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Innate Immunity Reviews

(75 References)

Alam, R. and M. Gorska (2003). "3. Lymphocytes." J Allergy Clin Immunol 111(2 Suppl): S476-85.

            The fundamental task of the immune system is to defend "self" from "nonself." Lymphocytes are the primary cells of the immune system that developed one of the most sophisticated and comprehensive defense mechanisms in the biological system. T cells play a central role in orchestrating the immune response. Further, they are instrumental in eliminating intracellular pathogens (viruses, some bacteria) through the generation of cytotoxic T cells. B cells defend against extracellular pathogens by producing antibodies. Natural killer cells are an important component of innate immunity. Dendritic cells play a key role in initiating the immune response by presenting foreign antigens to T cells. The interaction among T cells, B cells, dendritic cells, and natural killer cells constitute the fundamental defense network of the host. The failure of any of these components severely jeopardizes the integrity of the immune system and its ability to mount the most appropriate immune response.

Aoki, N., S. Kimura, et al. (2003). "Role of DAP12 in innate and adaptive immune responses." Curr Pharm Des 9(1): 7-10.

            DAP12 is a novel immunoreceptor tyrosine-based activation motifs (ITAM)-bearing transmembrane adapter molecule. This molecule, together with its partner receptor complex molecules including the killer cell activating receptors (KARs), myeloid DAP12 associating lectin-1 (MDL-1), triggering receptor expressed on myeloid cells 1/2/3 (TREM-1, TREM-2, TREM-3), and signal regulatory protein beta1 (SIRPbeta1), are expressed on the surface of NK and myeloid cells including antigen presenting cells. While the function of DAP12 and its associating molecules has just begun to be unveiled, emerging evidence suggests that these molecules play an important role in both innate and adaptive immune responses. In this review, we intend to provide an overview on what have been known and are still unknown to date about the function of these molecules based on the observations made by us and others.

Beutler, B. and E. T. Rietschel (2003). "Innate immune sensing and its roots: the story of endotoxin." Nat Rev Immunol 3(2): 169-76.

            How does the host sense pathogens? Our present concepts grew directly from longstanding efforts to understand infectious disease: how microbes harm the host, what molecules are sensed and, ultimately, the nature of the receptors that the host uses. The discovery of the host sensors--the Toll-like receptors--was rooted in chemical, biological and genetic analyses that centred on a bacterial poison, termed endotoxin.

Blasko, I. and B. Grubeck-Loebenstein (2003). "Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease." Drugs Aging 20(2): 101-13.

            The dysregulation in the metabolism of beta-amyloid precursor protein and consequent deposition of amyloid-beta (Abeta) has been envisaged as crucial for the development of neurodegeneration in Alzheimer's disease (AD). Amyloid deposition begins 10-20 years before the appearance of clinical dementia. During this time, the brain is confronted with increasing amounts of toxic Abeta peptides and data from the last decade intriguingly suggest that both the innate and the adaptive immune systems may play an important role in the disorder. Innate immunity in the brain is mainly represented by microglial cells, which phagocytose and degrade Abeta. As the catabolism of Abeta decreases, glial cells become overstimulated and start to produce substances that are toxic to neurons, such as nitric oxide and inflammatory proteins. Pro-inflammatory cytokines can be directly toxic or stimulate Abeta production and increase its cytotoxicity. A therapeutic possibility arises from clinical studies, which demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD. Recent data show that in addition to the suppression of inflammatory processes in the brain NSAIDs may decrease the production of Abeta peptides. The role of adaptive immunity lies mainly in the fact that Abeta can be recognised as an antigen. Immunisation with Abeta peptides and peripheral administration of Abeta-specific antibodies both decrease senile plaques and cognitive dysfunction in murine models of AD. A recent trial in humans seems still to be hampered by adverse effects. As adaptive immunity decreases with aging while innate immunity remains intact, immunotherapy for AD will have to be adapted to this situation. Strategies that combine vaccination and inflammatory drug treatment could be considered.

Capuron, L. and R. Dantzer (2003). "Cytokines and depression: the need for a new paradigm." Brain Behav Immun 17 Suppl 1: S119-24.

            Considerable clinical and experimental data support the existence of a relationship between cytokines and depression. At the experimental level, proinflammatory cytokines have been found to induce alterations in brain function analogous to the behavioral and biological abnormalities occurring in depressed patients, including social withdrawal, cognitive impairment, anhedonia, increased activity of the hypothalamus-pituitary-adrenal axis, altered neurotransmission, and cross-sensitization with stressors. At the clinical level, the evidence in favor of innate immune system activation in depressed patients is still controversial, despite accumulating evidence for an increased risk of depressive disorders in patients receiving recombinant cytokines for the treatment of cancer and viral infection. This last issue has received significant attention recently, given that the administration of therapeutic cytokines provides a quasi-experimental model for studying the mechanisms which underlie the effects of cytokines on mood, cognition, and neurovegetative functions. Although the vulnerability factors that account for the risk of depression have yet to be identified, tryptophan depletion, likely related to the induction of indoleamine 2,3-dioxygenase enzyme, may represent an important mediator for the development of depressed mood in cytokine-treated patients. This paper discusses ways in which these emerging data may lead to advances in the recognition and management of non-specific neurobehavioral symptoms associated with the development and progression of cancer.

Caucheteux, S. M., C. Kanellopoulos-Langevin, et al. (2003). "At the innate frontiers between mother and fetus: linking abortion with complement activation." Immunity 18(2): 169-72.

            The intricate mechanisms regulating fetomaternal interactions are still largely uncharacterized. Recent papers have revealed a major role for the innate immune system during abortion. Different experimental conditions-deletion of a complement regulator, injection of anti-phospholipid antibodies into mothers, or allo-recognition of fetuses in the presence of an IDO inhibitor-all lead to complement activation, inflammation, and fetal loss. These observations also raise new questions on the relationship between the adaptive and innate systems during pregnancy.

Chang, K. M. (2003). "Immunopathogenesis of hepatitis C virus infection." Clin Liver Dis 7(1): 89-105.

            HCV infection becomes persistent in many patients who are otherwise immune competent. There is increasing support for potential contribution of innate immune response and viral interference with its components to the subsequent outcome. As for the adaptive immune response, humoral immunity may be largely ineffective despite evidence for neutralizing antibody response directed to the E2 HVR region, perhaps due to rapid selection of antibody escape variants. Cellular immune response does seem to play a role in the virologic outcome during acute infection based on strong association of a sustained vigorous and multispecific antiviral CD4 and CD8 T cell response with HCV clearance during acute infection. Following clearance, vigorous CD4 T cell response to HCV is maintained for many years, whereas the memory CD8 T cell response may be maintained with variable efficiency. If unable to clear the virus quickly, the T cell response (particularly if focused) may also select for T cell escape variants that are poorly recognized by the circulating T cells or even actively inactivate them through T cell antagonism. In established chronic infection. HCV-specific T cell response is quantitatively weak, providing only minimal selection pressure for further escape mutation. Although earlier studies using conventional in vitro techniques suggest that this low-frequency T cell response may help control the virus and liver disease progression, the role and nature of these apparently defective T cells in the outcome of chronic HCV infection remains to be fully determined. In summary, much progress has been made in the field of HCV immune pathogenesis since the initial identification of HCV. Although more work is needed to define the mechanism of HCV persistence and liver cell injury, there is considerable hope as well as challenge for potential development of vaccine and immunotherapy for HCV infection (see article by Drs. Inchaupse and Feinstone). A better understanding of the relevant host and viral factors for clinical and virologic outcome, and the mechanism of selective immune defect against HCV, will be invaluable in our ability to treat the many patients infected with HCV.

Chaplin, D. D. (2003). "1. Overview of the immune response." J Allergy Clin Immunol 111(2 Suppl): S442-59.

            Host defense against pathogenic microbes requires dramatically different responses, depending on the character of the pathogen and on the tissue under attack. Central to the immune system's ability to mobilize a response to an invading pathogen is its ability to distinguish self from nonself. The host has evolved both innate and adaptive mechanisms to respond to and eliminate pathogenic microbes. Both of these mechanisms include self-nonself discrimination. This overview describes key mechanisms used by the immune system to respond to invading microbes and identifies settings in which disturbed immune function exacerbates tissue injury.

Chiba, H., S. Pattanajitvilai, et al. (2003). "Pulmonary surfactant proteins A and D recognize lipid ligands on Mycoplasma pneumoniae and markedly augment the innate immune response to the organism." Chest 123(3 Suppl): 426S.

Cook, D. N., S. Wang, et al. (2003). "The genetics of innate immunity in the lung." Chest 123(3 Suppl): 369S.

Cooper, E. L. (2003). "Comparative immunology." Curr Pharm Des 9(2): 119-31.

            Comparative Immunology has gained wide acceptance in biology, as an offspring of immunology and an amalgam of immunology and zoology. The prescient experiments of Metchnikoff on phagocytosis in invertebrates during the 19th century served to splinter immunology into its two main components: cellular and humoral. There is much interest in the immune system of invertebrates as representing early models or precursors of the innate system of vertebrates that by contrast possess the innate system as well as the more highly evolved adaptive system. With respect to mechanisms, we think of the invertebrate system as innate, natural, non-specific, non-anticipatory, and non-clonal. Innate immunity operates through leukocytes that are not components of the macrophage T and B interrelationships that characterize vertebrate adaptive immunity that is adaptive, induced, specific, anticipatory, and clonal. This symposium on invertebrate immunology has provided an overview of what is current and crucial to understanding the larger field of comparative immunology. Comparative immunology is now an established field, here since Metchnikoff but officially since about 1977, with a journal (Developmental and Comparative Immunology) (DCI) and an International Society of Developmental and Comparative Immunology (ISDCI). During this short but vigorous history several national, adherent societies have been organized in Japan, Italy and Germany with sporadic interest in a national group in the USA. Nevertheless, comparative immunology is here as vital to zoology in general and to immunology in particular as we delve deeper into unique but also shared characteristics.

Danelishvilli, L. and L. E. Bermudez (2003). "Role of type I cytokines in host defense against Mycobacterium avium infection." Curr Pharm Des 9(1): 61-5.

            Mycobacterium avium is a human pathogen that causes infection in immunocompetent as well as immunocompromised patients. Infection is acquired both by the respiratory and gastrointestinal routes, and bacterial invasion of mucosal epithelial cells is characteristic. M. avium crosses the mucosal barrier without triggering substantial inflammatory response. Once in the intestinal submucosa or in the alveolar space M. avium infects macrophages. Intracellular bacteria block the production of cytokines involved in the host response against the infection, such as TNF-alpha and IL-12, and suppress antigen presentation by the macrophage. Innate response against the infection is effective to certain extent but the ability of the bacterium to remain "silent" for a period of time prevents neutrophil and NK cells from effectively controlling the establishing of the infection. CD4+ T cells as well as CD8+ T cells are activated, although only CD4+ T cells appear to be effective in inducing anti-M. avium activity in macrophages. M. avium-specific CD8+ T cells undergo apoptosis early in the infection. Therefore, the immune mechanisms of the host and bacterial strategies for survival are complex and fascinating.

Das, G. and C. A. Janeway, Jr. (2003). "MHC specificity of iIELs." Trends Immunol 24(2): 88-93.

            Intestinal intra-epithelial lymphocytes (iIELs) are a major lymphocyte population, reside in close proximity to the intestinal lumen and are conserved throughout vertebrate evolution. iIELs consist of several unique T-cell phenotypes and express both non-rearranged innate immune receptors and rearranged adaptive immune receptors. The ligands for the innate immune receptors on iIELs, such as NKG2D (natural killer-cell receptor), often bind to non-classical MHC class I molecules, such as the human MHC class I-related molecules MICA or MICB. These ligands costimulate T-cell receptor (TCR)-mediated signaling. In most cases, the MHC molecules that bind to the TCR are still unknown. However, recent efforts to understand the MHC molecules that are involved in the development of and antigen recognition by iIELs have revealed several important results. Here, we focus systematically on recent developments in innate immunity and in TCR recognition of different subtypes of iIELs by various MHC molecules.

Dascher, C. C. and M. B. Brenner (2003). "CD1 antigen presentation and infectious disease." Contrib Microbiol 10: 164-82.

            Taken together, the data generated thus far strongly suggest that CD1 plays a role in the immune response against various infections (table 1). For obvious reasons, the data gathered thus far using model infection systems have focused primarily on the mouse and therefore only examine the role of CD1d. This leaves an important gap in our understanding of the CD1 antigen presentation pathway given the potential role of CD1a, CD1b and CD1c for contributing to antimicrobial immunity. The functional dichotomy between group 1 and group 2 CD1 isoforms obviously requires further analysis. However, we propose that the group 1 CD1 (CD1a, CD1b, CD1c) antigen presentation pathway is closer to the traditional adaptive immune response mechanisms with the capacity to present unique foreign antigens to specific T cells. This broadens the universe antigens that T cells can use to target pathogens and provides important antimicrobial effector mechanisms that may be critical for combating some types of infections. Lipid antigens may also provide a more effective means of targeting intracellular pathogens by T cells since CD1 is able to sample almost all of the intracellular reservoirs that are exploited by this class of pathogen and may provide an important component of the cytotoxic T cell response [80]. On the other hand, the group 2 CD1 protein (CD1d) may be more intermediate in terms of lying functionally between the innate and adaptive immune systems. The activation of CD1d-restricted T cells may, therefore, help bridge the temporal gap between the onset of innate immunity and the purely adaptive responses typified by the MHC-restricted T cells. Hence, the CD1d-restricted [table: see text] T cells are primed for rapid high-level cytokine release. In addition, the interaction of CD1d-restricted T cells with CD1d on DCs can trigger the release of IL-4 and GM-CSF to promote maturation of tissue-resident DC at the site of infection. The maturation of tissue DC would lead to migration of the activated DC to regional lymph nodes and initiation of MHC-restricted T cell responses. Subsequent IL-12 production by the DC in response to CD1d-mediated T cell stimulation could then drive IFN-gamma production by CD1d-restricted T cells and influence the polarization of the T cell response to infection. In addition, early bursts of IFN-gamma by CD1d-restricted T cells could also upregulate antimicrobial activity in macrophages and activate other important effector cells such as NK cells prior to MHC-restricted T cell responses. In the constant struggle between the microbial pathogen and its host, the evolutionary balance almost always favors the microbe. The rapid rate of evolution and adaptation of the microbe accounts for most of this advantage. Hence, it is not surprising that the host immune system has evolved a complex set of pathways, in addition to the MHC, that are able to recognize and target the unique molecular signatures of infectious microorganisms. The lipid antigens presented by CD1 add to this array and thus provide a further layer of immune defense to the host for combating pathogens.

de Eguileor, M., G. Tettamanti, et al. (2003). "Leeches: immune response, angiogenesis and biomedical applications." Curr Pharm Des 9(2): 133-47.

            The innate immune response is the first line of defence strategies in invertebrates against attack of infectious agents. A detailed analysis of the immune mechanisms involved in annelids has been performed in oligochaets, but few data are available in polichaets and hirudineans. The aim of this review is to describe the responses of leeches to different kinds of stimuli (infections following non-self agent attacks, surgical lesions, grafts). Furthermore, the use of this invertebrate as a novel experimental model to be used to screen drugs and genes, which are responsible for positive and negative modulation of angiogenesis, is discussed.

Desiderio, S. and J. Y. Yoo (2003). "A genome-wide analysis of the acute-phase response and its regulation by Stat3beta." Ann N Y Acad Sci 987: 280-4.

            The acute-phase response (APR) is the systemic inflammatory component of innate immunity. A global assessment of hepatic gene expression during an APR has been undertaken. In response to endotoxin, an inducer of the APR, about 7% of mouse genes exhibited significant changes in expression. Genes for cholesterol, fatty acid, and phospholipid synthesis were suppressed, while genes participating in innate defense and antigen presentation were induced. Upon challenge with endotoxin, mice deficient in Stat3beta, a dominant-negative variant of Stat3, exhibited impaired recovery and susceptibility to protracted shock. These findings are accompanied by overexpression and hyperresponsiveness of a subset of lipopolysaccharide (LPS)-inducible genes in liver, suggesting a critical role for Stat3beta in the control of systemic inflammation.

Desjardins, M. (2003). "ER-mediated phagocytosis: a new membrane for new functions." Nat Rev Immunol 3(4): 280-91.

            Genomics and other high-throughput approaches, such as proteomics, are changing the way we study complex biological systems. In the past few years, these approaches have contributed markedly to improving our understanding of phagocytosis. Indeed, the ability to study biological systems by monitoring hundreds of proteins provides a level of resolution that is not attainable by the usual 'one protein at a time' approach. In this article, I discuss how proteomic approaches have revealed surprising findings that enable us to revisit established concepts, such as the origin of the phagosome membrane, and to propose new models of cell organization and the link between innate and adaptive immunity.

Dhabhar, F. S. (2003). "Stress, leukocyte trafficking, and the augmentation of skin immune function." Ann N Y Acad Sci 992: 205-17.

            Delayed type hypersensitivity (DTH) reactions represent cell-mediated immune responses that exert important immunoprotective (resistance to viruses, bacteria, and fungi) or immunopathologic (allergic or autoimmune hypersensitivity) effects. We have used the skin DTH response as an in vivo model to study neuro-endocrine-immune interactions. We hypothesized that just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges (e.g., wounding) that may be imposed by a stressor (e.g., an aggressor). Studies showed that acute (2 hours) stress experienced before primary or secondary cutaneous antigen exposure induces significantly enhanced skin DTH. This enhancement involves innate as well as adaptive immune mechanisms. Adrenalectomy eliminates the stress-induced enhancement of DTH. Acute administration of physiological concentrations of corticosterone and/or epinephrine to adrenalectomized animals enhances skin DTH. Compared with those in controls, DTH sites from acutely stressed or hormone-injected animals show significantly greater erythema and induration, numbers of infiltrating leukocytes, and levels of cytokine gene expression. In contrast to acute stress, chronic stress is immunosuppressive. Chronic exposure to corticosterone or acute exposure to dexamethasone significantly suppresses skin DTH. These results suggest that during acute stress, endogenous stress hormones enhance skin immunity by increasing leukocyte trafficking and cytokine gene expression at the site of antigen entry. Elucidation of mechanisms mediating a stress-induced enhancement of skin immune function is important because such immunoenhancement can have protective (wound healing, resistance to infection) or pathological (allergic or autoimmune hypersensitivity) consequences.

Diefenbach, A. and D. H. Raulet (2003). "Innate immune recognition by stimulatory immunoreceptors." Curr Opin Immunol 15(1): 37-44.

Dimopoulos, G. (2003). "Insect immunity and its implication in mosquito-malaria interactions." Cell Microbiol 5(1): 3-14.

            Insects' resistance to infectious agents is essential for their own survival and also for the health of the plant, animal and human populations with which they closely interact. Several of the major human diseases are spread by insects and are rapidly expanding as a result of the development of insecticide resistance in vectors and drug resistance in parasites. A vector insects' permissiveness to a pathogen, and hence the spread of the disease, will largely depend on the compatibility of the molecular interactions between the two species and the capability of the insect immune system to recognize and kill the pathogen. The innate immune system comprises a variety of components and mechanisms that can discriminate between different microorganisms and mount specific responses to control pathogenic infections. An impressive body of knowledge on the insects' innate immunity has been generated from studies in the model organism Drosophila. These studies are now guiding the exploration of the immune system in the vector mosquito of human malaria, Anopheles, and its implication in the elimination of parasites. Anopheles immune responses have been linked to parasite losses and some refractory mosquitoes can kill all parasites through specific defence mechanisms. The recently sequenced Drosophila and Anopheles genomes provide a detailed and comparative view on their immune gene repertoires that in combination with post-genomic analyses is used to further dissect the complex mechanisms of Plasmodium killing in the mosquito.

Donovan, K. L. and N. Topley (2003). "What are renal defensins defending?" Nephron Exp Nephrol 93(4): e125-8.

            Defense against the susceptibility and damaging effects of urinary tract infection is complex and vital, as injury can lead to progressive renal injury and chronic renal failure. Recently the defensins, a family of small cationic antimicrobial peptides found in neutrophils and renal epithelial cells, have been shown to have a number of key biological properties that equip them to undertake a pivotal role in combating infection. We describe the capability of these ubiquitous and abundant peptides in the process of innate immunity, and more recently discovered roles in the adaptive immune response to infection. Furthermore, we also discuss their potential to influence other key components of the inflammatory response to infection. Despite the current state of knowledge, we are only just beginning to understand the significance of defensins as pivotal peptides in host defence and their possibilities as therapeutic targets of the future.

Dunne, A. and L. A. O'Neill (2003). "The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense." Sci STKE 2003(171): re3.

            The signal transduction pathways activated by the proinflammatory cytokine interleukin-1 (IL-1) have been the focus of much attention because of the important role that IL-1 plays in inflammatory diseases. A number of proteins have been described that participate in the post-receptor activation of the transcription factor nuclear factor kappaB (NF-kappaB), and stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK). It has also emerged that the type I IL-1 receptor (IL-1RI) is a member of an expanding receptor superfamily. These related receptors all have sequence similarity in their cytosolic regions. The family includes the Drosophila melanogaster protein Toll, the IL-18 receptor (IL-18R), and 10 Toll-like receptors (TLRs), TLR-1 to TLR-10, which bind to microbial products, activating host defense responses. Because of the similarity of IL-1RI to Toll, the conserved sequence in the cytosolic region of these proteins has been termed the Toll-IL-1 receptor (TIR) domain. The same proteins activated during signaling by IL-1RI also participate in signaling by other receptors with TIR domains. The receptor superfamily is evolutionarily conserved; members also occur in plants and insects, where they also function in host defense. The signaling proteins that are activated are also conserved across species. Differences are, however, starting to emerge in signaling pathways activated by different receptors. This receptor superfamily, therefore, represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses.

Elkins, K. L., S. C. Cowley, et al. (2003). "Innate and adaptive immune responses to an intracellular bacterium, Francisella tularensis live vaccine strain." Microbes Infect 5(2): 135-42.

            The immune response to intracellular bacterium, Francisella tularensis, which causes tularemia and is proposed to be a potential bioterrorism pathogen, has been studied in mice using the attenuated live vaccine strain (LVS). Here we review this infection model, which provides a convenient means of studying protective immune mechanisms not only for Francisella, but also for the large and important class of intracellular pathogens.

Elsbach, P. (2003). "What is the real role of antimicrobial polypeptides that can mediate several other inflammatory responses?" J Clin Invest 111(11): 1643-5.

            Antimicrobial peptides are effector molecules of innate immunity with microbicidal and pro- or anti-inflammatory activities. Their role is now widening following evidence that one such multifunctional peptide, LL-37, induces angiogenesis, a process essential for host defense, wound healing, and tissue repair.

Favoreel, H. W., G. R. Van de Walle, et al. (2003). "Virus complement evasion strategies." J Gen Virol 84(Pt 1): 1-15.

            The immune system has a variety of tools at its disposal to combat virus infections. These can be subdivided roughly into two categories: 'first line defence', consisting of the non-specific, innate immune system, and 'adaptive immune response', acquired over time following virus infection or vaccination. During evolution, viruses have developed numerous, and often very ingenious, strategies to counteract efficient recognition of virions or virus-infected cells by both innate and adaptive immunity. This review will focus on the different strategies that viruses use to avoid recognition by one of the components of the immune system: the complement system. Complement evasion is of particular importance for viruses, since complement activation is a crucial component of innate immunity (alternative and mannan-binding lectin activation pathway) as well as of adaptive immunity (classical, antibody-dependent complement activation).

Fondevila, C., R. W. Busuttil, et al. (2003). "Hepatic ischemia/reperfusion injury--a fresh look." Exp Mol Pathol 74(2): 86-93.

            Ischemia/reperfusion (I/R) injury is a multifactorial process that affects graft function after liver transplantation. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and ultimate organ failure. Increased experimental evidence has suggested that Kupffer cells and T cells mediate the activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase system is among the most critical of the cytoprotective mechanisms activated during cellular stress, exerting antioxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. Finally, the activation of toll-like receptors on Kupffer cells may play a fundamental role in exploring new therapeutic strategies based on the concept that hepatic I/R injury represents a case for a host "innate" immunity.

Gewirtz, A. T. (2003). "Intestinal epithelial toll-like receptors: to protect. And serve?" Curr Pharm Des 9(1): 1-5.

            The innate immune system uses a series of pattern recognition receptors to detect the presence of pathogens thus allowing for rapid host defense responses to invading microbes. A key component of such receptors are the "toll-like receptors" (TLRs), which recognize a panel of microbial molecules that tend to be somewhat invariant, at least in select regions, thus permitting a relatively small number of receptors to recognize a large number of different microbes. Accordingly, this panel of TLRs bears little ability to distinguish between commensal and pathogenic microbes as such organisms generally bear far more structural similarities than differences between them. For the professional phagocytic cells classically considered to be the primary mediators of innate immunity such distinction between commensal and pathogenic microbes is not particularly important since any microbe that breaches the outer host defensive barriers to reach these phagocytes, whether doing so by a pathogen-specific or opportunistic mechanism, is likely potentially hazardous to its host. However, epithelial cells that line mucosal surfaces, thus being on the front line of host defense, also play an active role in innate immunity particularly by secreting chemokines and other immune mediators in response to pathogenic microbes. Epithelial cells have been reported to express several TLRs suggesting these receptors play a role in intestinal epithelial innate immune signaling pathways. However, since some mucosal surfaces such as the intestinal epithelium are normally densely colonized by a wide variety of microbes, the ability to distinguish the occasional pathogen from the sea of commensals presents an important challenge. This minireview considers the current findings regarding TLR expression in the intestinal epithelium and the role these receptors might serve in host defense.

Granucci, F. and P. Ricciardi-Castagnoli (2003). "Interactions of bacterial pathogens with dendritic cells during invasion of mucosal surfaces." Curr Opin Microbiol 6(1): 72-6.

            Recent studies of mucosal immunity suggest a key role for dendritic cells in the regulation of gut immune responses, in both physiological and pathological conditions. Dendritic cells are widely distributed in the lamina propria of the gut and are involved in direct bacterial uptake across mucosal surfaces, which questions the role of dendritic cells in innate mucosal responses. Approximately 400 commensal microbial species are present in the gut lumen. So how do dendritic cells distinguish pathogens from luminal microflora? Are the cytokines and chemokines induced in dendritic cells tailored to the class of microbes being recognized? Several very important questions still need to be addressed.

Griffin, D. E. (2003). "Immune responses to RNA-virus infections of the CNS." Nat Rev Immunol 3(6): 493-502.

            A successful outcome for the host of virus infection of the central nervous system (CNS) requires the elimination of the virus without damage to essential non-renewable cells, such as neurons. As a result, inflammatory responses must be tightly controlled, and many unique mechanisms seem to contribute to this control. In addition to being important causes of human disease, RNA viruses that infect the CNS provide useful models in which to study immune responses in the CNS. Recent work has shown the importance of innate immune responses in the CNS in controlling virus infection. And advances have been made in assessing the relative roles of cytotoxic T cells, antibodies and cytokines in the clearance of viruses from neurons, glial cells and meningeal cells.

Hansen, T. K. (2003). "Growth hormone and mannan-binding lectin: emerging evidence for hormonal regulation of humoral innate immunity." Minerva Endocrinol 28(1): 75-84.

            An increasing number of studies in animals and humans indicate that growth hormone (GH) and insulin-like growth factor-I (IGF-I) modulate immune function. It was recently reported that, surprisingly, GH therapy increased the mortality in critically ill patients. The excessive mortality was almost entirely due to septic shock or multi-organ failure, which could suggest that a GH-induced modulation of immune function was involved. Mannan-binding lectin (MBL) is a plasma protein that plays an important role in innate immunity through activation of the complement cascade and inflammation following binding to carbohydrate structures. The serum concentration of MBL is subject to large between-subjects differences, which primarily are caused by genetic factors. However, mounting evidence supports a significant influence from growth hormone on MBL levels. In the present review, we focus on the function of MBL, on the influence of growth hormone on MBL levels, and on the possible clinical consequences of this new link between the endocrine and the immune system.

Harandi, A. M., J. Sanchez, et al. (2003). "Recent developments in mucosal immunomodulatory adjuvants." Curr Opin Investig Drugs 4(2): 156-61.

            A large proportion of pathogens either invade through, or cause disease at mucosal surfaces. Many new generation mucosal vaccine candidates lack important immunostimulatory features of the original pathogens and thus often do not elicit sufficiently strong immune responses. Despite numerous efforts, there is a profound lack of available agents with mucosal immunomodulatory and adjuvant activity. Immunomodulatory adjuvants are often derived from pathogens and thus efficiently activate the innate immune system leading to subsequent development of strong, specific acquired immunity. In this review, recent advances in mucosal immunomodulators/adjuvants are described with special emphasis on recently developed detoxified cholera toxin and Escherichia coli heat labile enterotoxin derivatives, and the newly described Toll-like receptor ligands CpG DNA and imidazoquinoline compounds. These agents hold much promise as useful mucosal immunomodulators/adjuvants for induction of strong innate immune response and also for subsequent development of specific acquired immunity against mucosal pathogens.

Heine, H. and E. Lien (2003). "Toll-like receptors and their function in innate and adaptive immunity." Int Arch Allergy Immunol 130(3): 180-92.

            Over the past 3 years our knowledge about how we sense the microbial world has been fundamentally changed. It has been known for decades that microbial products, such as lipopolysaccharide, lipoproteins, or peptidoglycan, have a profound activity on human cells. Whereas the structure of many different pathogenic microbial compounds has been extensively studied and characterized, the molecular basis of their recognition by the cells of the innate immune system remained elusive for a long time. It was Charles Janeway [Cold Spring Harb Symp Quant Biol 1989;54/1:1-13] who developed the idea of microbial structures forming pathogen-associated molecular patterns that would be recognized by pattern recognition receptors. The discovery of the family of Toll receptors in species as diverse as DROSOPHILA and humans, and the recognition of their role in distinguishing molecular patterns that are common to microorganisms have led to a renewed appreciation of the innate immune system. Moreover, it is now clear that the activation of the innate immune system through mammalian Toll-like receptors has also an instructive role for the responses of the adaptive immune response and, thus, may influence allergic diseases such as asthma.

Holt, B. F., 3rd, D. A. Hubert, et al. (2003). "Resistance gene signaling in plants--complex similarities to animal innate immunity." Curr Opin Immunol 15(1): 20-5.

Isaguliants, M. G. and N. N. Ozeretskovskaya (2003). "Host background factors contributing to hepatitis C virus clearance." Curr Pharm Biotechnol 4(3): 185-93.

            This review is an attempt to characterize the host in the earliest events of hepatitis C virus (HCV) infection before the on-set of adaptive immune response. Host meets the replicating HCV with innate immune response in the form of proinflammatory cytokine production, activation of natural killer (NK), NKT and dendritic cells. The potency of innate response is shaped by a wide panel of genetically predetermined constants and acquired variables. Higher rates of HCV clearance associate with white ethnicity and certain HLA haplotypes. Lower clearance rates correlate with genetic immune deficiencies/disorders. Recent findings link infection outcome with variation in the genes for the low-density lipoprotein and complement type 1 receptors. Important though insufficiently characterized is the role of polymorphisms in the genes responsible for induction of antiviral immunity. The outcome of HCV entry and of subsequent acute infection (if that occurs) is pre-determined by the immune competence of the host at the moment of infection. Higher rate of HCV clearance is observed for pediatric patients and young adults. Bad prognostic markers would be post-transplantation immune suppression, transfusion-related immune modulation, alcohol-induced immune imbalance and intoxication. Among host variables is the immune modulation induced by parasitic and viral co-infections. Some of the variables are transient and hard to define in retrospective. These host characteristics set up the potency, kinetics, and profile (Th1/Th2) of subsequent adaptive immune response. Better understanding of the host correlates of viral clearance would be a step towards prophylaxis of infection and an efficient anti-HCV vaccine.

Isaguliants, M. G. (2003). "Hepatitis C virus clearance: the enigma of failure despite an impeccable survival strategy." Curr Pharm Biotechnol 4(3): 169-83.

            Infection with human hepatitis C virus (HCV) as a result of a bilateral process of host-virus interactions. There are factors on both sides that contribute to clearance and to chronicity. Virus strategy to survive is built on several basic features. The first, recently recognized, is a wide cell tropism. HCV can infect not only hepatocytes, but also cells of immune system (B-cells, monocytes, macrophages, dendritic cells), epithelium, and immunologically privileged sites such as the central nervous system. Dendritic cells and platelets can also be passive virus carriers. Possibilities of virus clearance or abortive inapparent HCV infection at the stage of adsorption are considered. The second feature is rapid error-prone replication that leads to accumulation within one host of multiple virus variants (quasispecies). Viral heterogeneity could be multiplied by recombination of HCV genomic/subgenomic RNA molecules. Quasispecies nature gives virus an advantage in adaptation to varying host environment including availability of permissive cells, the presence of innate and adaptive immune response, and antiviral treatment. Analysis of HCV polymorphisms and their evolution rates may pinpoint the molecular (sequence) correlates of HCV clearance. The third feature is the capacity to modify or adapt host milieu. HCV core, envelope E2 and nonstructural NS2, NS3, NS5A proteins seem to hold a grip over the host cellular functions by down-regulating processes unfavorable and up-regulating processes favorable for virus replication and persistence. The relevance of the latter interactions to HCV infection outcome remains to be demonstrated. This review discusses recent developments in this area of HCV research.

Jobin, C. (2003). "Intestinal epithelial cells and innate immunity in the intestine: is CARD15/Nod2 another player?" Gastroenterology 124(4): 1145-9.

Jooss, K. and N. Chirmule (2003). "Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy." Gene Ther 10(11): 955-63.

            Viral vectors have provided effective methods for in vivo gene delivery for therapeutic purposes. The ability of viruses to infect a wide variety of cell types in vivo has been exploited for several applications, such as liver, lung, muscle, brain, eye and many others. Immune responses directed towards the viral capsids and the transgene products have severely affected the ability of these vectors to induce long-term gene expression. This paper reviews the influence of viral vectors on antigen-presenting cells (APC), which are central to the induction of innate as well as adaptive immune responses. In this respect, we have focused on adenovirus and adeno-associated viruses because of the polar responses these vector systems induce in vivo. While adenovirus vector can induce significant inflammatory responses, adeno-associated viral vectors are characterized by their inability to consistantly induce immune responses to the transgene product. Understanding the mechanism of infection, transduction and activation of APC by viral vectors will provide strategies to develop safe vectors and prevent immune responses in gene therapies.

Kaisho, T. and S. Akira (2003). "Regulation of dendritic cell function through Toll-like receptors." Curr Mol Med 3(4): 373-85.

            Higher animals establish host defense by orchestrating innate and adaptive immunity. This is mediated by professional antigen presenting cells, i.e. dendritic cells (DCs). DCs can incorporate pathogens, produce a variety of cytokines, maturate, and present pathogen-derived peptides to T cells, thereby inducing T cell activation and differentiation. These responses are triggered by microbial recognition through type I transmembrane proteins, Toll-like receptors (TLRs) on DCs. TLRs consist of ten members and each TLR is involved in recognizing a variety of microorganism-derived molecular structures. TLR ligands include cell wall components, proteins, nucleic acids, and synthetic chemical compounds, all of which can activate DCs as immune adjuvants. Each TLR can activate DCs in a similar, but distinct manner. For example, TLRs can be divided into subgroups according to their type I interferon (IFN) inducing ability. TLR2 cannot induce IFN-alpha or IFN-beta, but TLR4 can lead to IFN-beta production. Meanwhile, TLR3, TLR7, and TLR9 can induce both IFN-alpha and IFN-beta. Recent evidences suggest that cytoplamic adapters for TLRs are especially crucial for this functional heterogeneity. Clarifying how DC function is regulated by TLRs should provide us with critical information for manipulating the host defense against a variety of diseases.

Kang, W. and K. B. Reid (2003). "DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration?" FEBS Lett 540(1-3): 21-5.

            DMBT1 (deleted in malignant brain tumor 1), which encodes a large scavenger receptor cysteine rich (SRCR) B protein, has been proposed to be a tumor suppressor gene, due to the high frequency of its homozygous deletion and the lack of expression in a variety of cancers. However, studies on its physiological functions and its relationship with tumorigenesis are still at an initial stage. Two mucosal defense-related molecules, gp-340 and salivary agglutinin, have been identified to be alternatively spliced products of DMBT1, which suggests that DMBT1 is a pattern recognition receptor in innate immunity. Meanwhile, results from immunohistochemical staining and studies at the cellular level, began to associate DMBT1 with a proliferation to differentiation switching process in gastrointestinal epithelial cells. Together with its up-regulation in inflammation, these findings suggest that DMBT1 might be a local regulator of homeostasis, possibly through linking mucosal inflammation to the modulation of epithelial regeneration, and whose abnormality is a frequent cause of malignancy.

Klinman, D. (2003). "Does activation of the innate immune system contribute to the development of rheumatoid arthritis?" Arthritis Rheum 48(3): 590-3.

Koczulla, A. R. and R. Bals (2003). "Antimicrobial peptides: current status and therapeutic potential." Drugs 63(4): 389-406.

            Antimicrobial peptides (AMPs) are effector molecules of the innate immune system. A variety of AMPs have been isolated from species of all kingdoms and are classified based on their structure and amino acid motifs. AMPs have a broad antimicrobial spectrum and lyse microbial cells by interaction with biomembranes. Besides their direct antimicrobial function, they have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cell proliferation, immune induction, wound healing, cytokine release, chemotaxis and protease-antiprotease balance. AMPs qualify as prototypes of innovative drugs that may be used as antimicrobials, anti-lipopolysaccharide drugs or modifiers of inflammation. Several strategies have been followed to identify lead candidates for drug development, to modify the peptides' structures, and to produce sufficient amounts for pre-clinical and clinical studies. This review summarises the current knowledge about the basic and applied biology of AMPs.

Koreck, A., A. Pivarcsi, et al. (2003). "The role of innate immunity in the pathogenesis of acne." Dermatology 206(2): 96-105.

            Acne is a multifactorial disease of the pilosebaceous follicle. The most significant pathogenetic factors of acne are: abnormal ductal keratinization, increased sebum secretion, abnormalities of the microbial flora and inflammation. The pilosebaceous unit is an immunocompetent organ. Keratinocytes and sebocytes may act as immune cells capable of pathogen recognition and abnormal lipid presentation, and they might have an important role in initiating and perpetuating the activation of both innate and adaptive immune responses. The elements of the skin immune system are involved in the development of both noninflammatory and inflammatory acne lesions.

Kurz, C. L. and J. J. Ewbank (2003). "Caenorhabditis elegans: an emerging genetic model for the study of innate immunity." Nat Rev Genet 4(5): 380-90.

            Invaluable insights into how animals, humans included, defend themselves against infection have been provided by more than a decade of genetic studies that have used fruitflies. In the past few years, attention has also turned to another simple animal model, the nematode worm Caenorhabditis elegans. What exactly have we learned from the work in Drosophila? And will research with C. elegans teach us anything new about our response to pathogen attack?

Levy, D. E., I. Marie, et al. (2003). "Ringing the interferon alarm: differential regulation of gene expression at the interface between innate and adaptive immunity." Curr Opin Immunol 15(1): 52-8.

Liu, Q. and D. A. Muruve (2003). "Molecular basis of the inflammatory response to adenovirus vectors." Gene Ther 10(11): 935-40.

            Adenovirus vectors are extensively studied in experimental and clinical models as agents for gene therapy. Recent generations of helper-dependent adenovirus vectors have the majority of viral genes removed and result in vectors with a large carrying capacity, reduced host adaptive immune responses and improved gene transfer efficiency. Adenovirus vectors, however, activate innate immune responses shortly after administration in vivo. Unlike the adaptive response, the innate response to adenovirus vectors is transcription independent and is caused by the viral particle or capsid. This response results in inflammation of transduced tissues and substantial loss of vector genomes in the first 24 h. The adenovirus capsid activates a number of signaling pathways following cell entry including p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) that ultimately lead to expression of proinflammatory genes. Various cytokines, chemokines and leukocyte adhesion molecules are induced by the adenovirus particle in a wide range of cell types providing a molecular basis for the inflammatory properties of these vectors. An understanding of the innate response to adenovirus vectors is essential to overcome the last remaining hurdle to improve the safety and effectiveness of these agents.

Makrigiannakis, A., E. Zoumakis, et al. (2003). "Corticotropin-releasing hormone (CRH) and immunotolerance of the fetus." Biochem Pharmacol 65(6): 917-21.

            The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced by several tissues of the female reproductive system, including the endometrial glands and decidualized stroma, as well as the trophoblast, syncytiotrophoblast, and placental decidua. CRH is also secreted at inflammatory sites and possesses potent pro-inflammatory properties influencing both innate and acquired immune processes. Recent experimental findings show that uterine CRH participates in local immune phenomena associated with early pregnancy, such as differentiation of endometrial stroma to decidua and protection of the fetus from the maternal immune system. CRH induces the expression of apoptotic Fas ligand (FasL) on invasive extravillous trophoblast and maternal decidual cells at the fetal-maternal interface. Furthermore, CRH increases the apoptosis of activated T lymphocytes through FasL induction, participating in the processes of both implantation and early pregnancy tolerance.

Marciano-Cabral, F. and G. Cabral (2003). "Acanthamoeba spp. as agents of disease in humans." Clin Microbiol Rev 16(2): 273-307.

            Acanthamoeba spp. are free-living amebae that inhabit a variety of air, soil, and water environments. However, these amebae can also act as opportunistic as well as nonopportunistic pathogens. They are the causative agents of granulomatous amebic encephalitis and amebic keratitis and have been associated with cutaneous lesions and sinusitis. Immuno compromised individuals, including AIDS patients, are particularly susceptible to infections with Acanthamoeba. The immune defense mechanisms that operate against Acanthamoeba have not been well characterized, but it has been proposed that both innate and acquired immunity play a role. The ameba's life cycle includes an active feeding trophozoite stage and a dormant cyst stage. Trophozoites feed on bacteria, yeast, and algae. However, both trophozoites and cysts can retain viable bacteria and may serve as reservoirs for bacteria with human pathogenic potential. Diagnosis of infection includes direct microscopy of wet mounts of cerebrospinal fluid or stained smears of cerebrospinal fluid sediment, light or electron microscopy of tissues, in vitro cultivation of Acanthamoeba, and histological assessment of frozen or paraffin-embedded sections of brain or cutaneous lesion biopsy material. Immunocytochemistry, chemifluorescent dye staining, PCR, and analysis of DNA sequence variation also have been employed for laboratory diagnosis. Treatment of Acanthamoeba infections has met with mixed results. However, chlorhexidine gluconate, alone or in combination with propamidene isethionate, is effective in some patients. Furthermore, effective treatment is complicated since patients may present with underlying disease and Acanthamoeba infection may not be recognized. Since an increase in the number of cases of Acanthamoeba infections has occurred worldwide, these protozoa have become increasingly important as agents of human disease.

Matrosovich, M. and H. D. Klenk (2003). "Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding." Rev Med Virol 13(2): 85-97.

            Influenza viruses attach to susceptible cells via multivalent interactions of their haemagglutinins with sialyloligosaccharide moieties of cellular glycoconjugates. Soluble macromolecules containing sialic acid from animal sera and mucosal fluids can act as decoy receptors and competitively inhibit virus-mediated haemagglutination and infection. Although a role for these natural inhibitors in the innate anti-influenza immunity is still not clear, studies are in progress on the design of synthetic sialic acid-containing inhibitors of receptor binding which could be used as anti-influenza drugs.

Mayr, A. (2003). "Development of a non-immunising, paraspecific vaccine from attenuated pox viruses: a new type of vaccine." New Microbiol 26(1): 7-12.

            The various research periods leading to the development of paraspecific vaccines are described. Paraspecific vaccines are new, pyrogen-free, non-toxic preparations that contain non-immunising antigens and can be used to generate endogenic protective, non-antigen specific mechanisms in the sense of paramunization in humans and animals. They consist of highly attenuated and inactivated (0.05% Betapropiolactone) virus strains of various poxvirus genera. They activate the T helper cells and cellular elements of the paraspecific (innate) immune system and initiate the associated production and release of cytokines (cytokine cascade) with the goal of eliminating dysfunctions of the immune systems, rapidly enhancing the individual's non-pathogen- and non-antigen-specific defences and exerting a regulatory effect on the interplay between the immune, hormone, nervous and vascular systems (signal-transduction mediators). They can be used systemically (intramuscularly) and locally (mucous membranes, skin). Immunization with paraspecific vaccines does not lead to postvaccinal complications and can be carried out as often as necessary, even for a number of years. They are compatible with conventional medicines and conventional specific vaccines. Closely linked protein complexes in the envelopes of the virus particles are responsible for their efficacy, some of those envelope protein complexes possess the properties of weak super antigens. Paraspecific vaccines have proved effective in combating viral infections, in particular herpes and hepatitis B and C infections, and chronic inflammatory diseases, and also as adjuvant therapy for tumours, for curing stress-related disturbances and dysfunctions of the immune system.

Metz-Boutigue, M. H., Y. Goumon, et al. (2003). "Antimicrobial chromogranins and proenkephalin-A-derived peptides: Antibacterial and antifungal activities of chromogranins and proenkephalin-A-derived peptides." Ann N Y Acad Sci 992: 168-78.

            The secretory granules from adrenal medullary chromaffin cells contain a complex mixture of low-molecular mass constituents such as catecholamines, ascorbate, nucleotides, calcium, peptides, and several high-molecular mass water-soluble proteins including chromogranins and proenkephalin-A. These proteins are sequestered into secretory granules in which processing yields a large variety of peptides. These fragments are released into the extracellular space upon cell stimulation and are recovered in blood, lymph, cerebrospinal fluid, and synovial fluid. Some of them have biological activity on cells in an autocrine, paracrine, or endocrine fashion. In addition, we have shown that peptides with antimicrobial activity are present with the secretory chromaffin granules and demonstrated that they are released from stimulated chromaffin cells. We have shown that posttranslational modifications modulate the antimicrobial activities. For some peptides, using confocal laser microscopy, we have examined the interaction of the rhodaminated peptides with biological membranes. In addition, we have shown that chromofungin, the antifungal peptide corresponding to chromogranin A(47-66), can bind calmodulin in the presence of calcium and induce inhibition of calcineurin, a calmodulin-dependent enzyme. Because these antibacterial peptides are colocalized with catecholamines, they may be activated during stress, playing a role as a first protective barrier against bacterial infection, and thus act as factors of the innate immunity shortly after infection and before the induction and mobilization of an adaptative immune system.

Mutwiri, G., R. Pontarollo, et al. (2003). "Biological activity of immunostimulatory CpG DNA motifs in domestic animals." Vet Immunol Immunopathol 91(2): 89-103.

            Bacterial DNA contains a much higher frequency of CpG dinucleotides than are present in mammalian DNA. Furthermore, bacterial CpG dinucleotides are often not methylated. It is thought that these two features in combination with specific flanking bases constitute a CpG motif that is recognized as a "danger" signal by the innate immune system of mammals and therefore an immune response is induced when these motifs are encountered. These immunostimulatory activities of bacterial CpG DNA can also be achieved with synthetic CpG oligodeoxynucleotides (ODN). Recognition of CpG motifs by the innate immune system requires engagement of Toll-like receptor 9 (TLR-9), which induces cell signaling and subsequently triggers a pro-inflammatory cytokine response and a predominantly Th1-type immune response. CpG ODN-induced innate and adaptive immune responses can result in protection in various mouse models of disease. Based on these observations, clinical trials are currently underway in humans to evaluate CpG ODN therapies for cancer, allergy and infectious disease. However, potential applications for immunostimulatory CpG ODN in species of veterinary importance are just being explored. In this review, we will highlight what is presently known about the immunostimulatory effects of CpG ODN in domestic animals.

Opal, S. M. and C. T. Esmon (2003). "Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis." Crit Care 7(1): 23-38.

            The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.

Partida-Sanchez, S., T. D. Randall, et al. (2003). "Innate immunity is regulated by CD38, an ecto-enzyme with ADP-ribosyl cyclase activity." Microbes Infect 5(1): 49-58.

            Through its production of cyclic adenosine diphosphate ribose, the ecto-enzyme CD38 regulates calcium mobilization in neutrophils responding to some, but not all, chemoattractants. This signaling defect results in reduced chemotaxis of CD38-deficient neutrophils to bacterial peptides and increased susceptibility of CD38-deficient mice to bacterial infections.

Plevy, S. and L. Mayer (2003). "Meeting summary: Signal transduction pathways in immune and inflammatory cells. November 30-December 3, 2000, Amelia Island, Florida, U.S.A." Inflamm Bowel Dis 9(1): 28-33.

            Throughout this symposium, recurrent themes were highlighted that may provide important clues to the pathogenesis of mucosal inflammation and IBD. First, the mucosal immune system is unique: Studies describing signaling paradigms in peripheral immunocytes should be re-explored in the gut where the rules that govern cell signaling may not be the same. Paradigms are a point of departure to characterize similarities and differences in mucosal immunity. A good example is a differential requirement for costimulation through CD2 in lamina propria T cells compared with peripheral T cells. Furthermore, a new definition of T-cell "costimulation" is beginning to emerge. Costimulatory molecules may function to overcome physical barriers by allowing cognate interactions between other molecules or by targeting signaling complexes to membrane microdomains. This concept also relates to another recurrent theme: Interactions between signaling pathways and the cytoskeleton are functionally important. Finally, we were introduced to the novel concept of metabolic parameters as a readout for signal transduction in the immune system. In the recent past, cell signaling has been viewed as a linear exercise, connecting a cell surface receptor to a series of intermediate molecules to a program of gene expression. However, signal transduction is in fact a three-dimensional exercise in cell biology. The future challenge, as pointed out in the keynote address, is to integrate reductionist models into reality and describe networks of signal transduction pathways in complex biosystems. "Threshold" responses were emphasized, with a small incremental increase or decrease in enzymatic activity leading to an on-off phenomenon referred to as a "molecular switch." In IBD, minute genetically determined differences in enzymatic activity may be critical. This point emphasizes the power of a genetic approach in IBD. Without strong genetic evidence, it is unlikely that fuctional assays will clarify the importance of small differences in enzymatic activity that may have dramatic biologic consequences. This symposium identified recently described signal transduction molecules that may be attractive therapeutic targets in IBD. Characterization of signaling molecules such as SLP-76, SLAM, SAP, and Fyb in the mucosal immune system will be an important area of future research. Ultimately, well-developed scientific hypotheses need to be tested in human beings. This paradigm was perhaps best illustrated by PPARgamma, where reductionist models and mouse experiments have recently lead to small trials suggesting proof of concept in human IBD. This meeting also emphasized a renewed interest in innate immunity in IBD and inflammation research. The role of enteric flora in initiating and perpetuating inflammation in animal models of IBD suggests at some level the importance of the innate immune response. The role of TLRs and bacterial interactions were discussed, as was NF-kappaB as the prominent transcription factor target of innate immune activation. Numerous bridges between innate and adaptive immunity were highlighted, including IL-10, IL-12, IL-18, and IFN-gamma. Their production during an innate immune response can profoundly affect functional T-cell responses in humans. In conclusion, the challenge of understanding signal transduction in IBD is one of integrating well-characterized inflammatory pathways into a complex biologic system that is inhabited by diverse cell types that communicate, and is characterized by interactions with a complex microbial environment. Making sense of this complexity is a daunting task that will require a multifactorial approach utilizing reductionist systems, mouse models, genetic studies, and ultimately human clinical trials.

Polyak, S. J. (2003). "Hepatitis C virus--cell interactions and their role in pathogenesis." Clin Liver Dis 7(1): 67-88.

            In summary, HCV-cell interactions include those directly involved with the HCV life cycle such as virus attachment, entry, and replication. Included within this broad area of research are the interactions of HCV proteins with the IFN system, cytokine and chemokine pathways such as IL-8, and various other cellular proteins and pathways. The plethora of contradictory and sometimes confusing accessory HCV-host interactions defies precise predictions of their role in HCV biology. It is clear that these virus-cell interactions affect HCV replication, antiviral resistance, persistence, and pathogenesis. Because HCV-host interactions are initiated immediately on infection, they are operative during acute HCV infection, whereby HCV interacts with innate cellular antiviral and immune systems. The magnitude and duration of these HCV-host interactions therefore may influence the development of acquired immunity. Because HCV exists as a quasispecies in all infected individuals, heterogeneity in biological responses to HCV-host interactions is predicted, revealing opportunities for the development of various genotypic and phenotypic prognostic indicators. With the model systems in place, these hypotheses can be tested. The challenge for the future is to determine if there is a hierarchical importance to these interactions, to delineate how these virus-cell interactions affect the patient infected with HCV, and to determine whether any of these interactions represents a target for therapeutic intervention.

Prince, J. E., F. Kheradmand, et al. (2003). "16. Immunologic lung disease." J Allergy Clin Immunol 111(2 Suppl): S613-23.

            This review summarizes the recent advances regarding pathogenesis, diagnosis, and treatment of immunological diseases of the lung. Rather than attempt a comprehensive analysis, we have focused on selected diseases that are of particular relevance to the practicing physician, and the material has been organized according to the dominant immunologic mechanisms underlying the disease. Because of the redundancy that characterizes the mammalian immune repertoire, this system of classification inevitably produces overlap but facilitates acquisition of what is otherwise a disparate collection of facts. The principal lung immunologic mechanisms are most broadly classified as innate or adaptive immune processes. Innate immunity includes neutrophils and complement that are important in diseases, such as pneumonia and the acute respiratory distress syndrome. Adaptive immunity involves T and B cells capable of recognizing discrete antigens. T(H)1- and T(H)2-dependent adaptive immune responses underlie some of the most common and important of lung diseases, including tuberculosis and asthma, respectively. Other important immunopathologic processes include granulomatous inflammation that characterizes sarcoidosis and Churg-Strauss vasculitis, and autoimmunity, which is characteristic of antiglomerular basement membrane disease and others.

Ramirez-Montagut, T., M. J. Turk, et al. (2003). "Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity." Oncogene 22(20): 3180-7.

            Cancer cells express self-antigens that are weakly recognized by the immune system. Even though responses against autologous cells are difficult to induce, the immune system is still able to mount a response against cancer. The discovery of the molecular identity of antigens that are recognized by the immune system of melanoma patients has led to the elucidation of tumor immunity at a cellular and molecular level. Multiple pathways in both the priming and effector phases of melanoma rejection have been described. Animal models' active immunotherapies for melanoma show a requirement for the cellular compartment of the immune system in the priming phase, primarily CD4+T cells. More diverse elements are required for the effector phase, including components from the innate immune system (macrophages, complement and/or natural killer cells) and from the adaptive immune system (CD8+T cells and B cells). Minor differences in amino-acid sequences of antigens must determine the particular mechanisms involved in tumor rejection. Since the immune system contains T and B cells that recognize and reject autologous cells, a consequence of tumor immunity is potential autoimmunity. There are distinct pathways for tumor immunity and autoimmunity. The requirements for autoimmunity at the priming phase seem to be CD4+/IFN-gamma dependent while the effector mechanisms are alternative and redundant. Vitiligo (autoimmune hypopigmentation) can be mediated by T cells, FcgammaR+macrophages and/or complement.

Rosen, H. R. (2003). "Hepatitis C virus in the human liver transplantation model." Clin Liver Dis 7(1): 107-25.

            Hepatitis C virus-related liver failure is the single leading indication for liver transplantation, and the study of HCV in the transplant setting has enhanced the understanding of the natural history of disease and putative mechanisms by which HCV causes liver injury. In a subset of patients, allograft cirrhosis develops within a few years after transplantation, and recent findings suggest these individuals are immunologically impaired compared with individuals with mild HCV recurrence at long-term follow-up. Fig. 9 shows a conceptual paradigm of mechanisms potentially involved in shaping HCV outcome after transplantation. It is possible that relative antiviral control by innate and adaptive immune responses (to maintain HCV replication below a certain threshold) prevents direct cytopathic injury and induction of oxidative stress and apoptosis of cells. Additional phenomena that may contribute to induction of apoptosis (eg, genetic polymorphisms within the donor organ. CMV coinfection, and ischemic-preservation injury) may augment the initial cascade of liver injury. Recruitment to the allograft of nonspecific cells may decrease viral replication by way of noncytolytic mechanisms or augment viral replication (eg, Th2 phenotype) and direct cytopathic injury. The immune response is likely insufficiently vigorous to keep viral replication under control, but may maintain chronic liver injury. The liver transplant model is unique in that distinct phenotypic outcomes can be observed over a short period of time. A consideration of the temporal evolution of different mechanisms is also important, because mechanisms that initially predominate may become less important over time, and conversely, as suggested with the inverse correlation between viral load at 5 years and allograft fibrosis, new immune responses may emerge that modify the host-virus interaction. Prospective characterization of the immunoregulatory and virologic mechanisms involved in the liver transplantation model hopefully will help unravel the causal basis of reported associations, lead to the development of highly specific therapeutic strategies, and ultimately diminish the rate of graft loss from recurrent disease.

Sartor, R. B. (2003). "Innate immunity in the pathogenesis and therapy of IBD." J Gastroenterol 38 Suppl 15: 43-7.

Servet-Delprat, C., P. O. Vidalain, et al. (2003). "Measles virus and dendritic cell functions: how specific response cohabits with immunosuppression." Curr Top Microbiol Immunol 276: 103-23.

            Measles virus (MV) infection induces both an efficient MV-specific immune response and a transient but profound immunosuppression characterised by a panlymphopenia that occasionally results in opportunistic infections responsible for a high rate of mortality in children. On the basis of in vitro studies, the putative roles of dendritic cells (DCs) in MV infection are discussed. (1) DCs could participate in anti-MV innate immunity because MV turns on TNF-related apoptosis-inducing ligand (TRAIL)-mediated DC cytotoxicity. (2) Cross-priming by non-infected DCs might be the route of MV adaptive immune response. (3) After CD40-ligand activation in secondary lymphoid organs, MV-infected DCs could initiate the formation of Warthin-Finkeldey multinucleated giant cells, replicating MV and responsible for in vivo spreading of MV. (4) We review how integrated viral attack of the host immune system also targets DCs: Progress in understanding the immunobiology of MV-infected DCs that could account for MV-induced immunosuppression observed in vivo is presented and their potential role in lymphopenia is underlined. In conclusion, future research directions are proposed.

Shijubo, N., I. Kawabata, et al. (2003). "Clinical aspects of Clara cell 10-kDa protein/ uteroglobin (secretoglobin 1A1)." Curr Pharm Des 9(14): 1139-49.

            Clara cell 10-kDa protein (CC10)/ uteroglobin (UG) is a nonglycoprotein with a molecular mass of 16 kilodaltons, which is produced by mucosal epithelial cells in the lung (Clara cells), uterus and prostate. Like other low molecular weigh proteins it is catabolized in renal proximal tubules. Structurally it is a homodimer of subunits of 70 amino acids covalently bound in an antiparallel manner. It belongs to secretogobin (SCGB) family and is assigned as subgroup 1A1. The function of the protein so far elucidated is immunoregulatory and anti-inflammatory in innate immunity. The knockout mouse of UG gene resulted in aggravation of inflammation by allergic and hyperoxic stimuli. It also showed very similar pathological features with human IgA nephropathy. The value is changed in the lung fluid and serum of various inflammatory and allergic lung diseases. Several kinds of single nucleotide polymorphisms (SNPs) in human CC10/UG gene were recently discovered; Adenine allele accumulation in G38A SNP has possible association with asthma and IgA nephropathy, being paralleled with disease severity of IgA nephropathy. Its expression is enhanced by some transcriptional factors induced by cytokines such as interferon-gamma. For cancer cells, the protein functions as an antagonist of neoplastic phenotype. CC10/UG forms one of intra- and intercellular regulators involved in inflammation and malignant transformation in the respiratory and urogenital fields.

Sibilia, J. (2003). "[Corticosteroids and inflammation]." Rev Prat 53(5): 495-501.

            Corticoids are molecules which the organism synthesizes to regulate a large number of immune and metabolic physiological mechanisms. The compounds used as therapeutic agents have at higher doses very useful anti-inflammatory and immunomodulatory properties. Corticoids have most original mechanisms of action which are essentially genomic (transcriptional) and characterized by activation (transactivation) or inhibition (transrepression) of numerous target genes. These molecules act in many cells involved in innate immunity (macrophages, granulocytes, mastocytes) and adaptive immunity (lymphocytes) but also in other cells (fibroblasts, epithelial and endothelial cells). The anti-inflammatory efficacy of corticoids may be explained by their inhibition of the synthesis of numerous cytokines, enzymes and mediators of inflammation or induction of cytokines and anti-inflammatory molecules (lipocortin). Corticoids also regulate cellular activation and survival processes (apoptosis), which explains their cytostatic efficacy in certain malignant hematological disorders.

Silverman, R. H. (2003). "Implications for RNase L in prostate cancer biology." Biochemistry 42(7): 1805-12.

            Recently, the interferon (IFN) antiviral pathways and prostate cancer genetics and have surprisingly converged on a single-strand specific, regulated endoribonuclease. Genetics studies from several laboratories in the U.S., Finland, and Israel, support the recent identification of the RNase L gene, RNASEL, as a strong candidate for the long sought after hereditary prostate cancer 1 (HPC1) allele. Results from these studies suggest that mutations in RNASEL predispose men to an increased incidence of prostate cancer, which in some cases reflect more aggressive disease and/or decreased age of onset compared with non-RNASEL linked cases. RNase L is a uniquely regulated endoribonuclease that requires 5'-triphosphorylated, 2',5'-linked oligoadenylates (2-5A) for its activity. The presence of both germline mutations in RNASEL segregating with disease within HPC-affected families and loss of heterozygosity (LOH) in tumor tissues suggest a novel role for the regulated endoribonuclease in the pathogenesis of prostate cancer. The association of mutations in RNASEL with prostate cancer cases further suggests a relationship between innate immunity and tumor suppression. It is proposed here that RNase L functions in counteracting prostate cancer by virtue of its ability to degrade RNA, thus initiating a cellular stress response that leads to apoptosis. This monograph reviews the biochemistry and genetics of RNase L as it relates to the pathobiology of prostate cancer and considers implications for future screening and therapy of this disease.

Speth, C., H. Stoiber, et al. (2003). "Complement in different stages of HIV infection and pathogenesis." Int Arch Allergy Immunol 130(4): 247-57.

            The complement system is one of the most important weapons of innate immunity and is involved in all infectious processes. It is not only a mechanism for direct protection against an invading pathogen but it also interacts with the adaptive immunity to optimize the pathogen-specific humoral and cellular defence cascade in the body. One of the greatest challenges for the complement system is infection by HIV with its chronic course and sequential destruction of immune cells and immune organs. Due to its dual role as direct effector and as fine tuner of adaptive immunity, we focussed on complement in this review and analysed in detail the contribution of complement to the antiviral defence and to HIV pathogenesis on the one hand and the complement evasion strategies of the virus on the other hand. In the present review, this interplay between complement and the virus is illuminated for the three different stages of HIV pathogenesis and for events during therapy: (1) the acute infection process with the early events in mucosa and serum; (2) the asymptomatic stage with the complex interplay between complement-induced lysis and viral evasion strategies; (3) the symptomatic infection and AIDS stage with progressive destruction of the lymph nodes, opportunistic infections and development of neuropathogenesis, and (4) finally, during highly active antiretroviral therapy and in vaccination approaches.

Trinchieri, G. (2003). "Interleukin-12 and the regulation of innate resistance and adaptive immunity." Nat Rev Immunol 3(2): 133-46.

            Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-gamma (IFN-gamma), favours the differentiation of T helper 1 (T(H)1) cells and forms a link between innate resistance and adaptive immunity. Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN. Recent data, however, argue against an absolute requirement for IL-12 for T(H)1 responses. Our understanding of the relative roles of IL-12 and other factors in T(H)1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process of IL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.

Uhlmann, E. and J. Vollmer (2003). "Recent advances in the development of immunostimulatory oligonucleotides." Curr Opin Drug Discov Devel 6(2): 204-17.

            Some immune cells recognize distinct molecular structures present in pathogens through specific pattern recognition receptors that are able to distinguish prokaryotic DNA from vertebrate DNA. The detection of invading microbial DNA is based on the recognition of unmethylated deoxycytidyl-deoxyguanosin dinucleotide (CpG) motifs. Synthetic oligonucleotides (ODNs) containing these CpG motifs are able to activate both innate and acquired immune responses through a signaling pathway involving Toll-like receptor 9 (TLR9). Depending on the sequence, length, as well as number and positions of CpG motifs in an ODN, distinct immunostimulatory profiles can be observed. These immunostimulatory profiles can be further modified and fine-tuned by appropriate chemical modifications, leading to preclinical and clinical development of CpG ODNs in cancer, allergy, asthma and infectious diseases.

VanDeusen, J. B. and M. A. Caligiuri (2003). "New developments in anti-tumor efficacy and malignant transformation of human natural killer cells." Curr Opin Hematol 10(1): 55-9.

            For decades, the driving force behind many immunologic studies has been the hope of augmenting anti-cancer therapy through targeted immune-based strategies. The question remains: can immune cells be successfully manipulated to augment chemotherapy and aid in the elimination of malignancy? Such efforts have included work with natural killer (NK) cells, large granular lymphocytes that contribute to the early innate immune response by nonspecifically killing pathogens, virus-infected cells, and tumor cells, and by producing important early immunoregulatory cytokines such as interferon gamma (IFN-gamma). These qualities have made NK cells attractive candidates for therapy aimed at boosting host immunity against tumor cells and infectious pathogens. Recent advances in our understanding of how NK cells select targets for killing have improved our ability to design and test more effective immune-targeted therapies. However, our understanding of NK leukemias and lymphomas remains incomplete. NK leukemias and lymphomas, while rare, represent a significant challenge to the patients and physicians coping with them, as most lack effective treatment strategies. This brief review will summarize current directions in NK cell immune therapy and give an update on the classification and treatment of NK malignancies.

Villar, J. and S. Mendez-Alvarez (2003). "Heat shock proteins and ventilator-induced lung injury." Curr Opin Crit Care 9(1): 9-14.

            In this review, we discuss the heat shock response, a specific example of gene expression that has been studied over the past 25 years, and its relevance to acute lung injury and other critical conditions. The heat shock response has been observed in virtually all organisms and involves the rapid induction of a set of highly conserved genes that encode heat shock proteins (HSPs). The HSP70 family represents the most prominent eukaryotic group of HSPs. It has been suggested that members of the HSP70 family act in the protection of cellular damage by binding to denatured or abnormal proteins after heat shock, thereby preventing protein aggregation. The capacity of HSPs to subserve cytoprotection has produced considerable interest from the perspective of elucidating the pathophysiology of organ damage and dysfunction. Several studies support the hypothesis that HSPs are cytoprotective In addition, recent investigations have demonstrated that HSP70 is released into the systemic circulation and is involved in the activation of innate immunity.

von Pawel-Rammingen, U. and L. Bjorck (2003). "IdeS and SpeB: immunoglobulin-degrading cysteine proteinases of Streptococcus pyogenes." Curr Opin Microbiol 6(1): 50-5.

            The Gram-positive bacterium Streptococcus pyogenes is a major human pathogen causing substantial morbidity and mortality in society. S. pyogenes has evolved numerous molecular mechanisms to avoid the various actions of the human immune system and has established means to modulate both adaptive and innate immune responses. S. pyogenes produces and secretes proteolytic enzymes, which have an important impact on the ability of the bacteria to survive in the human host. Prominent among these are two immunoglobulin-degrading enzymes: the newly discovered streptococcal cysteine proteinase, IdeS, and the classical cysteine proteinase of S. pyogenes, SpeB.

Wakimoto, H., P. R. Johnson, et al. (2003). "Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells." Gene Ther 10(11): 983-90.

            Several clinical trials have or are being performed testing the safety and efficacy of different strains of oncolytic viruses (OV) for malignant cancers. OVs represent either naturally occurring or genetically engineered strains of viruses that exhibit relatively selective replication in tumor cells. Several types of OV have been derived from herpes simplex virus 1 (HSV1). Tumor oncolysis depends on the processes of initial OV infection of tumor, followed by subsequent propagation of OV within the tumor itself. The role of the immune responses in these processes has not been extensively studied. On the contrary, effects of the immune response on the processes of wild-type HSV1 infection and propagation in the central nervous system have been studied and described in detail. The first line of defense against a wild-type HSV1 infection in both naive and immunized individuals is provided by innate humoral (complement, cytokines, chemokines) and cellular (macrophages, neutrophils, NK cells, gammadelta T cells, and interferon-producing cells) responses. These orchestrate the lysis of virions and virus-infected cells as well as provide a link to effective adaptive immunity. The role of innate defenses in curtailing the oncolytic effect of genetically engineered HSV has only recently been studied, but several of the same host responses appear to be operative in limiting anticancer effects by the replicating virus. The importance of this knowledge lies in finding avenues to modulate such initial innate responses, in order to allow for increased oncolysis of tumors while minimizing host toxicity.

Werling, D. and T. W. Jungi (2003). "TOLL-like receptors linking innate and adaptive immune response." Vet Immunol Immunopathol 91(1): 1-12.

            Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, which is mediated by B and T lymphocytes, recognises pathogens by rearranged high affinity receptors. However, the establishment of adaptive immunity is often not rapid enough to eradicate microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defense mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors (PRR). Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns (PAMP) to TLR induces the production of reactive oxygen and nitrogen intermediates (ROI and RNI), pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this review, we will summarize the discovery and the critical roles of the TLR family in host defense, briefly allude to signaling mechanisms mediating the response to TLR ligands, and will provide an update on current knowledge regarding the ligand specificity of these receptors and their role in immunity of domestic animals, particularly cattle.

Wilson, S. B. and T. L. Delovitch (2003). "Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity." Nat Rev Immunol 3(3): 211-22.

            Invariant CD1D-restricted natural killer T (iNKT) cells function during innate and adaptive immunity and regulate numerous immune responses, such as autoimmune disease, tumour surveillance, infectious disease and abortions. However, the molecular basis of their functions and the nature of disease-associated defects of iNKT cells are unclear and have been the subject of recent controversy. Here, we review recent findings that underscore the potential importance of interactions between iNKT cells and dendritic cells (DCs) that indicate that iNKT cells regulate DC activity to shape both pro-inflammatory and tolerogenic immune responses. The ability to modulate iNKT-cell activity in vivo using the ligand alpha-galactosylceramide and to treat patients with autoimmune disease or cancer is evaluated also.

Workman, M. L. (2003). "The cellular basis of bacterial infection." Crit Care Nurs Clin North Am 15(1): 1-11.

            Innate and adaptive immune responses are responsible for the prevention of and recovery from bacterial infections. Fully immunocompetent humans make adaptations to the pathogens within their environment. Bacterial pathogens are capable of responding to immune adaptations to avoid destruction and elimination. Examination of the bacterial mechanisms of evasion has revealed the evolution of many elegant systems capable of thwarting host defenses. Undoubtedly, more mechanisms have yet to be discovered. A major concern as bacteria become more antibiotic resistant is whether human immune adaptation can evolve sufficiently to keep pace with bacterial evolution of evasion mechanisms.

Zanetti, M., P. Castiglioni, et al. (2003). "The role of relB in regulating the adaptive immune response." Ann N Y Acad Sci 987: 249-57.

            Dendritic cells (DCs), which represent a key type of antigen-presenting cell (APC), are important for the development of innate and adaptive immunity. DCs are involved in T cell activation in at least two main ways: priming via direct processing/presentation of soluble antigen taken up from the microenvironment (conventional priming), and processing/presentation of antigen released from other cells (cross-priming). relB, a component of the NF-kappaB complex of transcription factors, is a critical regulator of the differentiation of DCs. In mice, lack of relB impairs DCs derived from bone marrow both in number and function. Here relB (-/-) bone marrow chimera mice is used to study the APC function of residual DCs in presentation of soluble antigen and cross-priming. It is found that the DCs in these mice are profoundly deficient in their ability to both prime and cross-prime T cell responses. It was concluded that the relB gene is involved in regulating the APC function of DCs in vivo.

Zhang, W., J. Li, et al. (2003). "Concepts in immunology and diagnosis of hydatid disease." Clin Microbiol Rev 16(1): 18-36.

            Echinococcosis is a cosmopolitan zoonosis caused by adult or larval stages of cestodes belonging to the genus Echinococcus (family Taeniidae). The two major species of medical and public health importance are Echinococcus granulosus and E. multilocularis, which cause cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. Both CE and AE are both serious diseases, the latter especially so, with a high fatality rate and poor prognosis if managed inappropriately. This review discusses new concepts and approaches in the immunology and diagnosis of CE, but comparative reference has also been made to AE infection and to earlier pivotal studies of both diseases. The review considers immunity to infection in the intermediate and definitive hosts, innate resistance, evasion of the immune system, and vaccination of intermediate and definitive hosts, and it particularly emphasizes procedures for diagnosis of CE and AE, including the value of immunodiagnostic approaches. There is also discussion of the new advances in recombinant and related DNA technologies, especially application of PCR, that are providing powerful tools i