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Category: Immunology; Clinical Microbiology
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The Innate Immune Response to Infection delivers a review of the innate immune system, utilizing the most current concepts of cellular and molecular biology. Unique in its presentation, this volume covers all aspects of innate immunity with an emphasis on response to infectious agents. It is a valuable reference source for scientists and students active in all areas of immunology and microbiology, as well as virology, parasitology, and infectious diseases.
Written by experts in the field, the book focuses on evolutionary aspects, describing the major cells, humoral factors, and effector responses central to innate immunity and its important relation to acquired immunity. In-depth treatment is given to the performance of the innate immune system in various situations, including bacterial, viral, fungal, and parasitic infection.
Electronic Only, 465 pages, illustrations, index.
This chapter discusses evolutionary factors regarding the emergence and phylogenetic distribution of the innate immune system and the combinatorial or adaptive immune system, as well as the interactions between the two. Naturally occurring IgM antibodies, as well as induced antibodies, can recognize lipopolysaccharide (LPS) epitopes and feed into the NF-κB activation and differentiation cascade with one result being production of immunoglobulin (Ig) by B lymphocytes. The mannose-binding lectins (C lectins) are effective in complement fixation even in lower chordates, including tunicates, and occur in groups as ancient as Cnidarians. Ancestral deuterostomes branched off from the ancestral protostomes before the two major branches of protostomes, namely, iophotrochozoans (annelids, platyhelminths, and mollusks) and ecdysozoans (arthropods and nematodes), emerged. The chapter talks about interplay between innate and combinatorial immunity, molecules of innate immunity, and the adaptive or combinatorial immune response of jawed vertebrates. With the exception of the molecules defining the combinatorial or adaptive system, cyclostomes have molecules appropriate for their phylogenetic position with the percentage of sequence identity expected from the rates of divergence with the jawed vertebrates. It is likely that in each individual species where co-option occurred, it was followed by a coevolution dependent on the stringency of the selective environment.
The studies on antimicrobial peptide identification were rapidly extended to other insect species and eventually to Drosophila. During the past decade, the ease of genetic analysis has made the fruit fly an organism of choice for the study of innate host defense. This chapter concentrates on recent developments in this field of study. Drosophila , like all insects, is very resistant to microbial infections, mounting a multifaceted reaction against invading non-self. Drosophila blood cells (hemocytes) play a significant role in host defense. Three mature hemocyte types are found in circulation: plasmatocytes, crystal cells, and lamellocytes. Infection-dependent melanization is the most immediate response following microbial challenge or septic injury and requires the activation of phenoloxidase (PO), which is an oxidoreductase that catalyzes the conversion of phenols to quinones. The chapter then focuses on humoral immunity. In the early 1990s it was shown that the promoters of the antimicrobial peptides (AMP) genes contained sequence motifs related to mammalian NF- κB response elements. The Imd pathway governs defenses against gram-negative bacteria by controlling the induction of a number of genes, including most of those encoding the antibacterial peptides. Genetic screens and an RNAi-based screen in macrophagelike cultured cells have recently identified PRRs in Drosophila.
Neutrophils form the major type of leukocytes in peripheral blood, with counts ranging from 40 to 70% of the leukocytes under normal conditions. Neutrophilic granulocytes protect the human body against bacterial and fungal infections. For this purpose, neutrophils are equipped with a machinery to sense the site of an infection, to crawl toward the invading microorganisms, and to ingest and kill them. Neutrophils mature in the bone marrow in about 2 weeks, a process in which the myeloid-specific growth factors granulocyte colony stimulating factor (G-CSF) and granulocyte monocyte CSF (GM-CSF) play an important role. The bone marrow comprises a reserve pool of mature neutrophils of about 20 times the number of neutrophils in the circulation. Neutrophil elastase is normally synthesized in the myeloblasts as an inactive proenzyme but is packaged in the azurophil granules in its active form. Many of the chemotaxins involved in granulocyte movement are small proteins of about 60 to 100 amino acids, very homologous in structure, known as the chemokine superfamily. The processes of adhesion of neutrophils to endothelial cells and subsequent diapedesis take place at postcapillary venules. Extravasation is a multistep process involving adhesion molecules and activating agents that act as (pro-) inflammatory mediators. The chapter also talks about sensing danger signals, phagocytosis and microbicidal activity, and neutrophil apoptosis. Neutrophils are very useful but also very dangerous tools to protect the host from bacterial and fungal infections.
Macrophages are part of the innate immune system, recognizing, engulfing, and destroying many potential pathogens including bacteria, pathogenic protozoa, fungi, and helminths. The destructive potential of macrophages and their ability to secrete regulators of the function of neighboring cells contribute to many aspects of homeostasis. This chapter talks about the origins, differentiation, and functions of macrophages throughout the body. The study of mononuclear phagocyte biology in vivo was expedited by the advent of monoclonal antibodies that recognize some of the macrophage restricted molecules, as well as surface proteins of an unknown function. Embryonic phagocytes appear in the yolk sac and embryo proper before the formation of blood circulations and the occurrence of hepatic hematopoiesis. The regulation of functions of the macrophages requires expression of macrophage specific genes, which, in turn, is likely to involve a number of lineage-specific transcription factors. Peritoneal macrophages are the most studied primary macrophages in mice because they are easily isolated by peritoneal lavage. The splenic macrophages are an important component of the innate immune system, as evidenced by the incidence of septicemia following splenectomy. Microglia are the resident macrophage population in the normal healthy adult nervous system. Ovarian macrophages are mainly found in the interstitium, being excluded from the germ cell compartment, except in atretic follicles where macrophages are recruited for the destruction of defunct follicle. The availability of macrophage-specific transgenes, and transgenic approaches to lineage tracing, will provide new opportunities to explore the true function of this family of cells.
Cells of the dendritic cells (DC) lineage are continuously produced; they arise from bone marrow hematopoietic stem cells as myeloid progenitors and seed all organism tissues. Although rare, they are ubiquitously distributed in lymphoid and nonlymphoid tissues; together with macrophages, they recognize pathogens and regulate the inflammatory processes. The responsiveness of mucosal DC populations to inflammatory stimuli, in particular their rapid kinetics of recruitment that surprisingly is equivalent to that of neutrophils, underscores their relevance as antigen sentinels and regulators at the mucosal sites. Indeed, in pathological conditions, such as in Crohn’s disease, a good deal of recent evidence suggests that the failure of a physiological innate immune response could degenerate into an autoimmune response. In the absence of inflammation, innocuous antigens that are continuously encountered in the lungs by DCs induce antigen-specific unresponsiveness. In the lymphoid organs, DCs have the unique opportunity to encounter and present antigens to the rare unprimed antigen-specific T cells. Mannose receptors are believed to be expressed by DCs because internalization and presentation of mannosylated proteins are very efficient in DCs. The movement of the pseudopodia in activated DCs involves actin binding proteins, and it can be blocked by the drug cytochalasin D, which stops the polymerization of actin and inhibits phagocytosis. Natural killer (NK) cells activity is primed during the early phases of an immune response, a few hours after infection. As a matter of fact, physiological immune responses originate from a well-controlled inflammatory process.
This chapter reviews basic aspects of mast cell and basophil development and function, describes a mouse model for analyzing mast cell function in vivo, and then outlines the evidence that mast cells and/or basophils can contribute to innate immune responses. Both mast cells and basophils are derived from CD34+ hematopoietic progenitor cells present in adult blood and bone marrow, and these two cell types share many similarities in mediator content, surface receptor expression, and function. Mice that genetically lack only mast cells or basophils would represent ideal model animals for investigating the contributions of these two cell types to specific pathological or physiological processes. The mast cell knock-in mouse model has been used by several groups to show that mast cells can represent an important component of host defense against bacterial infection. Studies of mast cells and basophils in host defense against parasites have focused predominantly on the potential roles of these cells in acquired, rather than innate, immune responses. The studies in the cecal ligation and puncture (CLP) model in mice, and other lines of evidence, support the view that mast cells can have sentinel and effector functions in innate immunity to bacteria. The mast cell, so rightly considered a key “part of the problem” in the expression of anaphylaxis, atopic asthma, and other immunoglobulin E (IgE)-associated disorders, clearly can provide significant benefit in host defense during certain examples of bacterial infection, at least in mice.
This chapter describes and reviews the functions of natural killer (NK) cells, primarily from studies of their antitumor properties, and discusses recent advances in the understanding of NK cell responses in host defense against pathogens. The in vitro NK cell proliferative response to high concentrations of interleukin-2 (IL-2) is unlikely to be mimicked in vivo. The role of NK cells in infection is highlighted by the case of an adolescent woman with a selective NK cell deficiency in whom there were frequent, recurrent septicemic episodes due to uncontrolled viral infections, including cytomegalovirus (CMV), varicella-zoster virus, and herpes simplex virus. The NK cell compartment is not fully developed at birth, as indicated by lower natural killing by human cord blood lymphocytes and corroborated by studies on the ontogeny of NK cells in rodents. Classically, NK cells kill their targets by the triggered and directional release of preformed cytoplasmic granules containing perforin and granzymes, a process termed granule exocytosis. The role of NK cells in infection control is related to their receptors that regulate the natural killing function. The inhibitory receptors do not explain all aspects of NK cell specificity. As predicted by the two-receptor model, NK cell recognition also appears to involve activation receptors. The distribution of NK cells and recruitment therefore may be related to organ-specific differences in the NK cell effector mechanism controlling murine CMV (MCMV) replication.
Most studies on innate immunity have focused on macrophages, as these cells are crucial defenders against infection of the systemic compartments. This chapter talks about (i) the molecular mechanisms used by bacteria to trigger the innate host response, (ii) neutrophils as effectors of the antimicrobial defense of the urinary tract, and (iii) genetic defects in innate host defense pathways that explain the susceptibility to urinary tract infections (UTIs). P-fimbriated Escherichia coli is used to examine the role of recognition receptors and toll-like receptor-4 (TLR4) coreceptors in epithelial cell activation. Cell activation can proceed in two steps, involving a primary ligand-binding receptor and a second receptor responsible for transmembrane signaling, which in this model is TLR4. The authors have speculated that epithelial unresponsiveness to lipopolysaccharide (LPS) may be essential to maintain mucosal integrity, and have used the murine IL-8 receptor homologue (mIL-8Rh-/-) mouse to study chemokines and chemokine receptors in the defense against UTI. Inactivation of a single gene encoding mIL-8Rh is sufficient to convert the mice from a resistant to a susceptible phenotype, as defined both by acute disease susceptibility and by chronic disease development. The chemokine receptors must be functional to avoid the trapping of neutrophils that results in tissue destruction.
Paneth cells are specialized intestinal epithelial cells found mainly in the crypts of the small intestine. Paneth cells should be viewed as provisional until they can be confirmed by more specific markers. The presence of antimicrobial proteins in Paneth cells, which are secreted in response to bacterial products, implicates these cells in host defense against infection as part of the innate immune system. Paneth cells are present in the fetal intestine, although numbers are low at birth and increase postnatally, independently of the presence of intestinal microorganisms. The functions of Paneth cells are largely surmised from their repertoire of expressed genes, while direct experimentation has also confirmed a definite role in protection against enteric bacterial infection. In zinc deficiency, Paneth cell morphology is altered, and although metallothionein declines to undetectable levels in most epithelial cells, it can still be detected in the cytoplasm of Paneth cells. The location of Paneth cells adjacent to the stem cell zone of the small intestinal crypts has led to speculation that they play some role in maintaining stem cell function. Necrotizing enterocolitis (NEC) is probably triggered by intestinal infection, and inflammation and ischemia localized to the terminal ileum are prominent pathological features. Expression of antimicrobial genes, and experimental studies showing that Paneth cells respond to bacterial products and are required for enteric host defense, establish them as a significant component of innate immunity in the intestine.
This chapter focuses on one essential component of the innate immune system, that is, non-antibody-mediated pathogen recognition and opsonization. In particular, the focus is on the collectin subgroup of the superfamily of lectins, known as the C-type lectins. The collectins appear to play an important role as pattern recognition molecules in the protection of mammals from viral, fungal, and bacterial infection. In humans and rodents, mannose-binding lectin (MBL) is the only major serum collectin, although low levels of both surfactant protein A (SP-A) and surfactant protein D (SP-D) are also found in serum. Three additional serum collectins, con-glutinin, CL-43, and CL-46, have been identified in the cow but not yet in other species. The chapter describes the structure of the collectin. For MBL as a serum protein, its role appears to be as an ante-antibody as it acts like a broad-spectrum antibody and is able to activate complement via a novel mechanism. The chapter explores the experimental evidence that supports these contentions. The findings that SP-A and SP-D play a pivotal role in the regulation of macrophagemediated inflammation in the lung, in the defense against invasion by pathogens, and in modulating inflammatory responses to infection and allergenic stimuli have intriguing clinical implications for a range of lung diseases. A great deal of progress has been made in defining the role for collectins as first-line host defense molecules. The exciting possibility exists that this knowledge may be harnessed and translated into novel adjuvant therapies.
This chapter focuses on the general modus operandi of complement and its receptors in infection. It discusses the various pathways of complement activation and their microbial triggers and highlights some of the mechanisms and strategies pathogens have evolved to counteract or “hijack” the complement system. A portion examines how the source of complement affects adaptive immunity to infectious agents. Defined by the mode of activation and the subsequent proteolytic cascade in which activation occurs, three activation pathways are recognized: classical, mannan-binding lectin (MBL), and alternative. Complement receptors play an important role in the uptake and clearance of opsonized Ag, enhancing adaptive and innate cellular responses, and inducing inflammatory responses. The role of anaphylatoxin receptors becomes more complicated when relatively recent work describing an attenuating effect of C3aR on inflammation induced by lipopolysaccharides (LPSs) in an in vivo endotoxic shock model is considered. An additional factor that might have promoted cooperation between adaptive immunity and classical complement is the close linkage of some of their hallmark genes on the mammalian genome. To date, myeloid C3 is the only known source with a site-restricted complement function that does not overlap with alternative sources. Its fundamental importance in adaptive immunity in the periphery might make it a factor of consideration in vaccine development or possibly part of standard clinical analyses where serum complement is measured now.
This chapter summarizes the current information on the linkage between the regulation of the coagulation and inflammatory responses to infection. Inflammation can affect coagulation status in less overt fashions. Inflammatory mediators such as interleukin-6 (IL-6) can not only increase platelet production, but the platelets that are generated are more thrombogenic, demonstrating an increased sensitivity to platelet agonists like thrombin. Among the major anticoagulant mechanisms, the protein C anticoagulant pathway is the most complex and appears to be the most impacted by acute inflammatory responses. Both antithrombin and protein C inhibitor play major roles in inactivating thrombomodulin (TM)-bound thrombin, resulting in a half-life for the bound thrombin of about 1 to 2 s. The difference in efficacy in modulating the host response to bacterial and endotoxin infusion between artificial anticoagulants and the natural anticoagulants suggests that the anti-inflammatory activities of the natural anticoagulants may be very important aspects of their physiological functions. The role of cleavage of the protease-activated receptors in activated protein C (APC) function remains to be fully elucidated. Most of the downstream events following activation of these receptors enhance inflammation. TM accelerates thrombin activation of a plasma procarboxypeptidase B, often named thrombin-activatable fibrinolysis inhibitor (TAFI). It is now recognized that even the statins thought originally to function by lowering cholesterol have important anti-inflammatory effects as well. Further identification of the links between inflammation and thrombosis should provide novel approaches to new diagnostics and therapeutics.
This chapter focuses on recent advances in one's understanding of the function of toll-like receptors (TLRs), particularly with regard to their ligands and signaling. Fibrinogen has been shown to induce the production of chemokines from macrophages through recognition by TLR4. Thus, TLR4 is presumably involved in several inflammatory responses by recognizing endogenous ligands even in the absence of infection. Therefore, more careful experiments are required before one can conclude that TLR4 recognizes these endogenous ligands. The signaling pathways via TLRs originate from the Toll/interleukin-1 receptor (TIR) domain. MyD88 harboring the TIR domain in the carboxy-terminal portion associates with the TIR domain of TLRs. MyD88-deficient mice showed impaired responses to the IL-1 family of cytokines, whose receptors have the cytoplasmic TIR domain. IFN-α has been shown to be induced in response to the activation of TLR7 as well as TLR4. In attempts to characterize the MyD88-independent signaling pathway, a second adaptor molecule containing the TIR domain was identified and designated TIR adaptor protein (TIRAP) or MyD88- adaptor-like. Initial in vitro studies suggested that TIRAP specifically associates with TLR4 and acts as an adaptor in the MyD88-independent signaling pathway. These studies further indicate that the TIR domain-containing molecules provide the specificity for individual TLR-mediated signaling pathways. Elucidation of the signaling pathway that is specific to each TLR will provide one with an important clue to understanding the molecular mechanisms by which innate immunity is activated and finally lead to the development of antigen-specific adaptive immunity.
This chapter focuses on how pattern recognition is used by the innate immune system to distinguish self from nonself and how this discrimination is translated into induction of adaptive immunity. The past few years have seen significant advances in our understanding of how adaptive immune responses are controlled by the initial innate recognition of microbial infection. In particular, the identification of the Toll-like receptor (TLR) family as the critical receptor family involved in the recognition of infectious nonself has enabled researchers to examine the mechanisms by which adaptive responses are controlled by the innate immune system. Before discussing the specific mechanisms by which TLRs control adaptive immunity, the chapter talks about the general mechanisms by which self/nonself discrimination is regulated within the adaptive immune system. The second half of the chapter focuses on how TLRs control some of these mechanisms and link microbial recognition to self and nonself discrimination by the adaptive immune system. Upon activation, lymphocytes undergo a period of rapid proliferation. The innate immune system keeps the infection in check long enough for lymphocytes to expand and eventually eliminate the microbial challenge. Immature B cells that have receptors capable of recognizing membrane-bound selfantigens receive signals leading to apoptosis of the self-reactive B lymphocyte. IgG2 antibodies are effective at eliminating a variety of intracellular and extracellular pathogens because they can fix complement and direct the lysis of infected cells in a process called antibody-dependent cellular cytotoxicity.
This chapter discusses selected scavenger and lectinlike antigen-presenting cell (APC) receptors in relation to innate immunity to illustrate principles and provide questions for further study. Genes for the pattern recognition receptors (PRRs) of the innate immune system have become fixed in the germ line during evolution, unlike the recombinant genes generated in somatic cells, which determine clonotypic recognition by T and B lymphocytes in the acquired immune response. The SR-A molecule has two functional (I and II) and one nonfunctional (III) isoforms, depending on differential exon splicing. It is a distinct gene product from macrophage collagenous receptor (MARCO), a similar collagenlike type 2 transmembrane glycoprotein. SR-A function in innate immunity has not been fully analyzed in vivo, but in vitro model systems have contributed to our understanding of its role in uptake of bacteria. It is now clear that there are several distinct mannose recognition molecules expressed by mature macrophages and selected endothelia, including the classic multilectin mannose receptor (MR), DC-SIGN and DC-SIGN-related molecules, and Langerin. The chapter summarizes studies on the MR, for which a range of exogenous and endogenous ligands has been defined. Our knowledge of innate immune recognition by APC receptors and of the pathways leading to distinct responses is limited. This subject has become topical and will have considerable theoretical and practical implications in therapeutic modulation of host resistance to infection and vaccine development. In addition, improved understanding will bring insights into the pathogenesis of autoimmunity and of a range of inflammatory disease syndromes.
To achieve self-tolerance, many inhibitory receptors recognize major histocompatibility complex class I (MHC-I) molecules, which are normally expressed on healthy cells. In humans, inhibitory MHC-I receptors include the killer cell immunoglobulin (Ig)-like receptors (KIRs), the leukocyte Ig-like receptors (LILRs), and the CD94/NKG2A heterodimer. This chapter focuses on LILRs and, in particular, on their function during cytomegalovirus (CMV) infection and their ability to regulate adaptive responses during bacterial infection and following organ transplantation. The members of the LILR family--also known as immunoglobulin-like transcript (ILT), leukocyte Ig-like receptor (LIR), monocyte and macrophage Ig-like receptor (MIR), or CD85--include at least 11 distinct molecules, which have either two or four homologous extracellular Ig-like domains of the C2 type. Inhibitory LILRs (LILRB1, LILRB2, LILRB3, LILRB4, and LILRB5) contain long cytoplasmic domains with two to four immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Another group of LILRs (LILRA1, LILRA2, ILT7, ILT8, and ILT11) have short cytoplasmic domains that lack ITIMs or recognizable docking motifs for signaling mediators. If LILRs have evolved under the selective pressure of UL18, one would also expect that UL18 mutates to neutralize this strategy of the host immune system. A recent study suggests that the ability of inhibitory LILRs to regulate the function of antigen-presenting cells (APCs) may be an important mechanism utilized by suppressor T (Ts) cells to induce immunological tolerance.
Antimicrobial peptides are evolutionarily ancient weapons, which along with regulatory proteins such as the Toll receptor families have provided complex multicellular organisms with the defenses needed to effectively compete in a world dominated by microbes. Antimicrobial peptides from plants and animals have been discussed in the chapter. The amphipathic property of antimicrobial peptides permits them to achieve high concentrations both in the aqueous solution through which they must travel to reach their targets and in the fatty membranes of microbes into which they must penetrate. The discovery that Toll and Toll-like receptors (TLRs) played a role in antimicrobial peptide gene expression in insects and mammals led to a search for additional human homologues, driven by the hypothesis that the innate immune system utilizes specially tuned receptors to recognize specific and unique microbial chemical constituent patterns presented when microbes attack a multicellular organism. Antimicrobial peptides provide epithelial surfaces with protective agents that permit an animal to construct a physical barrier out of materials that could otherwise serve as a source of nutrients for microbes. Antimicrobial peptides, including both α- and β-defensins, are widely expressed in the male reproductive tracts of rats, mice, and humans. Antimicrobial peptides, released from circulating cells or induced in epithelia, can alert the adaptive immune system to trouble brewing. Over the past several years the functional categorization of antimicrobial peptides has been blurred somewhat by the discovery that numerous peptide hormones and cytokines exhibit potent antimicrobial activity in vitro.
Antimicrobial proteins are widely distributed in host defense cells and secretions. Antimicrobial proteins are also abundant in the secretions of epithelia exposed to environmental microbes (e.g., in the skin, nose and bronchi, the mouth, and the surface of the eyes). Classical characterization of antimicrobial proteins usually requires their extraction from the tissues or cells of origin, followed by activity-guided purification to homogeneity. Some antimicrobial proteins are enzymes that lyse the protein, lipid, carbohydrate, or perhaps nucleic acid components of microbes. Lysozyme is widely distributed in animal tissues. In humans, high concentrations of lysozyme are present in the cytoplasmic granules of neutrophils and Paneth cells, and in cellular and secretory compartments of monocytes and macrophages. Mice lacking neutrophil elastase are susceptible to infections with gram-negative bacteria, and mice doubly deficient in neutrophil elastase and cathepsin G are susceptible to fungal infection with Aspergillus fumigatus and resistant to the endothelial injury seen in endotoxic shock, suggesting an important role for serprocidins in both host defense and its pathological consequences. Both epithelia and phagocytes secrete protease inhibitors, of which the secretory leukoprotease inhibitor (SLPI) is the most abundant. Granulysin and its fragments display a broad spectrum of activity against many bacteria including Mycobacterium tuberculosis, and the protein has also been shown to contribute to CD8 T-cell-mediated killing of the yeast Cryptococcus Neoformans.
This chapter focuses on the sources, the regulation, the spectrum of activities, and the viral and microbial targets of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) generated by mammalian host cells. With respect to the control of infectious agents, the two most important oxygen-dependent pathways for the generation of antiviral or antimicrobial effector molecules are the phagocyte NADPH oxidase (Phox) and the inducible nitric oxide synthase (iNOS) pathways. One of the most intriguing discoveries in the field of ROIs in recent years was the observation by Wentworth and colleagues that antibodies, independent of their source or antigen specificity, can catalyze the generation of ROIs. Members of all groups of infectious pathogens (viruses, bacteria, protozoa, helminths, and fungi) were found to be controlled by RNIs. The significant improvement of certain infectious diseases after inhibition or genetic deletion of iNOS, which was without negative effects on the pathogen clearance, was unexpected. It can be explained by the inhibition of T-cell proliferation or induction of T-cell apoptosis via iNOS-positive suppressor cells (macrophages and dendritic cells) or by the tissue-damaging properties of RNIs. Transgenic mouse models have been extremely helpful to elucidate the relative contributions of ROIs and RNIs for the control of infectious pathogens. Viruses, bacteria, parasites, and fungi have developed multiple strategies to evade killing by oxygen-dependent effector mechanisms. Current research projects aim at the development of ROI or RNI precursors that enter only certain types of host cells and are activated by the infectious pathogens themselves.
Early progress was made for those chemokines with unique selectivity for cells of the innate immune system, giving the impression that T and B cells are poor targets for chemokines. Of course, it is now thoroughly established that chemokine selectivity reaches well beyond monocytes and phagocytes, embracing all types of leukocytes, including T and B cells as well as hematopoietic progenitor cells. Recent exciting progress focuses on the recognition that certain G-protein-coupled receptors (GPCRs) also signal by G-protein-independent mechanisms. Recent reports demonstrated the involvement of chemokines in tumor metastasis, a finding that seems to be related to the chemokine-typical control of leukocyte traffic. In support, one group reported dimerization of chemokine receptors (such as CXCR4, CCR2, or CCR5) and suggested that higher-order structure formation is a prerequisite for chemokine receptor signaling. Although tissue cell recruitment and localization may be fundamental roles played by chemokines in tissue remodeling and secondary tumor formation, elucidation of leukocyte mobilization-unrelated functions is one of the major topics in current chemokine research. Importantly, changes in the diversity of local chemokines during ongoing inflammatory processes directly affect the composition of the inflammatory infiltrates and, as such, dictate disease evolution. Future challenges in chemokine research are related to tissue cell responses to chemokines and include the potential effect of chemokines on tissue cell growth and differentiation during organogenesis and tissue repair.
Lipids are an essential constituent of cell membranes and are sources of energy. Lipid mediator generation can be entirely innate or composite via an adaptive immune step. This chapter addresses only primary innate or exogenous signals assessed in vitro and in vivo. In vivo discussion is limited to studies in null mouse strains for clarity. The activation of phospholipase A2 (PLA2) with release of arachidonic acid provides the substrate for all eicosanoids, namely, prostanoids and leukotrienes (LTs). Although certain residual lysophospholipids by acetylation become platelet-activating factor (PAF), other lysophospholipids are generated by more complex pathways. PLA2 comprises a diverse family of enzymes that cleave the sn-2 position of glycerophospholipids to form a fatty acid and a lysophospolipid. PLA2 is involved in the digestion of phospholipids in the diet and in the metabolism and turnover of phospholipids in cell membranes. Lysophosphatidic acid (LPA) and S1P are bioactive lysophospholipids with cell functions that include growth, inhibition of apoptosis, differentiation, migration, and cytoskeletal rearrangement. The major biosynthetic pathway of LPA is initiated by the action of phospholipase D on phospholipids to form phosphatidic acid and then the cleavage of the sn-2 position of the fatty acid by phosphatidic acid-specific PLA2 to form LPA. Two lysophospholipds containing lysophosphorylcholine, namely, sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC), are involved in many biological processes including cell proliferation and growth inhibition.
This chapter focuses on innate immunity against bacterial pathogens with emphasis on the local response at the two major sites of entry, lung and gut. Infection of a number of experimental animal species with Mycobacterium tuberculosis provides suitable models for in vivo studies. In terms of the host response, most has been learned from the immunologically well-established mouse model employing the physiological route of infection via aerosols. Recently, angiogenins (ANGs), RNases released from Paneth cells, have been identified to discriminate between commensal and exogenous bacteria in the intestine. In mammalian cells, activation via toll-like receptors (TLRs) results in stimulation of the innate immune system, including upregulation of cytokines, chemokines, costimulatory molecules, and oxidative burst. Listeriosis is characterized by bacterial dissemination from the gut lumen to the central nervous system via the blood-brain barrier and to the fetus via the fetoplacental barrier. The highly organized microarchitecture of secondary lymphoid organs forms the basis for antigen trapping. The spleen is responsible for filtering blood-borne particles. Kupffer cells, the resident tissue macrophages of the liver, adhere to the endothelial cells of the liver sinusoids and are most densely accumulated in the periportal region. Chemokines are critical mediators of leukocyte trafficking, including attraction to sites of inflammation. Mycobacteria-specific antibodies are produced by type 2 B cells abundantly during active tuberculosis. Tuberculosis patients exhibit elevated levels of pleural neutrophil defensins.
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