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Summary: The immune system plays a critical role in protecting the host against infection but is subject to numerous levels of control that are necessary to prevent pathological, tissue-damaging responses. Inappropriate inflammatory immune responses to self-antigens, innocuous commensal microorganisms, or environmental antigens can lead to chronic, debilitating, and degenerative diseases. Regulatory T cells have an essential, non-redundant, and dominant function in preventing pathological immune responses, as shown by the development of systemic fatal autoimmunity in humans and animals with a genetic deficiency in regulatory T cells. In addition to controlling immune responses, there is a growing understanding that regulatory T cells also contribute directly to tissue homeostasis by promoting tissue regeneration and repair. For these reasons, the prospect of enhancing regulatory T-cell numbers and/or function in patients represents an appealing therapeutic opportunity with potential applications in many diseases, including some where the pathological role of the immune system has only recently been recognized. Approaches to enhance regulatory T cells are now starting to be explored in clinical studies in humans. This review series brings together papers highlighting the Treg-enhancing approaches that are most advanced clinically and examples of therapeutic opportunities based on our growing understanding of regulatory T-cell functions. [ABSTRACT FROM AUTHOR]

Influenza affects most of the world's population annually, often causing a secondary infection, but pathological mechanisms of influenza virus infection remain unclear. We have found that influenza viruses have a selective preference for infecting monocytes and mature immune effector cells. This paper provides evidence that influenza virus infection increases the expression of granzyme B (GrB) in monocytes, activated T and B cells. All GrB+ cells had cytolytic function. GrB+CD62Lhigh central memory (TCM) cells were fast response population to virus infection when compared with GrB+CD62Llow population. The influenza virus-infected PBMC could be killed by GrB+ cells. We propose the following mechanism for influenza: (i) influenza virus within the respiratory tract overcomes humoral defenses; (ii) free virus is directly engulfed by the immune system effector cells and free virus also infects epithelial cells; (iii) virus-infected epithelial cells and the immune system cells are killed by cytotoxic cells. These indicated that an immune system that was combating a virus infection needs to sacrifice some of its immune system cells. Therefore, influenza viruses might temporally destroy the human immune system's line of defense, resulting in susceptibility to a secondary infection. This might be a prevalent mechanism existing in cell-mediated immune responses. [ABSTRACT FROM PUBLISHER]

Recent research has characterized the behavioral defense against disease. In particular the detection of sickness cues, the adaptive reactions (e.g. avoidance) to these cues and the mediating role of disgust have been the focus. A presumably important but less investigated part of a behavioral defense is the immune system response of the observer of sickness cues. Odors are intimately connected to disease and disgust, and research has shown how olfaction conveys sickness cues in both animals and humans. This study aims to test whether odorous sickness cues (i.e. disgusting odors) can trigger a preparatory immune response in humans. We show that subjective and objective disgust measures, as well as TNFα levels in saliva increased immediately after exposure to disgusting odors in a sample of 36 individuals. Altogether, these results suggest a collaboration between behavioral mechanisms of pathogen avoidance in olfaction, mediated by the emotion of disgust, and mechanisms of pathogen elimination facilitated by inflammatory mediators. Disgusting stimuli are associated with an increased risk of infection. We here test whether disgusting odors, can trigger an immune response in the oral cavity. The results indicate an increase level of TNFα in the saliva. This supports that disease cues can trigger a preparatory response in the oral cavity. [ABSTRACT FROM AUTHOR]

Controlling oxidative stress in shrimps under culture conditions is of vital importance to ensure that males have an optimal physiological status. The use of diets supplemented with vitamins are widely used for this purpose. We evaluated the effects of vitamin C on the metabolic, antioxidant, and immune responses of Penaeus brasiliensis Latreille, 1817 broodstock males under culture conditions. A formulated diet was used as a control (16 mg kg–1 of total ascorbic acid (vitamin C) content) and three diets were prepared with three vitamin C levels: 322 mg kg–1 (Diet A), 628 mg kg–1 (Diet B), and 934 mg kg–1 (Diet C). Triglycerides, cholesterol, glucose, and prophenoloxidase, total proteins, and quantity and type of hemocytes in the hemolymph were determined. We also quantified the antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx) and lipid peroxidation in the reproductive tract. Differentially expressed genes of the immune system, namely those of α-2 macroglobulin (α2M), peneidin (Pen), hemocyanin, prophenoloxidase, and the genes encoding the antioxidant enzymes SOD, CAT, and Gpx were quantified in the tract. Sperm quantity and quality were recorded. In males fed Diet C, the lowest cholesterol values and triglycerides obtained in the hemolymph were not significantly different from those fed the control diet (P < 0.05); those fed Diet C showed the highest amount of hyaline hemocytes, the lowest CAT enzyme activity, and the highest Gpx activity. The immune system genes only showed differences between α2M and Pen; sperm quantity and quality were not affected by diet. The results indicated that Diet C (13.9 g kg–1 vitamin C) was effective for the maintenance of P. brasiliensis broodstock males because it controlled cholesterol and triglyceride levels; there was less CAT activity and less activation of the immune system mediated by hemocytes. [ABSTRACT FROM AUTHOR]

The human gut microbiome interacts with each other and the host, which has significant effects on health and disease development. Intestinal homeostasis and inflammation are maintained by the dynamic interactions between gut microbiota and the innate and adaptive immune systems. Numerous metabolic products produced by the gut microbiota play a role in mediating cross‐talk between gut epithelial and immune cells. In the event of an imbalance between the immune system and microbiota, the body becomes susceptible to infections and homeostasis is compromised. This review mainly focuses on the interplay between microbes and the immune system, such as T‐cell‐ and B‐cell‐mediated adaptive responses to microbiota and signalling pathways for effective communication between the two. We have also highlighted the role of microbes in the activation of the immune response, the development of memory cells and how the immune system determines the diversity of human gut microbiota. The review also explains the relationship of commensal microbiota and their relation to the production of immunoglobulins. [ABSTRACT FROM AUTHOR]

Gut inflammation is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in enteric endocrine cells and various biologically active compounds produced by these cells. Although the change in enteric endocrine cells or their products is considered to be important in regulating gut physiology (motility and secretion), it is not clear whether the change plays any role in immune activation and in the regulation of gut inflammation. Due to the strategic location of enteric endocrine cells in gut mucosa, these gut hormones may play an important role in immune activation and promotion of inflammation in the gut. This review addresses the research on the interface between immune and endocrine systems in gastrointestinal (GI) pathophysiology, specifically in the context of two major products of enteric endocrine systems, namely serotonin (5-hydroxytryptamine: 5-HT) and chromogranins (Cgs), in relation to immune activation and generation of inflammation. The studies reviewed in this paper demonstrate that 5-HT activates the immune cells to produce proinflammatory mediators and by manipulating the 5-HT system it is possible to modulate gut inflammation. In the case of Cgs the scenario is more complex, as this hormone has been shown to play both proinflammatory and anti-inflammatory functions. It is also possible that interaction between 5-HT and Cgs may play a role in the modulation of immune and inflammatory responses. In addition to enhancing our understanding of immunoendocrine interaction in the gut, the data generated from the these studies may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammatory diseases which may lead ultimately to improved therapeutic strategies in inflammatory disorders. [ABSTRACT FROM AUTHOR]

One of the features of the genus Leishmania is the diversity of tropism/disease resulting from infection. With notable exceptions, the form (visceral, cutaneous, diffuse cutaneous, mucocutaneous) and severity of disease is a function of the infecting Leishmania species together with host genetics and consequent inflammatory and immune responses. It has become evident from genetic and immunological studies using the murine model that the various members of the genus Leishmania differ in aspects of their 'approach' to the host immune system. We are just beginning to appreciate the complexities of these interactions, which have import for the development of a vaccine against leishmaniasis. In this paper, what is currently understood concerning the mechanisms of leishmanial pathogenesis (based upon studies employing the murine model) is briefly summarized. [ABSTRACT FROM AUTHOR]

Several facets of the host immune response to Salmonella infection have been studied independently at great depths to understand the progress and pathogenesis of Salmonella infection. The circumstances under which a Salmonella -infected individual succumbs to an active disease, evolves as a persister or clears the infection are not understood in detail. We have adopted a system-level approach to develop a continuous-time mechanistic model. We considered key interactions of the immune system state variables with Salmonella in the mesenteric lymph node to determine the final disease outcome deterministically and exclusively temporally. The model accurately predicts the disease outcomes and immune response trajectories operational during typhoid. The results of the simulation confirm the role of anti-inflammatory (M2) macrophages as a site for persistence and relapsing infection. Global sensitivity analysis highlights the importance of both bacterial and host attributes in influencing the disease outcome. It also illustrates the importance of robust phagocytic and anti-microbial potential of M1 macrophages and dendritic cells (DCs) in controlling the disease. Finally, we propose therapeutic strategies for both antibiotic-sensitive and antibiotic-resistant strains (such as IFN-γ therapy, DC transfer and phagocytic potential stimulation). We also suggest prevention strategies such as improving the humoral response and macrophage carrying capacity, which could complement current vaccination schemes for enhanced efficiency. [ABSTRACT FROM AUTHOR]

Cardiac injury may have multiple causes, including ischaemic, non-ischaemic, autoimmune, and infectious triggers. Independent of the underlying pathophysiology, cardiac tissue damage induces an inflammatory response to initiate repair processes. Immune cells are recruited to the heart to remove dead cardiomyocytes, which is essential for cardiac healing. Insufficient clearance of dying cardiomyocytes after myocardial infarction (MI) has been shown to promote unfavourable cardiac remodelling, which may result in heart failure (HF). Although immune cells are integral key players of cardiac healing, an unbalanced or unresolved immune reaction aggravates tissue damage that triggers maladaptive remodelling and HF. Neutrophils and macrophages are involved in both, inflammatory as well as reparative processes. Stimulating the resolution of cardiac inflammation seems to be an attractive therapeutic strategy to prevent adverse remodelling. Along with numerous experimental studies, the promising outcomes from recent clinical trials testing canakinumab or colchicine in patients with MI are boosting the interest in novel therapies targeting inflammation in cardiovascular disease patients. The aim of this review is to discuss recent experimental studies that provide new insights into the signalling pathways and local regulators within the cardiac microenvironment promoting the resolution of inflammation and tissue regeneration. We will cover ischaemia- and non-ischaemic-induced as well as infection-related cardiac remodelling and address potential targets to prevent adverse cardiac remodelling. [ABSTRACT FROM AUTHOR]

IL‐2 was initially characterized as a T cell growth factor in the 1970s, and has been studied intensively ever since. Decades of research have revealed multiple and diverse roles for this potent cytokine, indicating a unique linking role between adaptive and innate arms of the immune system. Here, we review the literature showing that IL‐2 is expressed in a plethora of cell types across the immune system, where it has indispensable functions in orchestrating cellular interactions and shaping the nature and magnitude of immune responses. Emerging from the basic research that has revealed the molecular mechanisms and the complexity of the biologic actions of IL‐2, several immunotherapeutic approaches have now focused on manipulating the levels of this cytokine in patients. These strategies range from inhibition of IL‐2 to achieve immunosuppression, to the application of IL‐2 as a vaccine adjuvant and in cancer therapies. This review will systematically summarize the major findings in the field and identify key areas requiring further research in order to realize the potential of IL‐2 in the treatment of human diseases. [ABSTRACT FROM AUTHOR]

Summary: The human body is populated by a large number of microorganisms and exist in symbiosis with these immensely diverse communities, which are suggested to influence health and disease. The microbiota plays an essential role in the maturation and function of the immune system. The prevalence of atopic diseases has increased drastically over the past decades, and the co‐occurrence of multiple allergic diseases and allergic sensitization starting in early life has gained a great deal of attention. Immune responses in different organs affected by allergic diseases (e.g. skin, intestine and lung) may be linked to microbial changes in peripheral tissues. In the current review, we provide an overview of the current understanding of microbial interactions in allergic diseases and their potential role in the atopic march. [ABSTRACT FROM AUTHOR]

One of the basis of exceptional longevity is the maintaining of the balance between inflammatory and anti-inflammatory networks. The monocyte-macrophages activation plays a major role in tuning the immune responses, by oscillating between patrolling-protective to inflammatory status. Longevity-associated variant (LAV) of bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) activates calcium, PKC-alpha, and eNOS, rescuing endothelial dysfunction in aged mice and inducing revascularization. The BPIFB4's increment in serum of healthy long-living individuals (LLIs) compared to nonhealthy ones, its therapeutic potential in improving vascular homeostasis, which depends on immune system, together with its expression in bone marrow myeloid cells, suggests that LAV-BPIFB4 may improve immune regulation. Here we show that human monocytes exposed to LAV-BPIFB4 protein increased co-stimulatory molecules in resting state and reduced pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) after activating stimuli. Accordingly, a low percentage of CD69+ activated lymphocytes are found among LAV-BPIFB4-treated peripheral blood mononuclear cells (PBMCs). Moreover, human monocyte-derived dendritic cells (DCs) generated in presence of LAV-BPIFB4 secreted higher anti-(IL-10 and TGF-β) and lower pro-inflammatory (TNF-α and IL-1β) cytokines. Accordingly, LLIs' plasma showed higher levels of circulating IL-10 and of neutralizing IL-1 receptor antagonist (IL-1RA) compared to controls. Thus, LAV-BPIFB4 effects on myeloid compartment could represent one example of a genetic predisposition carried by LLIs to protect from immunological dysfunctions. [ABSTRACT FROM AUTHOR]

Summary: Mental illness exerts a major burden on human health, yet evidence‐based treatments are rudimentary due to a limited understanding of the underlying pathologies. Clinical studies point to roles for the immune system in psychiatric diseases, while basic science has revealed that the brain has an active and multi‐cellular resident immune system that interacts with peripheral immunity and impacts behavior. In this perspective, we highlight evidence of immune involvement in human psychiatric disease and review data from animal models that link immune signaling to neuronal function and behavior. We propose a conceptual framework for linking advances in basic neuroimmunology to their potential relevance for psychiatric diseases, based on the subtypes of immune responses defined in peripheral tissues. Our goal is to identify novel areas of focus for future basic and translational studies that may reveal the potential of the immune system for diagnosing and treating mental illnesses [ABSTRACT FROM AUTHOR]

Leukocyte adhesion is important for the proper functioning of the immune system. While leukocyte homing is mediated by adhesion receptors, the activation of these receptors is modulated by intracellular signaling molecules. In Leukocyte Adhesion Deficiency Type 3, the loss of the kindlin-3 prevents the activation of Leukocyte Function-associated Antigen-1 (LFA-1), which leads to a defect in adhesion, causing recurrent infections and bleeding disorders. Here, we use Integrated Signaling Adhesive Dynamics, a computer model of leukocyte rolling and adhesion combined with a simulated intracellular signaling cascade, to predict the response of T cells to depletion of kindlin-3. Our model predicts that cell adhesion is hypersensitive to the amount of kindlin-3 in the cell, while the rolling velocity is independent of kindlin-3 concentration. In addition, our simulation predicted that the time to stop, an important metric of adhesion, would increase with decreasing kindlin-3 expression. These predictions were confirmed experimentally in experiments using Jurkat cells with reduced expression of kindlin-3. These results suggest that Adhesive Dynamics is a versatile tool for quantifying adhesion in the immune response and predicting the effects of engineering cellular components. [ABSTRACT FROM AUTHOR]

Heparan sulfate is found on the surface of most cell types, as well as in basement membranes and extracellular matrices. Its strong anionic properties and highly variable structure enable this glycosaminoglycan to provide binding sites for numerous protein ligands, including many soluble mediators of the immune system, and may promote or inhibit their activity. The formation of ligand binding sites on heparan sulfate (HS) occurs in a tissue‐ and context‐specific fashion through the action of several families of enzymes, most of which have multiple isoforms with subtly different specificities. Changes in the expression levels of these biosynthetic enzymes occur in response to inflammatory stimuli, resulting in structurally different HS and acquisition or loss of binding sites for immune mediators. In this review, we discuss the multiple roles for HS in regulating immune responses, and the evidence for inflammation‐associated changes to HS structure. Review of the established and emerging roles of heparan sulfate as an immune regulator through binding inflammatory ligands in the microenvironment and on cell surfaces. [ABSTRACT FROM AUTHOR]

Organisms in the wild are likely to face multiple immune challenges as well as additional ecological stressors, yet their interactive effects on immune function are poorly understood. Insects are found to respond to cues of increased infection risk by enhancing their immune capacity. However, such adaptive plasticity in immune function may be limited by physiological and environmental constraints. Here, we investigated the effects of two environmental stressors – poor larval diet and an artificial parasite‐like immune challenge at the pupal stage – on adult immune function, growth and development in the greater wax moth (Galleria mellonella). Males whose immune system was activated with an artificial parasite‐like immune challenge had weaker immune response – measured as strength of encapsulation response – as adults compared to the control groups, but only when reared on high‐nutrition larval diet. Immune activation did not negatively affect adult immune response in males reared on low‐nutrition larval diet, indicating that poor larval diet improved the capacity of the insects to respond to repeated immune challenges. Low‐nutrition larval diet also had a positive independent effect on immune capacity in females, yet it negatively affected development time and adult body mass in both sexes. As in the nature immune challenges are rarely isolated, and adverse nutritional environment may indicate an elevated risk of infection, resilience to repeated immune challenges as a response to poor nutritional conditions could provide a significant fitness advantage. This study highlights the importance of considering environmental context when investigating the effects of immune activation in insects. [ABSTRACT FROM AUTHOR]

Expression of dominant‐negative Trim9 in zebrafish macrophages alters their cell shape and significantly reduces their motility in vivo. The vertebrate immune response comprises multiple molecular and cellular components that interface to provide defense against pathogens. Because of the dynamic complexity of the immune system and its interdependent innate and adaptive functionality, an understanding of the whole‐organism response to pathogen exposure remains unresolved. Zebrafish larvae provide a unique model for overcoming this obstacle, because larvae are protected against pathogens while lacking a functional adaptive immune system during the first few weeks of life. Zebrafish larvae were exposed to immune agonists for various lengths of time, and a microarray transcriptome analysis was executed. This strategy identified known immune response genes, as well as genes with unknown immune function, including the E3 ubiquitin ligase tripartite motif‐9 (Trim9). Although trim9 expression was originally described as "brain specific," its expression has been reported in stimulated human Mϕs. In this study, we found elevated levels of trim9 transcripts in vivo in zebrafish Mϕs after immune stimulation. Trim9 has been implicated in axonal migration, and we therefore investigated the impact of Trim9 disruption on Mϕ motility and found that Mϕ chemotaxis and cellular architecture are subsequently impaired in vivo. These results demonstrate that Trim9 mediates cellular movement and migration in Mϕs as well as neurons. [ABSTRACT FROM AUTHOR]

The complement system is an important part of the innate immune defence. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of the adaptive immune response. Besides a role in inflammation, complement is also involved in physiological processes such as waste disposal and developmental programmes. The complement system comprises several soluble and membrane-bound proteins. The bulk of the soluble proteins is produced mainly by the liver. While several complement proteins are produced by a wide variety of cell types, other complement proteins are produced by only a few related cell types. As these data suggest that local production by specific cell types may have specific functions, more detailed studies have been employed recently analysing the local and even intracellular role of these complement proteins. Here we review the current knowledge about extrahepatic production and/or secretion of complement components. More specifically, we address what is known about complement synthesis by cells of the human immune system. [ABSTRACT FROM AUTHOR]

Current studies using knockout mice have revealed that some Cys-Cys-Cys-His (CCCH)-type zinc-finger proteins, namely tristetraprolin (TTP), Roquin and Regnase-1, play important roles in the immune system. These proteins are closely associated with the fate of their target RNAs in normal immune responses. However, the functions of many RNA-binding proteins have not been characterized precisely. To understand the molecular mechanisms of RNA metabolism in the immune system, investigation of TTP/Roquin/Regnase-1 might provide new knowledge. In this review, we will discuss the current understanding of these proteins in immune regulation and homeostasis and discuss RNA metabolism in the immune system. [ABSTRACT FROM AUTHOR]

It has been shown that hematological traits can act as important indicators of immune function in both humans and livestock. T lymphocytes are key components of the adaptive immune system, playing a critical role in immune response. To identify genomic regions affecting hematological traits and T lymphocyte subpopulations, we performed both a SNP-based genomewide association study (GWAS) and a haplotype analysis for 20 hematological traits and 8 T cell subpopulations at 3 different time points (d 20, 33, and 35) in a Duroc × Erhualian F2 inter-cross population. Bonferroni correction was used to calculate the threshold P-values for suggestive and 5% genomewide significance levels. In total, for SNP-based GWAS, we detected 96 significant SNP, including 15 genomewide-significant SNP, associated with 23 hematological traits and 234 significant SNP, including 27 genomewide-significant SNP, associated with 8 T cell subpopulations. Meanwhile, we identified 563 significant SNP, including τ genomewide-significant SNP, associated with 5 hematological traits and 2,407 significant SNP, including 1,261 genomewide-significant SNP, associated with 8 T cell subpopulations by haplotype analysis. Among the significant regions detected, we propose both the NCK adaptor protein 2 (NCK2) gene and the four and a half LIM domains 2 (FHL2) gene on SSC3 as plausible candidate genes associated with CD8 + T lymphocytes at d 20. The findings provide insights into the basis of molecular mechanisms that are involved with immune response in the domestic pig and would aid further identification of causative mutations. [ABSTRACT FROM AUTHOR]8- T lymphocytes at d 20. The findings provide insights into the basis of molecular mechanisms that are involved with immune response in the domestic pig and would aid further identification of causative mutations. [ABSTRACT FROM AUTHOR]

Analyses of arthropod genomes have shown that the genes in the different innate humoral immune responses are conserved. These genes encode proteins that are involved in immune signalling pathways that recognize pathogens and activate immune responses. These immune responses include phagocytosis, encapsulation of the pathogen and production of effector molecules for pathogen elimination. So far, most studies have focused on insects leaving other major arthropod groups largely unexplored. Here, we annotate the immune-related genes of six arachnid genomes and present evidence for a conserved pattern of some immune genes, but also evolutionary changes in the arachnid immune system. Specifically, our results suggest that the family of recognition molecules of beta-1,3-glucanase-related proteins ( β GRPs) and the genes from the immune deficiency ( IMD) signalling pathway have been lost in a common ancestor of arachnids. These findings are consistent with previous work suggesting that the humoral immune effector proteins are constitutively produced in arachnids in contrast to insects, where these have to be induced. Further functional studies are needed to verify this. We further show that the full haemolymph clotting cascade found in the horseshoe crab is retrieved in most arachnid genomes. Tetranychus lacks at least one major component, although it is possible that this cascade could still function through recruitment of a different protein. The gel-forming protein in horseshoe crabs, coagulogen, was not recovered in any of the arachnid genomes; however, it is possible that the arachnid clot consists of a related protein, spätzle, that is present in all of the genomes. [ABSTRACT FROM AUTHOR]

This review discusses three inter-related topics: (1) the immaturity of the neonatal and infant immune response; (2) heterologous immunity, where prior infection history with unrelated pathogens alters disease outcome resulting in either enhanced protective immunity or increased immunopathology to new infections, and (3) epidemiological human vaccine studies that demonstrate vaccines can have beneficial or detrimental effects on subsequent unrelated infections. The results from the epidemiological and heterologous immunity studies suggest that the immune system has tremendous plasticity and that each new infection or vaccine that an individual is exposed to during a lifetime will potentially alter the dynamics of their immune system. It also suggests that each new infection or vaccine that an infant receives is not only perturbing the immune system but is educating the immune system and laying down the foundation for all subsequent responses. This leads to the question, is there an optimum way to educate the immune system? Should this be taken into consideration in our vaccination protocols? [ABSTRACT FROM AUTHOR]

Mucosal vaccines for the control of infectionsThe mucosal surface is the largest route through which pathogens enter the human body. To control the outbreak of mucosal infectious diseases, we must use our knowledge of the mucosal immune system to create vaccines that elicit protective mucosal and systemic immunity. Mucosal vaccines have advantages over traditional injectable vaccines in that they not only induce effective mucosal immune responses, but they also do not cause physical or psychological discomfort. Mucosal vaccines currently licensed for human use include oral vaccines against Vibrio cholerae, Salmonella typhi, poliovirus and rotavirus, and nasal vaccines against influenza virus. To further improve the existing vaccines, it will be necessary to develop novel vaccine production, storage and delivery systems through innovative strategies derived from interdisciplinary scientific research. Our accumulated knowledge of the innate and acquired arms of the mucosal immune system and the recent scientific and technical advancements in the fields of molecular biology, plant biology, bio-engineering and chemical engineering, genome biology and systems biology have created a unique research and development platform for the development of the next generation of mucosal vaccines. This review summarizes the current perspectives and future directions of mucosal vaccine development with emphasis on oral and nasal vaccines for the control of infectious diseases. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases are characterized by a deregulated immune response targeting the gut bacterial flora. Mucosal-associated invariant T ( MAIT) cells are major histocompatibility complex ( MHC) class Ib-restricted innate-like lymphocytes with anti-bacterial functions. They display an effector/memory phenotype and are found in large numbers in the blood, mucosae and liver. They have also been implicated in inflammatory diseases such as multiple sclerosis. Therefore, we aimed to analyse the possible involvement of MAIT cells in Crohn's disease ( CD) and ulcerative colitis ( UC). To this end, a phenotypical and functional analysis of MAIT cells isolated from the blood of healthy subjects, CD and UC patients was undertaken. MAIT cells were also quantified in ileal biopsies of CD patients. The frequency of blood MAIT cells was specifically reduced in IBD patients compared with healthy donors, whereas it was dramatically greater in the inflamed versus healthy tissue. MAIT cells were activated as they expressed significantly more the Ki67 antigen, and this was accompanied by phenotypical changes such as increased expression of natural killer ( NK)G2 D and B and T lymphocyte attenuator ( BTLA). Finally, in-vitro-activated MAIT cells from CD and UC patients secreted significantly more interleukin ( IL)-17, together with a decreased interferon ( IFN)-γ in CD but an increased IL-22 in UC. These data show that MAIT cells are activated in IBD, which results in an increased recruitment towards the inflamed tissues, an altered phenotype and a switch in the pattern of cytokine secretion. This is the first demonstration that MAIT cells are immune players in IBD, whose precise functions in this context need to be addressed. [ABSTRACT FROM AUTHOR]

This study examined the relation between immune response to cytomegalovirus (CMV) and all-cause and cardiovascular disease (CVD) mortality, and possible mediating mechanisms. Data were derived from the Sacramento Area Latino Study on Aging, a population-based study of older Latinos (aged 60–101 years) in California followed in 1998–2008. CMV immunoglobulin G (IgG), tumor necrosis factor, and interleukin-6 were assayed from baseline blood draws. Data on all-cause and CVD mortality were abstracted from death certificates. Analyses included 1,468 of 1,789 participants. For individuals with CMV IgG antibody titers in the highest quartile compared with lower quartiles, fully adjusted models showed that all-cause mortality was 1.43 times (95% confidence interval: 1.14, 1.79) higher over 9 years. In fully adjusted models, the hazard of CVD mortality was also elevated (hazard ratio = 1.35, 95% confidence interval: 1.01, 1.80). A composite measure of tumor necrosis factor and interleukin-6 mediated a substantial proportion of the association between CMV and all-cause (18.9%, P < 0.001) and CVD (29.0%, P = 0.02) mortality. This study is the first known to show that high CMV IgG antibody levels are significantly related to mortality and that the relation is largely mediated by interleukin-6 and tumor necrosis factor. Further studies investigating methods for reducing IgG antibody response to CMV are warranted. [ABSTRACT FROM PUBLISHER]

Aims: To develop probiotics for the control of vibriosis caused by Vibrio anguillarum and Vibrio ordalii in finfish. Methods and Results: Kocuria SM1, isolated from the digestive tract of rainbow trout, was administered orally to rainbow trout ( Oncorhynchus mykiss) for 2 weeks at a dose equivalent to c. 108 cells per g of feed and then challenged intraperitoneally with V. anguillarum and V. ordalii. Use of SM1 led to a reduction in mortalities to 15–20% compared to 74–80% mortalities in the controls. SM1 stimulated both cellular and humoral immune responses in rainbow trout, by elevation of leucocytes (5·5 ± 0·8 × 106 ml−1 from 3·7 ± 0·8 × 106 ml−1), erythrocytes (1·2 ± 0·1 × 108 ml−1 from 0·8 ± 0·1 × 108 ml−1), protein (23 ± 4·4 mg ml−1 from 16 ± 1·3 mg ml−1), globulin (15·7 ± 0·2 mg ml−1 from 9·9 ± 0·1 mg ml−1) and albumin (7·3 ± 0·2 mg ml−1 from 6·1 ± 0·1 mg ml−1) levels, upregulation of respiratory burst (0·05 ± 0·01 from 0·02 ± 0·01), complement (56 ± 7·2 units ml−1 from 40 ± 8·0 units ml−1), lysozyme (920 ± 128·8 units ml−1 from 760 ± 115·3 units ml−1) and bacterial killing activities. Conclusions: Kocuria SM1 successfully controlled vibriosis in rainbow trout, and the mode of action reflected stimulation of the host innate immune system. Significance and Impact of the Study: Probiotics can contribute a significant role in fish disease control strategies, and their use may replace some of the inhibitory chemicals currently used in fish farms. [ABSTRACT FROM AUTHOR]

Cancer may occur as a result of abnormal host immune system tolerance. Recent studies have confirmed the occurrence of spontaneous and induced antitumor immune responses expressed as the presence of tumor-infiltrating T cells in the tumor microenvironment in some cancer models. This finding has been recognized as a good prognostic factor in several types of tumors. Some chemotherapy agents, such as anthracyclines and gemcitabine, are effective boosters of the immune response through tumor-specific antigen overexpression after apoptotic tumor cell destruction. Other strategies, such as GM-CSF or interleukin-2, are pursued to increase immune cell availability in the tumor vicinity, and thus improve both antigen presentation and T-cell activation and proliferation. In addition, cytotoxic T lymphocyte antigen 4 -- blocking monoclonal antibodies enhance immune activity by prolonging T-cell activation. Strategies to stimulate the dormant immune system against tumors are varied and warrant further investigation of their applications to cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Several insect species show an increase in cuticular melanism in response to high densities. In some species, there is evidence that this melanism is correlated with an up-regulation of certain immune system components, particularly phenoloxidase (PO) activity, and with the down-regulation of lysozyme activity, suggesting a trade-off between the two traits. As melanism has a genetic component, we selected both melanic and nonmelanic lines of the phase-polyphenic lepidopteran, Spodoptera littoralis, in order to test for a causative genetic link between melanism, PO activity and lysozyme activity, and to establish if there are any life-history costs associated with the melanic response. We found that, in fact, melanic lines had lower PO activity and higher lysozyme activity than nonmelanic lines, confirming a genetic trade-off between the two immune responses, but also indicating a genetic trade-off between melanism and PO activity. In addition, we found that lines with high PO activity had slower development rates suggesting that investment in PO, rather than in melanism, is costly. [ABSTRACT FROM AUTHOR]

A cytokine-based periodic immunotherapy treatment is included in a model of tumour growth with a delay. The effects of dose schedule are studied in the case of a weak immune system and a growing tumour. We find the existence of 'metastable' states (that may last for tens of years) induced by the treatment and also potentially adverse effects of the dosage frequency on the stabilization of the tumour. These two effects depend on the delay between the tumour growth and the immune system response, the cytokine dose burden, and other parameters considered in the model. [ABSTRACT FROM AUTHOR]

Knowledge of the role of origin-related, environmental, sex, and age factors on host defence mechanisms is important to understand variation in parasite intensity. Because alternative components of parasite defence may be differently sensitive to various factors, they may not necessarily covary. Many components should therefore be considered to tackle the evolution of host–parasite interactions. In a population of barn owls ( Tyto alba), we investigated the role of origin-related, environmental (i.e. year, season, nest of rearing, and body condition), sex, and age factors on 12 traits linked to immune responses [humoral immune responses towards sheep red blood cells (SRBC), human serum albumin (HSA) and toxoid toxin TT, T-cell mediated immune response towards the mitogen phytohemagglutinin (PHA)], susceptibility to ectoparasites (number and fecundity of Carnus haemapterus, number of Ixodes ricinus), and disease symptoms (size of the bursa of Fabricius and spleen, proportion of proteins that are immunoglobulins, haematocrit and blood concentration in leucocytes). Cross-fostering experiments allowed us to detect a heritable component of variation in only four out of nine immune and parasitic parameters (i.e. SRBC- and HSA-responses, haematocrit, and number of C. haemapterus). However, because nestlings were not always cross-fostered just after hatching, the finding that 44% of the immune and parasitic parameters were heritable is probably an overestimation. These experiments also showed that five out of these nine parameters were sensitive to the nest environment (i.e. SRBC- and PHA-responses, number of C. haemapterus, haematocrit and blood concentration in leucocytes). Female nestlings were more infested by the blood-sucking fly C. haemapterus than their male nestmates, and their blood was less concentrated in leucocytes. The effect of year, season, age (i.e. reflecting the degree of maturation of the immune system), brood size, position in the within-brood age hierarchy, and body mass strongly differed between the 12 parameters. Different components of host defence mechanisms are therefore not equally heritable and sensitive to environmental, sex, and age factors, potentially explaining why most of these components did not covary. © 2007 The Linnean Society of London, Biological Journal of the Linnean Society, 2007, 90, 703–718. [ABSTRACT FROM AUTHOR]

Stress is generally considered to suppress the immune system and may lead to an increase in the occurrence of disease in the presence of a pathogen. The immune system is ordinarily brought back to a baseline response level after immune challenge through homeostatic processes, in part regulated by the hypothalamic-pituitary-axis. Often, findings reported from various studies investigating the effects of stress on the immune system are conflicting and difficult to reconcile into a cohesive and comprehensible set of universally applicable theories. These discrepancies may be partly explained by the types and durations of the stressors, the aspect(s) of immune system measured, genetics, and social status. A particular stressor may enhance cell-mediated immune responses while suppressing humoral responses or vice versa, thus disrupting the balance between these components of the immune system. How farm animals perceive their environment depends not only on traditional environmental stressors (e.g., heat, cold, humidity, pollutants), but also on aspects of their social environment. Dominant animals may have enhanced immune activation, whereas subordinates have suppression of the same immune component in response to the same stressor. This could explain why individual animals within a group respond differently to stressors and disease challenges. A better understanding of the consequences and complex interactions between social and environmental stressors for innate and adaptive immune traits must be developed so we can more fully understand the effects of stress on immunity in livestock. Once these complex relationships are better understood, more effective interventions can be designed to improve animal health and well-being. [ABSTRACT FROM AUTHOR]

Mounting an immune response has been suggested to be physiologically costly because of metabolic requirements of immune cells specifically and upregulation of the immune system in general. We investigated such costs in free-living water pythons (Liasis fuscus), immunized with a harmless antigen, keyhole limpet hemocyanin. In the present study, we analyze the independent effects of age, blood parasite load, and body condition on the ability to mount a humoral immune response (level of antibody production to novel antigens). Python humoral immune response decreased with increasing body length/age, decreased with increasing blood parasite load, and decreased with declining body condition. The results suggest an energetic trade-off between immunocompetence and other energetically costly processes. [ABSTRACT FROM AUTHOR]

The immune system of invertebrates can mount different responses, including melanotic encapsulation and several antibacterial defense mechanisms. Variation of the efficacies of these responses is generally considered to be a product of the evolutionary pressure on each response due to infection by parasites. However, potential interactions and trade-offs among the different responses of the immune system could constrain the evolutionary potential of each response. In a natural population of the mosquito Anopheles gambiae, we measured the genetic association between the melanization response and an antibacterial response in two environmental qualities (well-fed and undernourished larvae). In both environments the two immune responses were positively genetically correlated: in full-sib families that were most likely to melanize a bead, injected bacteria were most likely to be cleared. Thus, our data do not support the idea of a trade-off among different outcomes of the invertebrate immune system, but rather that some families are overall immunologically superior to others. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β has been demonstrated to play a key role in the regulation of the immune response, mainly by its suppressive function towards cells of the immune system. In humans, the effect of TGF-β on antigen-specific established memory T cells has not been investigated yet. In this study antigen-specific CD4+ T cell clones (TCC) were used to determine the effect of TGF-β on antigen-specific proliferation, the activation status of the T cells and their cytokine production. This study demonstrates that TGF-β is an adequate suppressor of antigen-specific T cell proliferation, by reducing the cell-cycle rate rather than induction of apoptosis. Addition of TGF-β resulted in increased CD69 expression and decreased CD25 expression on T cells, indicating that TGF-β is able to modulate the activation status of in vivo differentiated T cells. On the contrary, the antigen-specific cytokine production was not affected by TGF-β. Although TGF-β was suppressive towards the majority of the T cells, insensitivity of a few TCC towards TGF-β was also observed. This could not be correlated to differential expression of TGF-β signaling molecules such as Smad3, Smad7, SARA (Smad anchor for receptor activation) and Hgs (hepatocyte growth factor-regulated tyrosine kinase substrate). In summary, TGF-β has a pronounced inhibitory effect on antigen-specific T cell proliferation without modulating their cytokine production. [ABSTRACT FROM AUTHOR]

The article looks at a study regarding evaluation of the mitogen-induced proliferation and cell surface differentiation antigens of lymphocytes from pigs. It mentions cell surface differentiation antigens on the lymphocytes were evaluated for percentages of cells expressing class II molecules. It also mentions porcine immune system is not fully developed at birth and the expression of cell surface differentiation antigen.

Abnormalities in the numbers and function of thymus-derived and bone marrow-derived lymphocytes (T and B cells) and K cells were determined in sixty-nine consecutive patients with Crohn's disease or ulcerative colitis. Rosetting techniques to identify subpopulations of lymphocytes showed a significant decrease in E-rosettes (T cells) and significant increase in EA- and EAC- rosettes (B cells) in patients with inflammatory bowel disease when compared to normals. In vitro lymphocyte transformation responses to mitogens and antigens were depressed to a variable degree. Mean levels of K cell activity were not significantly different from normal controls. A considerable degree of individual variation was noted in all groups. When the results of each group were considered, none of the laboratory variables correlated with the site, duration or activity of disease, therapy, presence of iron deficiency anemia, weight loss or hypoalbuminaemia. Thus, in vitro evidence of abnormal immune responses in patients with inflammatory bowel disease cannot be directly related to clinical or laboratory variables and probably reflects a multi- factorial aetiology. [ABSTRACT FROM AUTHOR]

The article discusses the non-specific recognition mechanisms by mononuclear phagocytes. Phagocytic cells in higher animals are capable of discriminating between foreign material and self components. The recognition abilities that underlie this discriminating capacity must have evolved, at least in simple form, with the emergence of primitive species. Some form of self recognition mechanism is likely to have formed the basis of the abilities of colonial marine species to exclude unrelated forms from inclusion in their colonies. In addition, the cells lining the cavity of Porifera are capable of capturing micro-organisms present in the water drawn into the cavity. Phagocytosis also plays a role in the metamorphosis of insects in removing dead cells and disintegrated tissue.

The effect of human α2-macroglobulin on the recovery of the humoral immune response in X-irradiated mice has been assessed by measurement of antibody- forming cells in the spleen 5 days after challenge with sheep erythrocytes. The capacity of this protein to promote the recovery of immune responsiveness was variable, and appeared to be influenced by the strain and sex of the mice, and the dose of α2M given. [ABSTRACT FROM AUTHOR]

The article provides information on the impact of early diet on the development of immune systems. The study suggests that mother's immune response to fetal antigens asserts the development and growth of trophoblasts and placenta wherein the size of the placenta specify the size of the fetus. Breast feeding offers immediate and lasting influence on the susceptibility and tolerance of B cells and T cells of the offspring, while maternal under nutrition and deficiencies increases risky condition to the immune system. A schematic diagram and several tables are presented depicting immunological responses, effects of cytokines and immune reactivity.

The immune system is a complex of interrelated reactions, which protects animals from invasion by foreign substances. Many environmental substances, such as metals, organic pesticides, and gaseous pollutants, perturb the immune response and increase susceptibility to infectious disease. [Accepted for publication 19 January 1981) [ABSTRACT FROM AUTHOR]

Concerns have been raised about potential toxic interactions when colony-stimulating factors (CSFs) and chemoradiation are concurrently performed. In 2006, the ASCO guidelines advised against their concomitant use. Nevertheless, with the development of modern radiotherapy techniques and supportive care, the therapeutic index of combined chemotherapy, radiotherapy, and CSFs is worth reassessing. Recent clinical trials testing chemoradiation in lung cancer let investigators free to decide the use of concomitant CSFs or not. No abnormal infield event was reported after the use of modern radiotherapy techniques and concomitant chemotherapy regimens. These elements call for further investigation to set new recommendations in favour of the association of chemoradiation and CSFs. Moreover, radiotherapy could induce anticancer systemic effects mediated by the immune system in vitro and in vivo. With combined CSFs, this effect was reinforced in preclinical and clinical trials introducing innovative radioimmunotherapy models. So far, the association of radiation with CSFs has not been combined with immunotherapy. However, it might play a major role in triggering an immune response against cancer cells, leading to abscopal effects. The present article reassesses the therapeutic index of the combination CSFs-chemoradiation through an updated review on its safety and efficacy. It also provides a special focus on radioimmunotherapy. [ABSTRACT FROM AUTHOR]

In this article the author argues for the view that operationally distinguishes clonal immune responses to foreign antigens, versus the network-based immune operation of autoreactivities. This model suggests the co-existence of two fundamentally distinct types of organisation in the mammalian immune system, embodying different ensembles of lymphocytes and repertoires. It is one's conviction that, if autoimmune pathology represents a deviation of physiological autoreactivity, and the latter is reflected in the repertoires of natural serum antibodies, it should be possible in principle to detect such alterations before the pathological process has led to irreversible damage of the target tissues or functions.

This article focuses on the research in the field of immunity, autoimmunity and immunotherapy. The immune system is characterized by its capacity to respond with specificity. Re-exposure of the system to the same immunological stress may lead to an even more effective reaction. The advantage of specificity is linked with the maintenance of self-tolerance. In order to prevent an attack on the self-constituents in the body, the immune response has to be very selective in its recognition of antigen.