Innate immunity and apoptosis in IBD.
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Adaptor Proteins, Signal Transducing↗
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Paneth cells and the innate immune response.
PURPOSE OF REVIEW: To review recently published studies presenting novel and relevant information on Paneth cells and their function. RECENT FINDINGS: Paneth cells are secretory epithelial cells which are predominantly found in the small-intestinal crypts of Lieberkühn. Their most abundant products are alpha-defensins, which are endogenous antibiotics with activity against gram-negative and gram-positive bacteria, fungi, viruses and protozoa. The differentiation from stem-cell progenitors to Paneth cells is regulated by Wnt signalling via a complex gene programme, terminally including defensins. A disturbance of Paneth-cell differentiation and function may predispose to intestinal infections and appears to be a critical factor in the pathogenesis of ileal Crohn's disease, an inflammatory disease of the intestinal tract. SUMMARY: It is conceivable that these recent findings together with a better understanding of underlying mechanisms involved in the regulation and biology of Paneth cells will open up new therapeutic avenues for preventing infection as well as for causally treating inflammatory bowel diseases.
Animals↗
Paneth cells: their role in innate immunity and inflammatory disease.
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Humans↗
Epithelial regulation of innate immunity to respiratory syncytial virus.
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Humans↗
The innate immune system in cystic fibrosis lung disease.
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Antigens, Bacterial↗
[Innate immunity and acquired immunity].
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Animals↗
Cutting edge: innate immune system discriminates between RNA containing bacterial versus eukaryotic structural features that prime for high-level IL-12 secretion by dendritic cells.
RNA derived from bacterial but not eukaryotic sources, when transfected into human monocyte-derived dendritic cell precursors, induces high-level IL-12 secretion in conjunction with dendritic cell maturation stimuli. In vitro-transcribed mRNA that mimics the structure of bacterial mRNA in the lack of a long 3'-poly(A) tail likewise induces IL-12 secretion, but this property is lost upon efficient enzymatic 3'-polyadenylation. Among other tested RNAs, only polyuridylic acid induced IL-12 p70. This RNA response phenomenon appears biologically distinct from the classically defined response to dsRNA. RNA-transfected APC also polarize T cells in an IL-12-dependent manner toward the IFN-gamma(high)IL-5 (low) Th1 phenotype, suggesting a link between the detection of appropriately structured RNA and the skewing of immune responses toward those best suited for controlling intracellular microbes. RNA structured to emulate bacterial patterns constitutes a novel vaccine strategy to engender polarized Th1-type immune responses.
3' Untranslated Regions↗
Role of the mannose-binding lectin in innate immunity.
The ability to recognize infectious agents from self is intrinsic to innate immunity. One basic tenet of innate immunity is the evolution of classes of molecules that are termed "pattern-recognition" receptors and molecules. Many pattern-recognition molecules conspire together to protect the host in the first minutes and hours after exposure to an infectious challenge. The mannose-binding lectin (MBL; also termed "mannose-binding protein") is a prototypic pattern-recognition molecule that appears to play a role as an "ante-antibody" in first line host defense. The serum levels of the human MBL are regulated in serum so that any one person will display a phenotype of low, intermediate, or high levels. There appears to be a relationship between circulating MBL and susceptibility and resistance to infection. MBL levels also appear to be regulated by distinct haplotypes. Thus, the question to be answered is what constitutes the innate immunity haplotype in any individual and how does this impact on the relationship between the host and infectious agents?
Alleles↗
Invertebrates versus vertebrates innate immunity: In the light of evolution.
Invertebrates use a nonadaptive, innate immunity, the expression of germline encoded receptors, to identify the allogeneic and xenogeneic attributes. Vertebrates also have the capacity to express ontogenically related adaptive immunity which is a somatically selected gene rearrangement process. Several commonly accepted generalizations are utilized to explain the enigmatic lack of the adaptive immunity in invertebrates. All point to the primitive nature of the innate immunity and the primitive organization of the body plan and the life history patterns of invertebrates. Seven of the most common generalizations are reviewed and confuted by virtue of a biased literature presentation. Subsequently, three evolutionary puzzles are raised and the accepted paradigm that the vertebrate immunity is pathogenically directed is further challenged. This leads to an alternative idea suggesting that preserving the individuality against the threat of invading conspecific cells might have been the original function of the immune system. This ancient system has been co-opted later on to serve as a defence mechanism against pathogens. The secondary role arose in the form of a multiplicity of newly developed phenomena, one of them being the vertebrate adaptive immunity. This proposal is supported by the fact that vertebrates still exhibit two distinct but common types of naturally occurring transplantation events (natural chimerism) and by a variety of recent studies, providing evidence for the crucial role of the vertebrate's innate immunity in signalling and triggering the acquired effector mechanisms.
Adaptation, Physiological↗
Innate immune responses to Rhodococcus equi.
We examined innate immune responses to the intracellular bacterium Rhodococcus equi and show that infection of macrophages with intact bacteria induced the rapid translocation of NF-kappa B and the production of a variety of proinflammatory mediators, including TNF, IL-12, and NO. Macrophages from mice deficient in MyD88 failed to translocate NF-kappa B and produced virtually no cytokines in response to R. equi infection, implicating a TLR pathway. TLR4 was not involved in this response, because C3H/HeJ macrophages were fully capable of responding to R. equi infection, and because RAW-264 cells transfected with a dominant negative form of TLR4 responded normally to infection by R. equi. A central role for TLR2 was identified. A TLR2 reporter cell was activated by R. equi, and RAW-264 cells transfected with a dominant negative TLR2 exhibited markedly reduced cytokine responses to R. equi. Moreover, macrophages from TLR2(-/-) mice exhibited diminished cytokine responses to R. equi. The role of the surface-localized R. equi lipoprotein VapA (virulence-associated protein A), in TLR2 activation was examined. Purified rVapA activated a TLR2-specific reporter cell, and it induced the maturation of dendritic cells and the production of cytokines from macrophages. Importantly, TLR2(-/-)-deficient but not TLR4(-/-)-deficient mice were found to be compromised in their ability to clear a challenge with virulent R. equi. We conclude that the efficient activation of innate immunity by R. equi may account for the relative lack of virulence of this organism in immunocompetent adults.
Adaptor Proteins, Signal Transducing↗
Sexual dimorphism in innate immunity.
OBJECTIVE: To establish whether variation in innate immunity, as measured by the level of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-stimulated whole-blood culture, is related to sex or HLA. METHODS: Normal volunteers (72 women, 159 men) completed questionnaires and donated peripheral blood specimens. Blood samples were exposed to LPS in a 4-hour in vitro culture, and supernatants were then tested by sandwich-type immunoassay measuring TNF levels. Statistical techniques included multivariate analysis and maximal-likelihood modeling of allelic effects. RESULTS: Both male and female groups showed substantial within-group variation (coefficient of variation 59.1% for women, 40.3% for men). However, the mean +/- SD LPS-stimulated TNF level in the female group was nearly 30% lower than in the male group (1,556+/-919 pg/ml versus 2,203+/-889 pg/ml; P < 0.0001, unadjusted for covariates). Sex was independent of any microsatellite marker allele of TNF (covariate-adjusted increment of 785 pg/ml from female to male sex; P < 0.0001). In multivariate modeling of the female group, the LPS-stimulated TNF level was not independently influenced by menstrual cycle phase, oral contraceptive use, or plasma estradiol level. Allelic modeling showed that significant TNFab microsatellite allelic effects existed (P = 0.002 versus model omitting allelic effects). The female group showed a significantly downward deviation from mean TNF level with TNFa4b5 (-903 pg/ml deviation from the overall mean) and an upward deviation with TNFa10b4 (598 pg/ml). The male group showed significantly higher-than-mean levels with TNFa1b5 (909 pg/ml), TNFa5b7 (1,191 pg/ml), and TNFa6b5 (332 pg/ml). Thus, the two sex groups differed in which of their TNFab marker alleles showed significant deviations from the overall mean. CONCLUSION: Female subjects have a nearly 30% lower innate immune response, stemming largely from influence independent of the HLA-region TNF locus and without further independent variation stemming from plasma estrogen level.
Adult↗
Neuronal oxidative damage and dendritic degeneration following activation of CD14-dependent innate immune response in vivo.
The cause-and-effect relationship between innate immune activation and neurodegeneration has been difficult to prove in complex animal models and patients. Here we review findings from a model of direct innate immune activation via CD14 stimulation using intracerebroventricular injection of lipopolysaccharide. These data show that CD14-dependent innate immune activation in cerebrum leads to the closely linked outcomes of neuronal membrane oxidative damage and dendritic degeneration. Both forms of neuronal damage could be blocked by ibuprofen and alpha-tocopherol, but not naproxen or gamma-tocopherol, at pharmacologically relevant concentrations. This model provides a convenient method to determine effective agents and their appropriate dose ranges for protecting neurons from CD14-activated innate immunity-mediated damage, and can guide drug development for diseases, such as Alzheimer disease, that are thought to derive in part from CD14-activated innate immune response.
Journal Article↗
A molecular analysis of ascidian metamorphosis reveals activation of an innate immune response.
Ascidian metamorphosis represents a powerful model for comparative work on chordate development that has remained largely unexplored. We isolated transcripts differentially expressed during metamorphosis in the ascidian Boltenia villosa by suppressive PCR subtractions of staged larval and juvenile cDNAs. We employed a series of three subtractions to dissect gene expression during metamorphosis. We have isolated 132 different protein coding sequences, and 65 of these transcripts show significant matches to GenBank proteins. Some of these genes have putative functions relevant to key metamorphic events including the differentiation of smooth muscle, blood cells, heart tissue and adult nervous system from larval rudiments. In addition, a significant fraction of the differentially expressed transcripts match identified genes from the innate immune system. Innate immunity confers a rapid response to pathogen-specific molecules and/or compromised self-tissues. The activation of innate immunity genes during metamorphosis may represent the programmed maturation of the adult immune system. In addition, this immune response may be necessary for phagocytosis and re-structuring of larval tissues. An innate immune-related inflammatory response may also underlie two waves of trans-epidermal blood cell migration that occur during the swimming larval period and immediately upon settlement. We characterized these trans-epidermal migrations and discovered that some migratory cells leave the animal entirely through an anterior tunnel in the tunic. We show that these cells are positioned to detect external settlement cues and hypothesize that the innate immune system may also be employed to detect and rapidly respond to environmental settlement cues.
Animals↗
Epigenetic and metabolic reprogramming of innate immune cells establishes immunological memory in the Schistosomiasis vector snail Biomphalaria glabrata.
Innate immune memory enables non-vertebrates to mount faster and more effective immune responses upon re-exposure to a previously encountered pathogen, yet its cellular and molecular bases remain poorly understood. The freshwater snail Biomphalaria glabrata, intermediate host of the human parasite Schistosoma mansoni, provides a powerful model to investigate this phenomenon. Here, we show that innate immune memory in B. glabrata is carried by hemocytes and relies on profound metabolic and epigenetic reprogramming initiated during primary infection. Using an integrative multi-omics approach combining transcriptomics, chromatin accessibility profiling, whole-genome bisulfite sequencing and targeted metabolomics, we reveal that the first parasite encounter induces a stable rewiring of hemocyte metabolism and chromatin landscape. This reprogramming primes hemocytes for a massive and rapid transcriptional response upon secondary challenge, characterized by an immune shift toward highly specific humoral effector pathways. Metabolic analyses demonstrate an early switch toward aerobic glycolysis, altered tricarboxylic acid cycle activity and amino acid metabolism, consistent with a Warburg-like metabolic state previously described in vertebrate trained immunity. Notably, metabolic and epigenetic remodeling occurs primarily during the primary infection and remains stable upon secondary exposure, suggesting that immune memory is encoded prior to pathogen re-encounter. Together, our results identify conserved metabolic and epigenetic mechanisms underlying innate immune memory in a non-vertebrate host and provide direct evidence that hemocyte-mediated innate immune memory in B. glabrata shares core features with trained immunity described in vertebrates.
Animals↗
Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis.
The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.
Animals↗
Is innate enough? The innate immune response in Drosophila.
In recent years, the innate immune system has emerged from the shadow of adaptive immune responses as a major area of research in its own right. One of the most significant model systems that has been used to investigate this phenomenon has been the fruit fly, Drosophila melanogaster. Exploration of the differential immune response presented by Drosophila led to the discovery of important signalling events and transduction pathways, which were thereafter shown to be specific for the type of infecting pathogen. These factors and pathways were subsequently found to have homologues in many other organisms, including those with adaptive immune responses. In light of the present status of studies in innate immunity, this review describes the current state of understanding of the Drosophila immune response.
Animals↗
Innate immunity in critical care.
Innate and adaptive immunity are required for effective control of infection. Numerous breakthroughs have been achieved in the last 15 years with regard to the functioning of the innate immune system. This article focuses on new paradigms of microorganism recognition, discusses recently described (or rediscovered) cytokines that provide further insight into the development of sepsis, and reviews both pro- and anti-inflammatory pathways for control of infection. Finally, it discusses what has and has not worked with regard to controlling inflammatory pathways in septic patients.
Child↗
Toll-like receptors in innate immunity.
Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.
Animals↗