.

DIgRI is a novel DC-derived Ig-like receptor I with a single extracellular Ig-like domain. It has been identified on murine dendritic cells and exhibits significant homology with the human CMRF-35 antigens of monocytes, neutrophils and some T and B lymphocytes, and the polymeric immunoglobulin receptors (plgR) [57], The extracellular V-Ig domains of CMRF-35 A and CMRF-35H are highly homologous. However, the CMRF-35H contains three putative ITIM motifs suggesting an inhibitory role while the CMRF-35H has a very short cytoplasmic tail with no ITIM.

2.2.5. Hemolin

Hemolin, a four-Ig domain plasma protein Ig-superfamily member in insects is induced by microbial challenge and leads to binding and aggregation of bacteria and of yeast [58], Hemolin has two distinct LPS binding sites, one being the phosphate groups of lipid A and the other the O-specific antigen and the outer-core carbohydrates of LPS [58],

2.2.6. Transcription factors

Iterative data-base searches revealed that the Ig-like DNA-binding domain of the transcription factors NFkB and NFAT is a member of a distinct superfamily of intracellular and extracellular domains with an immunoglobulin fold [59].

2.2.7. Superantigens

Superantigens rapidly activate a large proportion of lymphocytes independent of the antigen specificity of the variable domain of their receptor but dependent on conserved components of the receptor [60]. T cell superantigens are proteins of bacterial (pyrogenic toxin SAG family; staphylococcus aureus enterotoxins, SEs; staphylococcus aureus toxic shock syndrome toxin-1, TSST-1) or viral (Epstein-Barr virus, EBV; mouse mammary tumour virus, MMTV) origin which bind MHC outside of the peptide-binding groove and also interact with the T cell receptor immunoglobulin V(3 domain bringing an MHC-bearing APC together with a T cell through a trimolecular complex to activate up to 10 percent of T cells [61].

Unlike conventional antigen binding to B cell receptors which involves interactions of native antigen with the hypervariable regions of both heavy and light immunoglobulin chain V regions, superantigens recognise heavy chains, usually more conserved solvent exposed surfaces or framework regions. There are B cell superantigens of bacterial (staphylococcal protein A, SPA; staphylococcal enterotoxins, SEAs), viral (HIV gp 120) and endogenous (i/I carbohydrate red blood cell antigens) origin. SPA can bind 17% of B cells [62],

Thus, both T and B cells, the signatory cells of the adaptive immune response, can be persuaded to contribute to an innate immune response. Further, SEA has been shown to indirectly activate NK-type T cells and NK cells for INF-y production and cytotoxicity through priming monocytes/macrophages for IL-12 production [63,64], demonstrating that lymphocytes of the innate immune system can also be activated by superantigens.

2.2.8. Immunoglobulin

The conventional role for polyclonal natural antibody (NAb) found in the circulation of normal, not-intentionally immunized individuals has been ascribed to early defence against infectious agents. However, a contribution to the early resistance against tumours has been suggested [65-67, rev in 68] and the autoreactivity of NAb has led several investigators to propose a regulatory function for NAb particularly regarding the immune system, and/or extending to organism homeostasis [69,70], The multispecificity and low affinity for much of this NAb binding to cells have provided obstacles to the identification of cell surface targets and thus to the mechanisms of NAb-mediated cell regulation and a potentially unifying concept of NAb functions. However, analysis of pre-immune monoclonal antibodies has revealed a polyspecific autoreactive binding with apparently unrelated self-antigens including deoxyribonucleic acid and the highly conserved cellular proteins, actin and tubulin [71], and more recent reports suggest NAb binds to cell surface molecules including CD4 and the T cell receptor [rev. in 72],

2.3. Toll-like receptors (TLRs)

TLRs are a large family of pattern recognition receptors detected in several species, initially flies and subsequently rodents and humans, which exhibit some specificity in the recognition of particular invariant and ubiquitously expressed features of pathogens leading to the generation of inflammatory responses [73]. Several TLRs are employed simultaneously on immune cells to detect different types of epitopes on a pathogen. Analysis of murine cell lines revealed TLR mRNA transcripts predominantly in the cells of the innate immune system including, dendritic, macrophage, mast and neutrophil cell lines suggesting they play a dominant role in the first immune response to pathogens [74]. Ligands on pathogens can be protein, carbohydrate, lipid or nucleic acid in nature. However, reactivity with self ligands has also been discovered. The best characterized, TLR4 is a receptor for LPS. LPS is taken up by serum LPS-binding protein (LBP) allowing CD 14 to interact with LPS. The LPS and CD 14 form a complex with TLR4 and the extracellular accessory protein MD-2 which is required for TLR4 signalling in response to LPS. While high levels of TLR2, TLR4 and CD 14 were expressed on human PBL monocytes, lower levels were detected on PMNs, only TLR2 and TLR4 on basophils and none of the three on eosinophils [75]. LPS was considered to play little role in regulating peripheral blood eosi-

nophil or basophil function, and contaminating monocytes were thought likely to contribute to the observed PMN responses to LPS [75], Fibroblast expression of TLR2, TLR4 and CD 14 is consistent with their activation by LPS [76,77], Leucine-rich repeats associated with proteinprotein binding are found on the TLRs and on CD 14. The TLRs exhibit a conserved cytoplasmic domain homologous with the IL-1 receptor (Toll/IL-IR homology; TIR) which accounts for similarities in TLR and IL-1R signalling. The intracellular propagation of the signal recruits the cytoplasmic adapter molecule MyD88 through TIR/TIR domain interaction activating the IRAK family of serine threonine kinases, which can then interact with TRAF6 which activates TAK1. Subsequently, the signal is split leading to activation of the JNK pathway and to translocation of NF-kB with activation of an inflammatory response. Differential recognition of cellular expression of TLRs is related to differential responses against the same pathogen [78], Recognition of pathogens by combinations of different TLRs provides redundancy and specificity for the responses [79],

Endogenous ligands leading to an inflammatory response after interaction with TLR4 are heat-shock protein 60 (HSP60) and the extra domain A (EDA) region of fibronectin which appears due to alternative splicing in response to tissue injury [reviewed in 73], HSPs are considered important as endogenous ligands for stimulation of TLRs when they are released upon cell necrosis. However, recognition of apoptotic cells by CD 14 does not generate an inflammatory response [reviewed in 80],

2.4. Antimicrobial peptides

Numerous and diversely structured antimicrobial peptides are broadly expressed in nature [reviewed in 11 J. The defensins, broadly reactive cationic antimicrobial peptides which must undergo enzymatic activation, exhibit a P-pleated structure with a hallmark six-cysteine motif which forms three intramolecular disulfide bonds [81]. The a-defensins are present in neutrophil granules and in Paneth cells beneath the epithelial stem cells at the base of the crypts in the small intestine. Human neutrophil protein (HNP) a-defensins were induced in IL-2 stimulated T- and NK-enriched human lymphocytes, p-defensins are made in epithelial cells of the skin, respiratory tract and heart skeletal muscle. They arc induced in human epithelial cells by microorganisms and cytokines [82]. Circular © minidefensins have been found in rhesus monkeys. Defensins provide a direct antimicrobial action in a non-receptor-mediated manner by binding anionic microbial surface components via electrostatic interactions and damaging bacterial cell membranes. Additional functions suggest that they also contribute to immunostimulation of innate immune responses. This is evident in the ability of a-defensins to enhance phagocytosis by macrophages, to degranulate mast cells releasing histamine, to stimulate IL-8 production from epithelial cells, and to bind and activate complement, with support for receptor mediated interactions with eucaryotic cells for degranulation and IL-8 production [reviewed in 83]. Murine p-defensin-2 has been shown to activate immature DCs directly through TLR-4 [84], a-defensins also contribute to adaptive immune responses through their selective chemotactic abilities observed at 1/10 to 1/100 their bactericidal concentration, HNP for CD4+ CD45RA+ T cells and CD8+ T cells, p- defensins for CD4+ CD45RO+ T cells and a- and p- defensins for immature dendritic cells [reviewed in 83],

2.5. Complement and the complement receptor system

The complement system is important for activating the cells of the innate immune system. It consists of over 30 cell surface and plasma proteins, some with protease activity which can be activated by an earlier acting proteolytic component resulting in a cascading induction of potent biological activity including phagocytosis, lysis and generation of an inflammatory response [reviewed in 15], Clq is a calcium-dependent carbohydrate-binding protein (C-type lectin), of the collectin family with collagen and C-type lectin domains. Complement components C3, C4 and C5 are considered to have originated from gene duplication of the ancestral a-2 macroglob-ulin gene [reviewed in 11], Natural immune activation of complement likely involves the classical pathway employing in the main natural IgM and possibly natural IgG antibodies in addition to the evolutionarily ancient alternative pathway with the stabilization of the low concentration of C3b spontaneously activated by serum enzymes, or the lectin pathway initiated by mannose binding lectin (MBL) and ficolins. C3 a target component of all three activation pathways and essential for the development of the lytic pathway, contains a hidden thioester bond which is exposed on C3b after C3a is split off and is reactive, forming covalent bonds with hydroxyl and amine groups or is hydrolysed and inactivated by water. C3b, iC3b and C3d are ligands for the complement cell receptors CD35, CD21, CD1 lb and CD1 lc [85], Complement receptor 1 (CR1), a large single transmembrane chain lectin-like molecule is a receptor for C3b, the homologous C4b, inactivated forms of C3b, plus Clq and MBL, but requires additional binding to mediate phagocytosis [86], The lectin-like CR2 (CD21) and integrins CR3 (CD1 lb/CD 18) and CR4 (CD11 c/CD 18) bind inactive forms of C3b, with CR3 and CR4 able to facilitate phagocytosis. Phagocytic activation of macrophages is associated with the release of proinflammatory mediators generating a local inflammatory response. Cellular receptors for the small, anaphylactic, split products C5a (C5aR) and C3a (C3aR) are seven-span receptors which interact with intracellular guanine-nucleotide-binding proteins to initiate activation signals.

2.6. Cytokines and their receptors

Cytokines of diverse structures including IL-1, IL-6, TNF-a, IL-12 and IL-8 are released from microbe-activated macrophages. These small molecular weight proteins can act locally in an autocrine or paracrine manner or at a distance after travelling through the circulation or tissue fluids. IL-6 of the large hemopoietin structural family, TNF-a (cachectin) of the TNF family and the unassigned IL-1, induce the liver to release acute phase reactants. IL-1 a and IL-1 [3 binding to the IL-1RI (CD121a) through the ligand binding domain consisting of three immunoglobulin-type (Ig-type) domains leads to intracellular signal transduction through the cytoplasmic TIR domain [87], However, binding to IL-1RII (CD121b) which has a similar extracellular domain fails to activate due to its very short cytoplasmic domain. Sertoli cells are the main epithelial cells of the testes, surrounding the germinal cells and providing them with an immunologically protected environment [88]. Sertoli cells in adult rat testes constitutively express mRNA of IL-1 a, dependent upon their contact with the germ cells and without producing inflammation [89] supporting the idea that IL-1 a may play a physiological role for IL-1 a as a germ cell growth factor in testes. TNF binds cellular TNFR-I and TNFR-II with homotrimer formation needed for signal induction for activating macrophages for NO production. IL-12 is also released and binds with IL-12Rp 1 and IL-12(32 stimulating NK cells.

2.7. Chemokines and their receptors

Over 50 small 8-10 kD, heparin-binding proteins with related amino acid sequences are divided into 4 chemokine subfamilies based on particular aminoacid sequence and the presence of cysteine [90,91], With their chemokine receptors of the seven transmembrane receptor family, they direct the movement of cells and contribute to the activation of natural immune responses [91]. Depending on the combination of TLRs stimulated, tissue macrophages and dendritic cells release a subset of chemokines following NF-kB activation [92]. This can include IL-8 (CXCL8), MlP-la (CCL3), MIP-lp (CCL4), RANTES (CCL5) and IP-10 (CXCL10). IL-8 binds and activates CXCR1/2 bearing PMNs. CCR5 bearing NK cells bind the CC chemokines and CXCR3 bearing activated T cells bind IP-10, so that all of these cells can be drawn from the circulation into the inflammatory site. Stimulation of immature dendritic cells through their constitutively expressed CCR1, CCR5 and CCR6 chemokine receptors leads to their maturation with downmodulation of CCR1, CCR5 and CCR6 and upregulation of CCR7 receptors directing the cells to migrate into the lymphatics. All bacteria produce proteins with amino terminal N-formylated methionine which act as chemoattractants for inflammatory cells particularly PMNs. The peptide f-Met-Leu-Phe (fMLP) acts similarly through the fMLPR [93] which is a seven-span receptor similar to the receptors for chemokines and for C3a and C5a, arguing that chemokines, complement components and bacterial products attract and activate PMNs through a common mechanism.

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