Home   About Us   eMedicine Search   Drug Development   Feedback   Google Scholar Search   Intranet 
Literature Database   News   Photo Gallery   Publications   Site Map   Site Search   Useful Links 
 

Back to Multiple Sclerosis (MS)

Enhanced by Neuroinformation

Innate Immunity Reviews: 2003

(170 References)

Abbas, A. K. (2003). "The control of T cell activation vs. tolerance." Autoimmun Rev 2(3): 115-8.

            B7 costimulators and the T cell growth factor IL-2 are important stimuli for the activation of T lymphocytes and the development of effective immune responses. Recent studies show that the same signals promote the development of regulatory T cells or the apoptotic death of activated T cells, and thus, function to terminate immune responses and maintain self-tolerance. The balance between the different outcomes of the same signals may be determined by the magnitude of these signals and the presence or absence of concomitant stimuli, such as those generated during innate immune responses to microbes.

Akira, S. and H. Hemmi (2003). "Recognition of pathogen-associated molecular patterns by TLR family." Immunol Lett 85(2): 85-95.

            Toll-like receptors (TLRs) are type I transmembrane proteins involved in innate immunity by recognizing microbial conserved structures. Recent studies have shown that TLR3 recognizes dsRNA, a viral product, whereas TLR9 recognizes unmethylated CpG motifs frequently found in the genome of bacteria and viruses, but not vertebrates. TLR7 recognizes small synthetic immune modifiers including imiquimod, R-848, loxoribine, and bropirimine, all of which are already applied or promising for clinical use against viral infections and cancers. Plasmacytoid dendritic cells express TLR7 and TLR9, and respond to TLR7 and TLR9 ligands by producing a large amount of interferon (IFN-alpha). These results indicate that TLR3, TLR7 and TLR9 may play an important role in detecting and combating viral infections.

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.

Alegado, R. A., M. C. Campbell, et al. (2003). "Characterization of mediators of microbial virulence and innate immunity using the Caenorhabditis elegans host-pathogen model." Cell Microbiol 5(7): 435-44.

            The soil-borne nematode, Caenorhabditis elegans, is emerging as a versatile model in which to study host-pathogen interactions. The worm model has shown to be particularly effective in elucidating both microbial and animal genes involved in toxin-mediated killing. In addition, recent work on worm infection by a variety of bacterial pathogens has shown that a number of virulence regulatory genes mediate worm susceptibility. Many of these regulatory genes, including the PhoP/Q two-component regulators in Salmonella and LasR in Pseudomonas aeruginosa, have also been implicated in mammalian models suggesting that findings in the worm model will be relevant to other systems. In keeping with this concept, experiments aimed at identifying host innate immunity genes have also implicated pathways that have been suggested to play a role in plants and animals, such as the p38 MAP kinase pathway. Despite rapid forward progress using this model, much work remains to be done including the design of more sensitive methods to find effector molecules and further characterization of the exact interaction between invading pathogens and C. elegans' cellular components.

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.

Artavanis-Tsakonas, K., J. E. Tongren, et al. (2003). "The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology." Clin Exp Immunol 133(2): 145-52.

            Throughout history malaria has proved to be a significant threat to human health. Between 300 and 500 million clinical cases occur each year worldwide, approximately 2 million of which are fatal, primarily in children. The vast majority of malaria-related deaths are due to infection with Plasmodium falciparum; P. vivax causes severe febrile illness but is rarely fatal. Following repeated exposure to infection, people living in malaria endemic areas gradually acquire mechanisms to limit the inflammatory response to the parasite that causes the acute febrile symptoms (clinical immunity) as well as mechanisms to kill parasites or inhibit parasite replication (antiparasite immunity). Children, who have yet to develop protective immune mechanisms are thus at greater risk of clinical malaria, severe disease and death than adults. However, two epidemiological observations indicate that this is, perhaps, an oversimplified model. Firstly, cerebral malaria - a common manifestation of severe malaria - typically occurs in children who have already acquired a significant degree of antimalarial immunity, as evidenced by lower mean parasite densities and resistance to severe anaemia. One potential explanation is that cerebral malaria is, in part, an immune-mediated disease in which immunological priming occurs during first infection, eventually leading to immunopathology on re-infection. Secondly, among travelers from nonendemic areas, severe malaria is more common - and death rates are higher - in adults than in children. If severe malaria is an immune-mediated disease, what might be priming the immune system of adults from nonendemic areas to cause immunopathology during their first malaria infection, and how do adults from endemic areas avoid severe immunopathology? In this review we consider the role of innate and adaptive immune responses in terms of (i) protection from clinical malaria (ii) their potential role in immunopathology and (iii) the subsequent development of clinical immunity. We conclude by proposing a model of antimalarial immunity which integrates both the immunological and epidemiological data collected to date.

Ayala, A., C. S. Chung, et al. (2003). "Mechanisms of immune resolution." Crit Care Med 31(8 Suppl): S558-71.

            Initially after injury, the innate/proinflammatory and some aspects of the acquired immune response are up-regulated to maintain a defense against foreign pathogens, clear tissue debris present at the wound site, and orchestrate aspects of tissue remodeling, cell proliferation and angiogenic process, associated with the wound response. However, for proper wound healing to progress, this initial inflammatory response has to be regulated or shut down so as to allow for the reestablishment of matrix, recellularization, and tissue remodeling. Inability to properly resolve the extent of innate/acquired response at a site of injury can lead to poor wound healing, immune suppression, and recurrent infectious episodes. This review attempts to summarize information on regulatory mechanisms that are thought to be involved in controlling/resolving innate or acquired immune responses so as to provide a framework for use in thinking about the impact these processes and their manipulation may have on wound healing and its potential management.

Babiuk, L. A., S. Gomis, et al. (2003). "Molecular approaches to disease control." Poult Sci 82(6): 870-5.

            Recent advances in molecular biology, genomics, and immunology are revolutionizing our approach to managing infectious diseases of humans, livestock, and poultry. One of the most interesting additions to the armamentarium of research focusing on controlling infectious diseases has been a better understanding of how the host's innate immune system recognizes "danger" signals. Additionally, there has been recognition of the relationship between the innate and the specific arms of the immune system. For example, the recent discovery that CpG motifs can modulate immune responses has been used both as an adjuvant to enhance the responses to vaccines, as well as a direct immunostimulant to prevent infections. Using an Escherichia coli chicken model, we have been able to prevent cellulitis in chickens with CpG alone. Thus, CpG can be used immunoprophylactically to reduce infectious diseases. In addition, we will describe how CpG formulations with various antigens; recombinant proteins, peptides, and conventional vaccines can enhance immune responses to each of these different vaccine combinations. What is even more interesting is that CpG incorporation in vaccines can shift the immune response from a predominant T helper 2 (Th2)-like immune response generally induced by killed or subunit proteins to a much more balanced Th1-Th2 response. These immunomodulatory effects have significant implications for management of infectious diseases of all vertebrates.

Berche, P. (2003). "[Bacterial aggression]." Ann Pharm Fr 61(4): 270-5.

            In all living species, the first line of defence against microbial aggressions is constituted by innate immunity. During Evolution, it appears in invertebrates and plants, long before adaptive immunity, which appears in vertebrate. Adaptive immunity induces acquired resistance against microorganisms through random somatic rearrangements of genes encoding immunoglobulins and T cell receptors, thus generating a high level of diversity of receptors (>10(9)) in response to microbial aggressions. Acquired resistance is not vertically transmitted and reflects the "infectious history" of every individual. In contrast, innate immunity relies on recognition of antigens by a small number of weakly specific receptors (>10(2)) designated Pattern-Recognition Receptors (PRR) and is vertically transmitted by germinal cells. The PRR are expressed on macrophages dendritic cells and B lymphocytes and recognize antigenic structures highly conserved in the living world, termed Pathogen-Associated Molecular Patterns (PAMP), as lipopolysaccharides peptidoglycanes and lipoteichoic acids. PRR are secreted (complement, lectins), or expressed at the cell surface of cells to induce endocytosis or signaling (Toll-like receptors or TLRs). The recognition of antigens induces an immediate inflammatory response and triggers adaptive immunity. Among secreted PRR, the system of complement plays a major role in the immediate inflammatory response, controlling infections by its major role in opsonization, chemotactism and activation of leucocytes. TLRs induce the inflammatory response against microorganisms through NF-kB, a cytoplasmic factor controlling transcription of many genes, including cytokines (TNF, INF, IL-1, IL-2, IL-8, IL-12.) and defensines. So, within few minutes following microbial aggression, the inflammatory response is rapidly triggered to destroy infectious agents and to generate a long-term memory against pathogens.

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.

Beutler, B. (2003). "Innate immune responses to microbial poisons: discovery and function of the Toll-like receptors." Annu Rev Pharmacol Toxicol 43: 609-28.

            There are many circumstances under which a toxin exploits an endogenous receptor or another protein of host origin to work its untoward effects. In most instances, the receptor normally fulfills a function that has nothing to do with the toxin per se; that is, the toxin is not the "natural" ligand. The situation with endotoxin, however, is a remarkable one. The endotoxin receptor evolved to detect endotoxin. Why have mammals maintained a gene that can undermine their survival? The search for the endotoxin receptor answered this question and also revealed the essential function and biological strategy of the Toll-like receptors: principal sensors of the innate immune system.

Beyan, H., L. R. Buckley, et al. (2003). "A role for innate immunity in type 1 diabetes?" Diabetes Metab Res Rev 19(2): 89-100.

            Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and gammadelta T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes.

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.

Boman, H. G. (2003). "Antibacterial peptides: basic facts and emerging concepts." J Intern Med 254(3): 197-215.

            Antibacterial peptides are the effector molecules of innate immunity. Generally they contain 15-45 amino acid residues and the net charge is positive. The cecropin type of linear peptides without cysteine were found first in insects, whilst the defensin type with three disulphide bridges were found in rabbit granulocytes. Now a database stores more than 800 sequences of antibacterial peptides and proteins from the animal and plant kingdoms. Generally, each species has 15-40 peptides made from genes, which code for only one precursor. The dominating targets are bacterial membranes and the killing reaction must be faster than the growth rate of the bacteria. Some antibacterial peptides are clearly multifunctional and an attempt to predict this property from the hydrophobicity of all amino acid side chains are given. Gene structures and biosynthesis are known both in the fruit fly Drosophila and several mammals. Humans need two classes of defensins and the cathelicidin-derived linear peptide LL-37. Clinical cases show that deficiencies in these peptides give severe symptoms. Examples given are morbus Kostmann and atopic allergy. Several antibacterial peptides are being developed as drugs.

Bourlioux, P., B. Koletzko, et al. (2003). "The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium "The Intelligent Intestine," held in Paris, June 14, 2002." Am J Clin Nutr 78(4): 675-83.

            The intestine is an extremely complex living system that participates in the protection of the host through a strong defense against aggressions from the external environment. This defensive task is based on 3 constituents that are in permanent contact and dialog with each other: the microflora, mucosal barrier, and local immune system. We review herein current knowledge about these important functions. The gut microflora play a major role against exogenous bacteria through colonization resistance, but the mechanism of action is not yet established, although it is linked to the bacteria colonizing the gut. This colonization involves bacteria-bacteria dialog, bacteria-mucins interactions, and bacteria-colonocytes cross-talk associated with environmental factors. The intestinal mucosa is a cellular barrier and the main site of interaction with foreign substances and exogenous microorganisms. It is a complex physicochemical structure consisting of a mucous layer linked to cellular and stromal components that participate in the defense of the host through mucosal blood flow, mucosal secretions, epithelial cell functionals, surface hydrophobicity, and defensin production. The intestine is the primary immune organ of the body represented by the gut-associated lymphoid tissue through innate and acquired immunity. This immune system can tolerate dietary antigens and the gut-colonizing bacteria and recognizes and rejects enteropathogenic microorganisms that may challenge the body's defenses. In cooperation with these endogenous barriers, some in-transit bacteria, such as probiotics, can act as partners of the defense system of the intestine.

Brake, D. A. (2003). "Parasites and immune responses: memory illusion?" DNA Cell Biol 22(6): 405-19.

            Immunological memory responses to intracellular protozoa and extracellular helminths govern host resistance and susceptibility to reinfection. Humans and livestock living in parasitic disease endemic regions face continuous exposure from a very early age that often leads to asymptomatic chronic infection over their entire lifespan. Fundamental immunological studies suggest that the generation of T-cell memory is driven by tightly coordinated innate and adaptive cellular immune responses rapidly triggered following initial host infection. A key distinguishing feature of immune memory maintenance between the majority of parasitic diseases and most bacterial or viral diseases is long-term antigen persistence. Consequently, functional parasite immune memory is in a continuous, dynamic flux between activation and deactivation producing functional parasite killing or functional memory cell death. In this sense, T-cell immune memory can be regarded as "memory illusion." Furthermore, due to the finite capacity of memory lymphocytes to proliferate, continuous parasite antigen stimulation may exceed a threshold level at some point in the chronically infected host. This may result in suboptimal effector immune memory leading to host susceptibility to reinfection, or immune dysregulation yielding disease reactivation or immune pathology. The goal of this review is to highlight, through numerous examples, what is currently known about T-cell immune memory to parasites and to provide compelling hypotheses on the survival and maintenance of parasite "memory illusion." These novel concepts are discussed in the context of rationale parasite vaccine design strategies.

Bray, M. (2003). "Pathogenesis and potential antiviral therapy of complications of smallpox vaccination." Antiviral Res 58(2): 101-14.

            Vaccination against smallpox may result in a variety of complications, ranging in severity from benign to lethal. Universal vaccination was halted in the US in 1972, so almost half the present population has never been vaccinated. Because side effects occur most often in first-time vaccinees, current plans for rapid large-scale vaccination in the event of bioterrorist attack raise concerns about the occurrence of a large number of adverse events. Most complications result from the excessive replication of vaccinia virus, making them potential targets for antiviral therapy. Effective treatment is especially needed for persons with atopic dermatitis or eczema, who are unusually susceptible to the initiation and spread of vaccinia infection because of defects of innate immunity in the skin, and for individuals with defective cell-mediated immunity, who are unable to eliminate vaccinia infection once it has begun. In the past, many complications were treated with vaccinia immune globulin (VIG) and/or the antiviral drug methisazone, but neither was tested in placebo-controlled trials. New antiviral drugs are now available, but have not yet been evaluated for treating vaccinia infections in humans. Both laboratory research and clinical studies are needed to help prevent serious complications in any major vaccination campaign.

Brown, G. D. and S. Gordon (2003). "Fungal beta-glucans and mammalian immunity." Immunity 19(3): 311-5.

            Beta-glucans are structural cell wall polymers of many fungi which possess immunomodulatory activities. Although the therapeutic benefits associated with these compounds, particularly as anti-infective and antitumorigenic agents, have led to a large body of published research over the last five decades, it is still unclear how these carbohydrates mediate their effects. Recent studies, however, are starting to shed some light on the cellular receptors and molecular mechanisms involved, which also have direct relevance on the innate immune response to fungal pathogens.

Brubaker, R. R. (2003). "Interleukin-10 and inhibition of innate immunity to Yersiniae: roles of Yops and LcrV (V antigen)." Infect Immun 71(7): 3673-81.

Buentke, E. and A. Scheynius (2003). "Dendritic cells and fungi." Apmis 111(7-8): 789-96.

            Fungi comprise a group of microorganisms that in the past 20 years has become increasingly important as a cause of human disease. Few fungi are professional but instead opportunistic pathogens, and some fungi can even act as allergens. Dendritic antigen-presenting cells function as a link between innate and adaptive immunity and are therefore important in recognition of pathogens. Effective defense requires the host to discriminate between different pathogens to induce an appropriate response. Signaling from different groups of microbes can be mediated via the Toll-like receptors (TLRs), leading to activation of conserved host defense signaling pathways that control the expression of a variety of immune response genes. Different dendritic cells (DCs) express different patterns of recognition molecules, which indicate that they are more or less efficient when responding to certain pathogens. DCs have an important role in the induction of cell-mediated immune responses to fungi, and the studies reviewed here show that fungi, or possibly fungi-derived factors, provide a powerful activation stimulus to DCs, resulting in DC maturation with upregulation of co-stimulatory molecules and production of cytokine patterns leading to different T cell responses. The possibility of using ex vivo-generated DCs as therapeutic tools for restoring anti-fungal immunity is a challenge for the future.

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.

Casal, J. and D. Tarrago (2003). "Immunity to Streptococcus pneumoniae: Factors affecting production and efficacy." Curr Opin Infect Dis 16(3): 219-24.

            Streptococcus pneumoniae is a complex human pathogen and a major cause of morbidity and mortality. The genetic background of pneumococci and the chemical structure of their capsules is largely unraveled as well as the basic role of anticapsular antibodies and other opsonins interacting to enhance phagocytosis. Many experimental studies are improving our knowledge on the complex molecular mechanisms underlying those events. Pneumococcal optimal clearance requires the cooperation of a plethora of reactions from both innate and adaptive immunity. The last advances in the complexity of the immune response and protection are reviewed: phagocyte-pneumococcus interactions mediated by opsonins; the role of complement, reactive C protein and natural antibodies; details of novel immune evasion mechanisms; the complex role of the inflammatory mediators in the susceptibility to pneumococcal infections; why capsular polysaccharides do not yield an anamnestic response after primary immunization; the central question of whether T cells regulate in-vivo anti-polysaccharide immunoglobulin responses to intact pathogens. All of these are topics where new data and some answers are offered. The state of the art on the research of pneumococcal protein vaccines as an alternative to plain polysaccharide or conjugated vaccine and the establishment of immunologic correlates of protection to facilitate efficacy trial assessment are also reviewed.

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.

Chakravortty, D. and M. Hensel (2003). "Inducible nitric oxide synthase and control of intracellular bacterial pathogens." Microbes Infect 5(7): 621-7.

            Inducible nitric oxide synthase (iNOS) has important functions in innate immunity and regulation of immune functions. Here, the role of iNOS in the pathogenesis of various intracellular bacterial infections is discussed. These pathogens have also evolved a broad array of strategies to repair damage by reactive nitrogen intermediates, and to suppress or inhibit functions of iNOS.

Chang, D. H. and M. V. Dhodapkar (2003). "Dendritic cells and immunotherapy for cancer." Int J Hematol 77(5): 439-43.

            Dendritic cells, nature's adjuvant, are antigen-presenting cells specialized to initiate and regulate immunity. Their potent antigen-presenting function has encouraged targeting of dendritic cells (DCs) for harnessing the immune system against cancer. DCs are efficient at activating not only CD4+ helper T-cells and CD8+ killer T-cells but also B-cells and innate effectors such as natural killer and natural killer T-cells. Early studies of adoptive transfer of tumor antigen-loaded DCs have shown promise. However, DC vaccination is at an early stage, and several parameters still need to be established. The complexity of the DC system brings about the necessity for its rational manipulation for achieving protective and therapeutic immunity in patients.

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.

Charron, D. (2003). "Immunogenomics of hematopoietic stem cell transplantation." Transfus Clin Biol 10(3): 156-8.

            Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) incur the risk of graft-versus-host disease (GVHD) even when the donor is a sibling who shares the major histocompatibility antigens. Therefore, even the perfect HLA match does not represent the optimal genetic match between donors and recipients in HSCT. In addition to the HLA complex other genetic systems operate and affect the outcome of HSCT. These include minor histocompatibility systems (inducing bona fide allogeneic responses) as well as a series of functional polymorphisms in cytokines and chemokines and receptors genes. Among the items affecting the outcome of HSCT the incidence and severity of infections have an important impact. Polymorphisms of genes controlling both arms of the immune responses to pathogens (innate vs. cognate) are strong candidates for susceptibility factors to infection in allogeneic transplantation. These include the MHC alleles (HLA class I, class II, MIC) CD1, Toll and TLR genes MBP, MPO genes.). In addition to the NK alloreactivity induced by HLA class I epitopes mismatching (a common situation in HSCT) variations in the genotype of the KIR genes may also be encountered between the donor and the recipient leading to potentially harmful or beneficial combinations. An integrated knowledge of the role and hierarchy of the most important genetic factors (MHC and non-MHC) will provide the rationale for a comprehensive matching in HSCT. This short review provides a panorama of this strategic issue for further development of HSCT.

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.

Chowdhury, P., W. Zhou, et al. (2003). "Complement in renal transplantation." Nephron Clin Pract 95(1): c3-8.

            Previous research and therapy in renal transplantation largely focused on the cellular arm of the adaptive immune response. Evidence is emerging that innate immune mechanisms, particularly complement, play a greater role in inflammatory and immune responses against the graft than has been previously recognized. Alternative complement pathway activation appears to mediate renal ischaemia/reperfusion injury, and proximal tubular cells may be both the source and the site of attack of complement components in this setting. Locally produced complement also plays a role in the development of both cellular and antibody-mediated immune responses against the graft. C4d staining has emerged as a useful marker of humoral rejection both in the acute and in the chronic setting and led to renewed interest in the significance of anti-donor antibody formation. A number of therapies are in development which inhibit complement or reduce local synthesis, and may lead to an improved clinical outcome following renal transplantation.

Clemenza, L., F. Dieli, et al. (2003). "Research on complement: old issues revisited and a novel sphere of influence." Trends Immunol 24(6): 292-6.

            Immunology in recent years has taken a somewhat surprising turn, expressed by a renewed interest in innate immunity. Especially intriguing is the regulatory role exerted by the innate components on the adaptive response, with Toll receptors and complement components being the most investigated. This function has been firmly established for complement protein CR2 (CD21) as part of the BCR co-receptor CD19/CD21/CD81. New findings are now providing a broader picture of complement and its tuning of the immune response; for example, complement proteins have been implicated in the control of T-cell-mediated responses. We will review some of these data here and summarize new discoveries in areas of research on more traditional topics within the complement literature, such as complement and renal diseases, and the therapeutic use of C1-Inhibitor. We cover papers selected from studies presented at the XIX International Complement Workshop, held in Palermo in September 2002, and published within the past six months.

Colino, J. and C. M. Snapper (2003). "Dendritic cells, new tools for vaccination." Microbes Infect 5(4): 311-9.

            Our rapidly expanding knowledge of the biology of the dendritic cell (DC), a major antigen-presenting cell connecting innate and adaptive immunity, suggests new possibilities for the development of vaccines and therapeutic strategies against pathogens, through the manipulation of their function in vivo, or the injection of the DC itself, once properly instructed ex vivo.

Collette, Y., A. Gilles, et al. (2003). "A co-evolution perspective of the TNFSF and TNFRSF families in the immune system." Trends Immunol 24(7): 387-94.

            Within the 'success story' of vertebrate evolution, the acquisition and refinement of the adaptive immune system is far from the least impressive example of co-evolution. Members of the tumour necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) have crucial roles in both innate and adaptive immunity. Here, we propose a detailed description of the phylogenetic relations of the TNFSF and TNFRSF members and offer evidence that the divergence of the TNFSF and TNFRSF families paralleled the emergence of the adaptive immune system, at least partly through en bloc duplication. Unexpectedly, TNFSF subfamilies form monophyletic groups with shared functions, including TNFRSF usage. Finally, the mechanisms of (co-)evolution of TNFSF and TNFRSF are discussed.

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.

Dabbagh, K. and D. B. Lewis (2003). "Toll-like receptors and T-helper-1/T-helper-2 responses." Curr Opin Infect Dis 16(3): 199-204.

            PURPOSE OF REVIEW: Toll-like receptors (TLRs) are a family of pattern recognition receptors that are activated by specific components of microbes and certain host molecules. They constitute the first line of defense against many pathogens and play a crucial role in the function of the innate immune system. Recently, TLRs were observed to influence the development of adaptive immune responses, presumably by activating antigen-presenting cells. This has important implications for our understanding of how the host tailors its immune response as a function of specific pathogen recognition. The present review discusses the recent studies that demonstrate the role of TLRs in the regulation of adaptive T-helper-1 (Th1) and Th2 responses, and the mechanisms by which the effects are carried out. RECENT FINDINGS: Most studies have focused on the role of TLRs and components of their signaling pathways in the control of Th1-type immune responses, and on the implications for their use as antimicrobial agents, such as adjuvants in vaccines, or to treat or prevent the Th2-type dominated immune responses seen in allergies. TLR-deficient mice have been described and used to come to these conclusions. Although controversial, there is also evidence that TLRs may be important for Th2-type responses, possibly by augmenting the overall maturity of dendritic cells. SUMMARY: A greater understanding of the processes by which TLRs regulate adaptive immunity may yield not only improved ways to treat infectious diseases but also new approaches to the treatment and prevention of allergic and certain autoimmune disorders.

Dalpke, A. and K. Heeg (2003). "Suppressors of cytokine signaling proteins in innate and adaptive immune responses." Arch Immunol Ther Exp (Warsz) 51(2): 91-103.

            Suppressors of cytokine signaling (SOCS) proteins have been identified as important mediators of negative regulatory circuits within cytokine receptor signaling. They are induced upon stimulation by an increasing set of cytokines as well as further immunological stimuli and are capable to inhibit Janus kinases and signal transducer and activator of transcription signaling. Inhibition is mediated by interfering directly with signal transduction at the receptor as well as targeting of associated molecules for proteosomal degradation. Targeted gene deletion approaches have revealed the importance of SOCS mediated termination of cytokine signaling during normal cellular activation. In addition to their function as classical feedback inhibitors SOCS proteins display a broad panel of inhibitory activity thereby mediating cross-talk modulation between different stimuli. The consequences for regulation of innate and adaptive immune responses are thus obvious. Finally, there are emerging data showing involvement of SOCS proteins in various immune diseases. Modulating SOCS activity could be a promising new approach for molecular therapeutic strategies.

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.

DeVries, M. E., K. A. Hosiawa, et al. (2003). "The role of chemokines and chemokine receptors in alloantigen-independent and alloantigen-dependent transplantation injury." Semin Immunol 15(1): 33-48.

            Transplantation injury and rejection involves the interplay of innate and acquired immune responses. Immune-related injury manifests itself in three temporal phases: early innate immune driven alloantigen-independent injury, acquired immune driven alloantigen-dependent injury, and chronic injury. Sequential waves of chemokine expression play a central role in regulating graft injury through the recruitment of phagocytes shortly after transplantation and activated lymphocytes and phagocytes in the weeks and years following transplantation. This review focuses on recent studies demonstrating the role of chemokines in transplantation.

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.

Dong, V. M., D. H. McDermott, et al. (2003). "Chemokines and diseases." Eur J Dermatol 13(3): 224-30.

            Chemokines are a group of small, pro-inflammatory molecules first described for their pivotal role in the mobilization of specific leukocyte subsets towards sites of inflammation and their activation once they arrive. They have now emerged as key regulators in the development, differentiation and anatomic distribution of inflammatory cells. Chemokines also orchestrate both the innate immune response and antigen specific immunity through their coordination of dendritic cells and lymphocytes. Due to their vast functional responsibilities, they are linked to the pathogenesis of many seemingly unrelated diseases that include HIV infection, cancer, atherosclerosis, autoimmune diseases, graft rejection and dermatological disorders. This review focuses on the physiology of chemokines and their significant roles in the pathogenesis and progression of major diseases.

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.

Elward, K. and P. Gasque (2003). ""Eat me" and "don't eat me" signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system." Mol Immunol 40(2-4): 85-94.

            A full innate immune system (e.g. complement system, scavenger receptors, Toll-like receptors (TLR)) has been described in the CNS and is thought to be an extremely efficient army designed to fight against invading pathogens and toxic cell debris such as apoptotic cells and amyloid fibrils. The binding of soluble or secreted innate immune molecules on pathogen-associated molecular patterns (PAMPs) as well as apoptotic cell-associated molecular patterns (ACAMPs) provide several "eat me" signals to promote the safe disposal of the intruders by professional and amateur phagocytes. These patterns are deciphered by receptors (pattern recognition receptors, PRRs; e.g. CR3) that control phagocytosis and associated inflammatory response depending on the meaning of these signals. Importantly, in order to avoid excessive collateral damage of surrounding cells, it is increasingly evident that "don't eat me" signals (coined herein as self-associated molecular patterns, SAMPs; e.g. complement regulatory proteins, CD200) are of paramount importance to signal a robust anti-inflammatory response and promote tissue repair. Further knowledge of the innate immune response in the CNS will greatly help to delineate the novel therapeutic routes to protect from CNS inflammation and neurodegeneration.

Evans, J. T., C. W. Cluff, et al. (2003). "Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529." Expert Rev Vaccines 2(2): 219-29.

            MPL (Corixa) adjuvant is a chemically modified derivative of lipopolysaccharide that displays greatly reduced toxicity while maintaining most of the immunostimulatory activity of lipopolysaccharide. MPL adjuvant has been used extensively in clinical trials as a component in prophylactic and therapeutic vaccines targeting infectious disease, cancer and allergies. With over 33,000 doses administered to date, MPL adjuvant has emerged as a safe and effective vaccine adjuvant. Recently, scientists at Corixa Corporation have developed a library of synthetic lipid A mimetics (aminoalkyl glucosaminide 4-phosphates) with demonstrated immunostimulatory properties. Similar to MPL adjuvant, these synthetic compounds signal through Toll-like receptor 4 to stimulate the innate immune system. One of these compounds, Ribi.529 (RC-529), has emerged as a leading adjuvant with a similar efficacy and safety profile to MPL adjuvant in both preclinical and clinical studies.

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).

Fernandez, M. I. and P. J. Sansonetti (2003). "Shigella interaction with intestinal epithelial cells determines the innate immune response in shigellosis." Int J Med Microbiol 293(1): 55-67.

            Shigellae are Gram-negative bacilli that cause bacillary dysentery in humans. This review summarizes current knowledge of Shigella pathogenesis and pathogenicity factors, invasion of epithelial cells, intracellular motility and cell-to-cell spreading, as well as components of the host cell involved in innate immune responses.

Figdor, C. G. (2003). "Molecular characterization of dendritic cells operating at the interface of innate or acquired immunity." Pathol Biol (Paris) 51(2): 61-3.

            Dendritic Cells (DC) are natural adjuvants able to elicit specific cellular interactions and priming of naive T cells at a mature stage of their differentiation. Recent genomic approaches helped defining DC or Langherans Cells (LC) in more molecular terms. DC-SIGN, the DC specific ICAM-3 grabbing non integrin is a C-type lectin, absent on LC but expressed on dermal, lymph node and tonsils DC. DC-SIGN is defined as an ICAM-3 receptor supporting DC mediated-T cell proliferation. Moreover, DC-SIGN plays an important role in binding and presentation of HIV virions, because DC-SIGN specifically binds the gp120 coat protein of HIV.DC-SIGN also plays a part in DC trafficking since it not only binds ICAM-3 but also ICAM-2 expressed by many endothelial cells, supporting tethering and rolling of DC on endothelium and chemokine induced-transmigration of DC across both resting and activated endothelium in vitro. ALCAM (Activated Leukocyte Cell Adhesion Molecule) is another cell surface protein expressed by DC upon differentiation from monocytes. ALCAM appears to be expressed on activated leukocytes and might be involved in inflammatory processes. ALCAM belongs to the IgG superfamily of proteins and mediate heterotypic (T cell antigen ligand CD6) or homotypic interactions. ALCAM is linked to the cytoskeleton and might play a role in DC migration. Measurements of cell/cell contacts at single molecular levels using optical traps is a useful tool to investigate intercellular interactions.

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.

Fukao, T. and S. Koyasu (2003). "PI3K and negative regulation of TLR signaling." Trends Immunol 24(7): 358-63.

            Excessive immune responses are detrimental to the host and negative feedback regulation is crucial for the maintenance of immune-system integrity. Recent studies have shown that phosphoinositide 3-kinase (PI3K) is an endogenous suppressor of interleukin-12 (IL-12) production triggered by Toll-like receptor (TLR) signaling and limits excessive Th1 polarization. Unlike IRAK-M (IL-1 receptor-associated kinase-M) and SOCS-1 (suppressor of cytokine signaling-1) that are induced by TLR signaling and function during the second or continuous exposure to stimulation, PI3K functions at the early phase of TLR signaling and modulates the magnitude of the primary activation. Thus, PI3K, IRAK-M and SOCS-1 have unique roles in the gate-keeping system, preventing excessive innate immune responses.

Gallo, R. L. and V. Nizet (2003). "Endogenous production of antimicrobial peptides in innate immunity and human disease." Curr Allergy Asthma Rep 3(5): 402-9.

            Antimicrobial peptides are diverse and evolutionarily ancient molecules produced by all living organisms. Peptides belonging to the cathelicidin and defensin gene families exhibit an immune strategy as they defend against infection by inhibiting microbial survival, and modify hosts through triggering tissue-specific defense and repair events. A variety of processes have evolved in microbes to evade the action of antimicrobial peptides, including the ability to degrade or inactivate antimicrobial peptides, or suppress host production of the peptide in response to infection. Animal models and clinical investigations have shown that an absence of cathelicidin or defensin antimicrobials can lead to disease. In this article, we review important recent advances in understanding the biology of antimicrobial peptides and their role in normal immunity and human disease.

Ganz, T. (2003). "Defensins: antimicrobial peptides of innate immunity." Nat Rev Immunol 3(9): 710-20.

            The production of natural antibiotic peptides has emerged as an important mechanism of innate immunity in plants and animals. Defensins are diverse members of a large family of antimicrobial peptides, contributing to the antimicrobial action of granulocytes, mucosal host defence in the small intestine and epithelial host defence in the skin and elsewhere. This review, inspired by a spate of recent studies of defensins in human diseases and animal models, focuses on the biological function of defensins.

Ganz, T. (2003). "Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation." Blood 102(3): 783-8.

            Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone. The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. Evidence from transgenic mouse models indicates that hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from macrophages. The key role of hepcidin is confirmed by the presence of nonsense mutations in the hepcidin gene, homozygous in the affected members, in 2 families with severe juvenile hemochromatosis. Recent evidence shows that deficient hepcidin response to iron loading may contribute to iron overload even in the much milder common form of hemochromatosis, from mutations in the HFE gene. In anemia of inflammation, hepcidin production is increased up to 100-fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.

Garred, P., F. Larsen, et al. (2003). "Mannose-binding lectin deficiency--revisited." Mol Immunol 40(2-4): 73-84.

            There is an emerging interest for mannose-binding lectin (MBL) due to its role in innate immunity. In this survey we present a mixture of old and new data describing the effect MBL polymorphisms may have on the level and function of the molecule.Three single nucleotide substitutions in exon 1 of the mbl2 gene cause a dominant decrease of functional MBL in the circulation. Additionally, promoter variants influence expression of MBL. It has been assumed that the structural variant alleles may disrupt the assembly of MBL trimers or accelerate the degradation of the protein, thereby causing the decrease in MBL serum concentrations.We have analysed 1183 different sera in a double sandwich antibody ELISA using the same antibody to capture and detect MBL and find the same results as have been presented previously showing that different MBL promoter alleles have profound effect of on the MBL serum concentration. The use of a new anti-MBL monoclonal antibody, however, has shown that the amount of MBL in the circulation is less dependent on the presence of structural variant alleles than previously anticipated.Molecular characterisation of MBL revealed that sera from donors homozygous for the normal MBL genotype predominantly contained high molecular weight MBL, while sera from individuals heterozygous for the variant alleles contained both high and low molecular weight MBL. The ratio between high and low molecular weight MBL was dependent on the MBL promoter type on the normal haplotype. Sera deriving from individuals homozygous for MBL variant alleles contained mainly low molecular weight MBL. Of the different oligomers of MBL only the high molecular weight forms bound mannan efficiently and activated complement.In contrast to a previous notion, we demonstrate that variant alleles give rise to relatively high levels of MBL in the circulation. However, the variant MBL has lower molecular weight and is dysfunctional compared to normal MBL. The physiological relevance of variant MBL remains to be established.

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., I. Zanoni, et al. (2003). "Dendritic cell regulation of immune responses: a new role for interleukin 2 at the intersection of innate and adaptive immunity." Embo J 22(11): 2546-51.

            Dendritic cells are professional antigen-presenting cells able to initiate innate and adaptive immune responses against invading pathogens. In response to external stimuli dendritic cells undergo a complete genetic reprogramming that allows them to become, soon after activation, natural killer cell activators and subsequently T cell stimulators. The recent observation that dendritic cells produce interleukin 2 following microbial stimulation opens new possibilities for understanding the efficiency of dendritic cells in regulating immune system functions. This review discusses how dendritic cells control natural killer, T- and B-cell responses and the relevance of interleukin 2 in these processes.

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.

Holmgren, J., A. M. Harandi, et al. (2003). "Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA." Expert Rev Vaccines 2(2): 205-17.

            The mucosal immune system consists of an integrated network of lymphoid cells that work in concert with innate host factors to promote host defence. Mucosal immunization can be used both to protect the mucosal surfaces against colonization and invasion by microbial pathogens and to provide a means for immunological treatment of selected autoimmune, allergic or infectious-immunopathological disorders through the induction of antigen-specific tolerance. The development of mucosal vaccines, whether for prevention of infectious diseases or for oral tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems. Significant progress has recently been made to generate partly or wholly detoxified derivatives of cholera toxin (including the completely nontoxic cholera toxin B subunit) and the closely related Escherichia coli heat-labile enterotoxin, with retained adjuvant activity. Cholera toxin B subunit is a protective component of a widely registered oral vaccine against cholera, and has proven to be a promising vector for either giving rise to anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. Promising advances have also recently been made in the design of efficient mucosal adjuvants based on bacterial DNA that contains CpG-motifs and various imidazoquinoline compounds binding to different Toll-like receptors on mucosal antigen-presenting cells.

Holmskov, U., S. Thiel, et al. (2003). "Collections and ficolins: humoral lectins of the innate immune defense." Annu Rev Immunol 21: 547-78.

            Collectins and ficolins, present in plasma and on mucosal surfaces, are humoral molecules of the innate immune systems, which recognize pathogen-associated molecular patterns. The human collectins, mannan-binding lectin (MBL) and surfactant protein A and D (SP-A and SP-D), are oligomeric proteins composed of carbohydrate-recognition domains (CRDs) attached to collagenous regions and are thus structurally similar to the ficolins, L-ficolin, M-ficolin, and H-ficolin. However, they make use of different CRD structures: C-type lectin domains for the collectins and fibrinogen-like domains for the ficolins. Upon recognition of the infectious agent, MBL and the ficolins initiate the lectin pathway of complement activation through attached serine proteases (MASPs), whereas SP-A and SP-D rely on other effector mechanisms: direct opsonization, neutralization, and agglutination. This limits the infection and concurrently orchestrates the subsequent adaptive immune response. Deficiencies of the proteins may predispose to infections or other complications, e.g., reperfusion injuries or autoimmune diseases. Structure, function, clinical implications, and phylogeny are reviewed.

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.

Huffnagle, G. B. and G. S. Deepe (2003). "Innate and adaptive determinants of host susceptibility to medically important fungi." Curr Opin Microbiol 6(4): 344-50.

            The host response is the outcome of an interplay between innate immunity, adaptive immunity (Th1, Th2, T regulatory cells, B cells and antibodies) and fungal virulence factors. Dendritic cells are the gatekeepers between innate and adaptive immunity and have been the intense focus of recent studies on innate immunity to fungi because of their ability to distinguish between different forms of a fungal species, to drive Th1 versus Th2 versus T regulatory responses, and potentially be modulated by fungal products. New mechanisms have been described by which anti-fungal antibodies can modulate infection and augment T cell immunity. Th1 responses are central to limiting infection with many fungi; thus, a great deal of attention has been focused recently on the antigen(s) that trigger such a response.

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