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Depression is a serious public health problem, and adolescence is an 'age of risk' for the onset of Major Depressive Disorder. Recently, we and others have proposed neuroimmune network models that highlight bidirectional communication between the brain and the immune system in both mental and physical health, including depression. These models draw on research indicating that the cellular actors (particularly monocytes) and signaling molecules (particularly cytokines) that orchestrate inflammation in the periphery can directly modulate the structure and function of the brain. In the brain, inflammatory activity heightens sensitivity to threats in the cortico‐amygdala circuit, lowers sensitivity to rewards in the cortico‐striatal circuit, and alters executive control and emotion regulation in the prefrontal cortex. When dysregulated, and particularly under conditions of chronic stress, inflammation can generate feelings of dysphoria, distress, and anhedonia. This is proposed to initiate unhealthy, self‐medicating behaviors (e.g. substance use, poor diet) to manage the dysphoria, which further heighten inflammation. Over time, dysregulation in these brain circuits and the inflammatory response may compound each other to form a positive feedback loop, whereby dysregulation in one organ system exacerbates the other. We and others suggest that this neuroimmune dysregulation is a dynamic joint vulnerability for depression, particularly during adolescence. We have three goals for the present paper. First, we extend neuroimmune network models of mental and physical health to generate a developmental framework of risk for the onset of depression during adolescence. Second, we examine how a neuroimmune network perspective can help explain the high rates of comorbidity between depression and other psychiatric disorders across development, and multimorbidity between depression and stress‐related medical illnesses. Finally, we consider how identifying neuroimmune pathways to depression can facilitate a 'next generation' of behavioral and biological interventions that target neuroimmune signaling to treat, and ideally prevent, depression in youth and adolescents. [ABSTRACT FROM AUTHOR]

We study a mathematical model of immune response by T cells where the regulatory T cells (Treg) inhibit interleukin 2 (IL‐2) secretion. We model the suppression of the autoimmune line of T cells after a different line of T cells responded to a pathogen infection. In this paper, we show that if the population of the pathogen responding line of T cells becomes large enough, the competition for IL‐2 and the increase in the death rates may lead to a depletion in the concentration of autoimmune T cells. Provided this lasts for a sufficiently long time, the concentration of autoimmune T cells can be brought down to values inside the basin of attraction of the controlled state, and autoimmunity can be suppressed. [ABSTRACT FROM AUTHOR]

Epidermal Langerhans cells (LC) express several co-stimulatory molecules such as B7/BH1, which has been implicated as one of the important determinants for potent antigen-presenting function of LC. Recent studies have shown that B7/BB1 antigens comprise three distinct molecules termed B7-1, B7-2 and B7-3. Previous studies have revealed that the phenotypic and functional properties of murine LC are enormously affected by various cytokines including granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-l (IL-l), and tumour necrosis factor α (TNT-α) derived from surrounding keratinocytes. We have already demonstrated that the expression of B7-1 of murine LC is significantly enhanced by GM-CSF, IL-1 or TNF-α. In this paper, we present that IL-1, but not TNF-α, synergistically up-regulates the GM-CSF-induced B7-1 expression of murine LC. [ABSTRACT FROM AUTHOR]

There has been much interest in the role of the immune system in the pathophysiology of chronic fatigue syndrome (CFS), as CFS may develop following an infection and cytokines are known to induce acute sickness behaviour, with similar symptoms to CFS. Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls. Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation. Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines. Following physical exercise there were no differences in circulating cytokine levels between cases and controls and exercise made no difference to already elevated TGF-β concentrations. The finding of elevated TGF-β concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue. [ABSTRACT FROM AUTHOR]

Monocytes represent a class of immune cells that play a key role in the innate and adaptive immune response against infections. One mechanism employed by monocytes for sensing foreign antigens is via toll-like receptors (TLRs)--transmembrane proteins that distinguish classes of foreign pathogens, for example, bacteria (TLR4, 5, and 9) vs. fungi (TLR2) vs. viruses (TLR3, 7, and 8). Binding of antigens activates a signaling cascade through TLR receptors that culminate in secretion of inflammatory cytokines. Detection of these cytokines can provide valuable clinical data for drug developers and disease investigations, but this usually requires a large sample volume and can be technically inefficient with traditional techniques such as flow cytometry, enzyme-linked immunosorbent assay, or luminex. This paper describes an approach whereby antibody arrays for capturing cells and secreted cytokines are encapsulated within a microfluidic device that can be reconfigured to operate in serial or parallel mode. In serial mode, the device represents one long channel that may be perfused with a small volume of minimally processed blood. Once monocytes are captured onto antibody spots imprinted into the floor of the device, the straight channel is reconfigured to form nine individually perfusable chambers. To prove this concept, the microfluidic platform was used to capture monocytes from minimally processed human blood in serial mode and then to stimulate monocytes with different TLR agonists in parallel mode. Three cytokines, tumor necrosis factor-a, interleukin (IL)-6, and IL-10, were detected using anti-cytokine antibody arrays integrated into each of the six chambers. We foresee further use of this device in applications such as pediatric immunology or drug/vaccine testing where it is important to balance small sample volume with the need for high information content. [ABSTRACT FROM AUTHOR]

During the last decade, blood purification therapies have been proposed as an effective therapy to control the cytokines dysregulation in systemic inflammatory syndromes. Among them, the treatment with high cut-off membranes is characterized by larger pore size and more effective clearance for middle molecular weight molecules (cytokines). In this paper, we performed a thoughtful review of the literature on HCO being used for blood purification indications in all systemic inflammation syndromes. Clinical and experimental studies show that the use of high effluent flows in a pure diffusive treatment effectively removes serum cytokines with a safe profile in albumin clearance. In clinical studies, the removal of these inflammatory mediators is associated with a significant improvement in hemodynamic condition, oxygenation indices, and organ dysfunction. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The Genetic Markers of Inflammation Study (GenIMS) was conceived to investigate the role of severe sepsis, which is typically defined as system-wide multi-organ failure, on survival. One major hypothesis for this systemic collapse, and reduction in survival, is a cascade of pro-inflammatory and anti-inflammatory cytokines. In this paper, we devised a novel joint modeling strategy to evaluate the joint effect of longitudinal anti-inflammatory marker IL-6 and pro-inflammatory marker IL-10 on 90-day survival. We found that, on average, patients with high initial values of both IL-6 and IL-10, that tend to increase over time, are associated with a reduction in survival expectancy and that accounting for their assumed correlation was justified. [ABSTRACT FROM PUBLISHER]

Objective Somatization is a symptom cluster characterized by 'psychosomatic' symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome ( ME/ CFS). This article reviews the data regarding the pathophysiological foundations of 'psychosomatic' symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms. Method This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune ( CMI). Results The physio-somatic symptoms of depression, ME/ CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite ( TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc. Conclusion Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders. [ABSTRACT FROM AUTHOR]

Probiotic bacteria have been shown to modulate immune responses and could have therapeutic effects in allergic and inflammatory disorders. However, little is known about the signalling pathways that are engaged by probiotics. Dendritic cells (DCs) are antigen-presenting cells that are involved in immunity and tolerance. Monocyte-derived dendritic cells (MoDCs) and murine DCs are different from human gut DCs; therefore, in this study, we used human DCs generated from CD34+ progenitor cells (hematopoietic stem cells) harvested from umbilical cord blood; those DCs exhibited surface antigens of dendritic Langerhans cells, similar to the lamina propria DCs in the gut. We report that both a novel probiotic strain isolated from faeces of exclusively breast-fed newborn infants, Lactobacillus paracasei CNCM I-4034, and its cell-free culture supernatant (CFS) decreased pro-inflammatory cytokines and chemokines in human intestinal DCs challenged with Salmonella. Interestingly, the supernatant was as effective as the bacteria in reducing pro-inflammatory cytokine expression. In contrast, the bacterium was a potent inducer of TGF-β2 secretion, whereas the supernatant increased the secretion of TGF-β1 in response to Salmonella. We also showed that both the bacteria and its supernatant enhanced innate immunity through the activation of Toll-like receptor (TLR) signalling. These treatments strongly induced the transcription of the TLR9 gene. In addition, upregulation of the CASP8 and TOLLIP genes was observed. This work demonstrates that L. paracasei CNCM I-4034 enhanced innate immune responses, as evidenced by the activation of TLR signalling and the downregulation of a broad array of pro-inflammatory cytokines. The use of supernatants like the one described in this paper could be an effective and safe alternative to using live bacteria in functional foods. [ABSTRACT FROM AUTHOR]

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β1 (TGF-β1) regulates cellular proliferation, differentiation, migration, and survival. The human TGF-β1 transcript is inherently poorly translated, and translational activation has been documented in relation to several stimuli. In this paper, we have sought to identify in cis regulatory elements within the TGF-β1 5'Untranslated Region (5'UTR). In silico analysis predicted formation of stable secondary structure in a G/C-rich element between nucleotides +77 to +106, and demonstrated that this element is highly conserved across species. Circular dichroism spectroscopy confirmed the presence of secondary structure in this region. The proximal 5'UTR was inhibitory to translation in reporter gene experiments, and mutation of the secondary structure motif increased translational efficiency. Translational regulation of TGF-β1 mRNA is linked to altered binding of YB-1 protein to its 5'UTR. Immunoprecipitation-RT-qPCR demonstrated a high basal association of YB-1 with TGF-β1 mRNA. However, mutation of the secondary structure motif did not prevent interaction of YB-1 with the 5'UTR, suggesting that YB-1 binds to this region due to its G/C-rich composition, rather than a specific, sequence-dependent, binding site. These data identify a highly conserved element within the TGF-β1 5'UTR that forms stable secondary structure, and is responsible for the inherent low translation efficiency of this cytokine. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines have been used for several years in patients with advanced cancer but their administration is typically associated with severe toxicity hampering their application to therapeutically active regimens. This problem can be overcome by using immunocytokines (cytokines fused to antibody or antibody fragments) which selectively deliver the active cytokine to the tumor environment. Preclinical and recent clinical results confirmed that this approach is a very promising avenue to go. We designed an immunocytokine consisting of the scFv(F8) specific to extra-domain A of fibronectin and the very potent human cytokine interleukin-12 (IL12). The heterodimeric nature of IL12 allows the engineering of various immunocytokine formats, based on different combinations of the two subunits (p35 and p40) together with the scFv. In comparison to monomeric or homodimeric cytokines, the construction of a heterodimeric immunocytokine poses many challenges, e.g. gene dosing, stable high-yield expression as well as good manufacture practice (GMP) purification and characterization. In this paper, we describe the successful construction, characterization and production of the heterodimeric immunocytokine F8-IL12. The positive outcome of this feasibility study leads now to GMP production of F8-IL12, which will soon enter clinical trials. [ABSTRACT FROM PUBLISHER]

Toll-like, vitamin A and D receptors and other innate proteins participate in various immune functions. We determined whether innate gene-sequence variations are associated with rubella vaccine-induced cytokine immune responses. We genotyped 714 healthy children (11–19 years of age) after two doses of rubella-containing vaccine for 148 candidate SNP markers. Rubella virus-induced cytokines were measured by ELISA. Twenty-two significant associations (range of P values 0.002–0.048) were found between SNPs in the vitamin A receptor family (RARA, RARB, TOP2B and RARG), vitamin D receptor and downstream mediator of vitamin D signaling (RXRA) genes and rubella virus-specific (IFN-γ, IL-2, IL-10, TNF-α, and GM-CSF) cytokine immune responses. A TLR3 gene promoter region SNP (rs5743305, −8441A > T) was associated with rubella-specific GM-CSF secretion. Importantly, SNPs in the TRIM5 gene coding regions, rs3740996 (His43Tyr) and rs10838525 (Gln136Arg), were associated with an allele dose-related secretion of rubella virus-specific TNF-α and IL-2/GM-CSF, respectively, and have been previously shown to have functional consequences regarding the antiviral activity and susceptibility to HIV-1 infection. We identified associations between individual SNPs and haplotypes in, or involving, the RIG-I (DDX58) gene and rubella-specific TNF-α secretion. This is the first paper to present evidence that polymorphisms in the TLR, vitamin A, vitamin D receptor, and innate immunity genes can influence adaptive cytokine responses to rubella vaccination. [ABSTRACT FROM AUTHOR]

The dysfunction of pancreatic β-cell and the reduction in β-cell mass are the decisive events in the progression of type 2 diabetes. There is increasing evidence that cytokines play important roles in the procedure of β-cell failure. Cytokines, such as IL-1β, IFN-γ, TNF-α, leptin, resistin, adiponectin, and visfatin, have been shown to diversely regulate pancreatic β-cell function. Recently, isletderived cytokine PANcreatic DERived factor (PANDER or FAM3B) has also been demonstrated to be a regulator of islet β-cell function. The change in cytokine profile in islet and plasma is associated with pancreatic β-cell dysfunction and apoptosis. In this paper, we summarize and discuss the recent studies on the effects of certain important cytokines on pancreatic β-cell function. The imbalance in deleterious and protective cytokines plays pivotal roles in the development and progression of pancreatic β-cell dysfunction under insulin-resistant conditions. [ABSTRACT FROM AUTHOR]

Neutrophils have a dual affect on epithelial pIgR/SC, the critical receptor for transcellular routing ofmucosal IgA, but mechanisms of pIgR/SC upregulation remain elusive. Requirements of cytokine, redox, and signalling pathways for pIgR/SC production were assessed in human bronchial epithelial (Calu-3) cells cocultured with increasing numbers of blood neutrophils. Increased SC production was observed after incubation for 48 hrs with intermediate neutrophil numbers (1.25 to 2.5 × 106), was favoured by the elastase inhibitor SLPI, and correlated with increased TGF-β production. Exogenous TGF-β stimulated SC production with a maximal effect at 48 hrs and both TGF-β- and neutrophil-driven SC upregulation were dependent on redox balance and p38 MAP-kinase activation. This paper shows that activated neutrophils could upregulate epithelial pIgR/SC production through TGF-β-mediated activation of a redox-sensitive and p38 MAPK-dependent pathway. An imbalance between the two neutrophildriven opposite mechanisms (SC upregulation and SC degradation) could lead to downregulation of pIgR/SC, as observed in severe COPD. [ABSTRACT FROM AUTHOR]

Cytokine-induced killer (CIK) cells are polyclonal T effector cells generated when cultured under cytokine stimulation. CIK cells exhibit potent, non-MHC-restricted cytolytic activities against susceptible tumor cells of both autologous and allogeneic origins. Over the past 20 years, CIK cells have evolved from experimental observations into early clinical studies with encouraging preliminary efficacy towards susceptible autologous and allogeneic tumor cells in both therapeutic and adjuvant settings. This paper is our attempt to summarize the available published literature related to CIK cells. Looking into the future, we anticipate that the continuous therapeutic application of CIK cells will likely be developed along two major directions: overcoming the challenge to organize large prospective randomized clinical trials to define the roles of CIK cells in cancer immunotherapy and expanding its spectrum of cytotoxicity towards resistant tumor cells through experimental manipulations. [ABSTRACT FROM AUTHOR]

The ultimate outcome of T cell receptor recognition is determined by the context in which the antigen is encountered. In this fashion both antigen-presenting cells and T cells must integrate multiple environmental cues in the form of pathogen-associated molecular patterns, cytokines and accessory molecule signals. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental signals critical to regulating metabolism and cell survival. In this paper we review the data demonstrating that mTOR integrates signals from the immune microenvironment and therefore facilitates the generation of the adaptive immune response. Specifically, we review the role of mTOR in promoting dendritic cell activation and maturation, in regulating full T cell activation versus anergy, and influencing the induction of regulatory T cells. [ABSTRACT FROM AUTHOR]

Advances in free radical research show that reactive oxygen and nitrogen oxide species, for example superoxide, nitric oxide (NO) and peroxynitrite, play an important role in the pathogenesis of different viral infections, including dengue virus. The pathogenic mechanism of dengue haemorrhagic fever (DHF) is complicated and is not clearly understood. The hallmarks of the dengue disease, the antibody-dependent enhancement, the shift from T-helper type 1 (Th1) to Th2 cytokine response and the cytokine tsunami resulting in vascular leakage can now be explained much better with the knowledge gained about NO and peroxynitrite. This paper makes an effort to present a synthesis of the current opinions to explain the pathogenesis of DHF/shock syndrome with NO on centre stage. [ABSTRACT FROM AUTHOR]

The suppressor of cytokine signaling 1 (SOCS-1), as the name implies, is a member of proteins that regulate cytokine signaling pathways by inhibiting the events of key tyrosine phosphorylation on cytokine receptors and signaling molecules such as Janus kinase family members. Although mammalian SOCS-1 homologues were characterized in several species, no similar research work has been reported in fish yet. In this paper, we initially cloned the SOCS-1 genes from Tetraodon nigroviridis and Danio rerio, and identified other two SOCS-1 genes from Fugu rubripes and Gasterosteus aculeatus. The results showed that the fish SOCS-1-encoding genes consist of two exons and a single intron, a typical characteristic of SOCS family in gene organization. Moreover, two alternatively spliced transcripts that encoded 220 and 196 amino acids were obtained in T. nigroviridis, proving the distinct existence of alternative splicing in fish SOCS-1 different from higher vertebrates. By reverse transcriptase polymerase chain reaction (PCR) and real-time quantitative PCR, gene expression studies indicated that both two alternatively spliced transcripts of Tetraodon SOCS-1 were expressed extensively in major tissues as we examined and their corresponding expression levels could be strikingly raised at 3 h postinjection with lipopolysaccharide, which strongly suggested that SOCS-1 proteins in fish might be involved in inflammatory responses. This is the first report of cloning and characterization of SOCS-1 complementary deoxyribonucleic acids and genes in fish. [ABSTRACT FROM AUTHOR]

Asthma is a waxing and waning disease that leads to structural changes in the airways, such as subepithelial fibrosis, increased mass of airway smooth muscle and epithelial metaplasia. Such a remodeling of the airways futher amplifies asthma symptoms, but its etiology is unknown. Transforming growth factor β1 is a pleiotropic cytokine involved in many fibrotic, oncologic and immunologic diseases and is believed to play an essential role in airway remodeling that occurs in asthmatic patients. Since it is secreted in an inactive form, the overall activity of this cytokine is not exclusively determined by its level of expression, but also by extensive and complex post-translational mechanisms, which are all importanin modulating the magnitude of the TGFβ1 response. Even if TGFβ1 upregulation in asthma is considered as a dogma by certain investigators in the field, the overall picture of the published litterature is not that clear and the cellular origin of this cytokine in the airways of asthmatics is still a contemporaneous debate. On the other hand, it is becoming clear that TGFβ1 signaling is increased in the lungs of asthmatics, which testifies the increased activity of this cytokine in asthma pathogenesis. The current work is an impartial and exhaustive compilation of the reported papers regarding the expression of TGFβ1 in human asthmatics. For the sake of comparison, several studies performed in animal models of the disease are also included. Inconsistencies observed in human studies are discussed and conclusions as well as trends from the current state of the litterature on the matter are proposed. Finally, the different points of regulation that can affect the amplitude of the TGFβ1 response are briefly revised and the possibility that TGFβ1 is disregulated at another level in asthma, rather than simply in its expression, is highlighted. [ABSTRACT FROM AUTHOR]

This paper reviews the new biologic agents that selectively block the immunologic steps implicated in the pathogenesis of psoriasis. Four strategies have been targeted: reduction of the number of pathogenic T cells; inhibition of T-cell activation and migration; modulation of the immune system; and blockage of the activity of inflammatory cytokines. There are three classes: monoclonal antibodies, fusion proteins and recombinant cytokines or growth factors. The actions, efficacy and side-effect profile of the biologic agents, alefacept, efalizumab, etanercept and infliximab, are reviewed. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokine gene polymorphisms have been demonstrated to associate with gastric cancer risk, of which IL1B−31T/C and −511C/T changes have been well investigated due to the possibility that they may alter the IL1B transcription. The signal transduction target upon interleukin 1 beta (IL1β) stimulation, the nuclear factor of kappa B (NFκB) activation, supports cancer development, signal transduction in which is mediated by FS-7 cell-associated cell surface antigen (FAS) signaling. Based on recent papers describing the prognostic roles of the polymorphisms and the NFκB functions on cancer development, we sought to determine if Japanese gastric cancer patients were affected by the IL1B −31/−511 and FAS−670 polymorphisms. A case-control study was conducted on incident gastric adenocarcinoma patients ( n=271) and age–gender frequency-matched control subjects ( n=271). We observed strong linkage disequilibrium between the T allele at −511 and the C allele at −31 and between the C allele at −511 and the T allele at −31 in IL1B in both the cases and controls ( R 2=0.94). Neither IL1B−31, −511 nor FAS−670 polymorphisms showed significantly different risks of gastric adenocarcinoma. Though FAS−670 polymorphisms did not show any significant difference, the proportion of subjects with IL1B−31TT (or IL1B−511CC) increased according to stage (trend P=0.019). In particular, subjects with stage IV had a two times higher probability of having either IL1B−31TT (or IL1B−511CC) genotype compared with stage I subjects. These observations suggest that IL1B−31TT and IL1B−511CC are associated with disease progression. [ABSTRACT FROM AUTHOR]

Inflammatory processes are known to be involved at least in the early phase of complex regional pain syndrome type 1 (CRPS1). Blister fluid obtained from the involved extremities displayed increased amounts of proinflammatory cytokines IL-6 and TNFα compared with the noninvolved extremities. The aim of this paper is to investigate the involvement of mediators by measurement of several other cytokines using new detection techniques that enable multiple cytokine measurement in small samples. The use of a multiplex-25 bead array cytokine assay and Luminex technology enabled simultaneous measurement of representative (1) proinflammatory cytokines such as GM-CSF, IL-1β, IL-1RA, IL-6, IL-8, and TNF-α; (2) Th1/Th2 distinguishing cytokines IFN-γ, IL-2, IL-2R, IL-4, IL-5, and IL-10; (3) nonspecific acting cytokines IFN-α, IL-7, IL-12p40/p70, IL-13, IL-15, and IL-17; and (4) chemokines eotaxin, IP-10, MCP-1, MIP-1α, MIP-1β, MIG, and RANTES. Although minimal detection levels are significantly higher in the bead array system than those in common ELISA assays, in blister fluid, IL-1RA, IL-6, IL-8, TNF-α, IL-12p40/p70, MCP-1, and MIP-1β were detectable and increased in CRPS1 affected extremities. Levels of IL-6 and TNF-α simultaneously measured by ELISA (Sanquin Compact kit) and by multiplex-25 bead array assay (Biosource) were highly correlated (r = 0.85,P < .001 for IL-6 and r = 0.88, P < .001 for TNF-α). Furthermore, IP-10 and eotaxin were detectable but diminished in CRPS1, whereas detectable amounts of IL-10 were similar in involved and noninvolved extremities. Multiplex bead array assays are useful systems to establish the involvement of cytokines in inflammatory processes by measurements in blister fluids of CRPS1. Ten representative cytokines were detectable. However, detection levels and amounts measured are at least 3 times higher in the multiplex-25 array assay than in the ELISA assays used simultaneously for the measurement of cytokines. [ABSTRACT FROM AUTHOR]

Aim: The pathophysiology of perinatal brain lesions is probably complex and multifactorial. The development and characterization of distinct yet complementary animal models should help to unravel the cellular and molecular mechanisms underlying perinatal brain lesions. This paper reviews experimental data obtained in animal models of neonatal excitotoxic brain lesions that closely mimic some of the lesions found in human cerebral palsy.Conclusion: Available data point to a key role for brain macrophages and oligodendrocytes in neonatal rodent excitotoxic brain lesions and underline the impact of cytokines on these lesions. [ABSTRACT FROM AUTHOR]

The role of cytokines in the accumulation of eosinophil granulocytes in inflamed tissue has been studied extensively during recent years, and these molecules have been found to participate throughout the whole process of eosinophil recruitment. Haematopoietic cytokines such as IL-3, IL-5 and GM-CSF stimulate the proliferation and differentiation of eosinophils in the bone marrow, and the release of mature eosinophils from the bone marrow into the blood is probably promoted by IL-5. Priming of eosinophils in the blood following, for example, allergen challenge is performed mainly by IL-3, IL-5 and GM-CSF. An important step in the extravasation of eosinophils is their adhesion to the vascular endothelium. Adhesion molecules are upregulated by, e.g. IL-1, IL-4, TNF- α and IFN- γ and the same cytokines may also increase the affinity of adhesion molecules both on eosinophils and endothelial cells. Finally, a number of cytokines have been shown to act as eosinophil chemotactic factors, attracting the cells to the inflammatory focus in the tissue. Some of the most important eosinophil chemoattractant cytokines are IL-5, IL-8, RANTES, eotaxin, eotaxin-2, eotaxin-3, MCP-3, MCP-4 and TNF- α. Th2 cells, mast cells and epithelial cells are important sources of proinflammatory cytokines, but in recent years, the eosinophils have also been recognized as cytokine-producing and thereby immunoregulatory cells. The aim of this paper is to review the role of cytokines in the process of eosinophil recruitment in asthma, allergy and ulcerative colitis. [ABSTRACT FROM AUTHOR]

Introduction. Chronic fatigue syndrome is a disease that includes a number of various symptoms, among which the most characteristic symptom is fatigue. Diagnostic criteria are not unambiguous and vary depending on the scientific society by which they were developed. The aim of this review is to discuss the phenomenon of chronic fatigue, including its diagnostic criteria, epidemiology, pathophysiology, symptoms, and pharmacological and non-pharmacological strategies. Material and methods. 45 articles published were reviewed and placed in the PubMed and Google Scholar databases. Results. Chronic fatigue syndrome is defined as a group of symptoms whose dominant symptom is fatigue that persists after rest for at least 6 months. The Oxford or CDC criteria are most commonly used to make the diagnosis. Statistics on prevalence are inconclusive. There are several theories of origin - infectious, immunological, neuroendocrine, bioenergetic, neurological, autonomic and genetic. Other symptoms of chronic fatigue syndrome include sleep and memory disorders or muscle and joint pain. Current treatment focuses on symptomatic treatment, including education, diet, and physical activity, as well as pharmacotherapy for pain, sleep, and cognition. Discussion. Diagnosis and treatment of chronic fatigue syndrome undoubtedly is a medical challenge, due to non-specific symptoms, multifactorial pathogenesis and difficult to estimate prevalence of this disease. Future scientific development should focus especially on exploring the pathomechanism of CFS, which would enable the implementation of causal treatment. [ABSTRACT FROM AUTHOR]

This paper describes the bacterial expression and purification of bioactive recombinant ovine interleukin-2 (rovIL-2), interleukin-l α (rovIL-1 α) and tumour necrosis factor α. These purified proteins had specific activities in appropriate bioassays of 1 × 107, 1 × 10 and 1 × 105 U/mg, respectively. Recombinant ovIL-1 α was assessed as an immunological adjuvant for the sheep response to the model protein avidin. When delivered either intradermally or intramuscularly in conjunction with avidin in aluminium hydroxide the rovIL-1 α significantly enhanced the secondary humoral response. Doses of 1, 10 or 100 μg per sheep enhanced the humoral response to a similar extent. Recombinant ovIL-1 β had similar adjuvant activity in that it was demonstrated to significantly enhance the sheep humoral response to an experimental H. contortus antigen. This increase in specific antibody, however, did not correlate with enhanced protection against infection with third stage H. contortus larvae. In addition incorporation of rovIL-1 β into the formulation was shown not to alter the isotype profile of H. contortus antigen specific antibody. [ABSTRACT FROM AUTHOR]

Background Selected cytokines produced by allergen specific CD4+ T cells from atopic individuals contribute to both the specific and non-specific effector mechanisms of the allergic immune response. The chemokine family of cytokines and tumour necrosis factor (TNF)-α are leucocyte regulatory and proinflammatory molecules. The chemokines include interleukin (IL)-8 and the RANTES/SIS cytokines. Objective There bas been no systematic survey of chemokine production in T-cell subtypes. Because of their wide range of biological properties, it might be expected that they would be closely regulated by T cells. This paper illustrates one way (through the characterization of T-cell clones) these questions might be addressed. Methods Northern blot analysis was used to quantitate steady state transcription of selected cytokine genes and enzyme linked immunosorbent assay (ELISA) was used to quantitate soluble product. Results mRNA expression of the chemokines (IL-8. HuMIP-lα and HuMIP-lβ) and TNFα is upregulated in TH2-like cloned house dust mite reactive human CD4+ T cells under conditions of activation and during the induction phase of anergy. Although the development of anergy superinduces mRNA for both IL-8 and TNFα, protein production is low compared with that released during activation. In contrast, RANTES, a chemoattractant for CD4+ /CD45RO+ memory T cells, eosinophils and basophils, is constitutively expressed at the RNA level by the T cells and not modulated by signals of activation and anergy induction. The production of IL-2, IL-4 and IL-5 mRNA and proteins during the induction of anergy peaks at 2h after stimulation, whereas the kinetics following activation of the T cells is delayed in comparison. Conclusion These data show that the induction of the anergic state coincides with post-transcriptional regulation of selected cytokine genes. Further study of these phenomena will impact on our understanding of the mechanisms of induction of anergy and the regulation of allergic immune responses in desensitization. [ABSTRACT FROM AUTHOR]

Highlights the papers with implications for allergy and respiratory cellular immunology that are presented during the 7th International Congress of Immunology in Berlin, Germany. Biology of the lower affinity Fc receptor for immunoglobulin E; Interactions between cytokines and endothelial cells; Role of T cell bearing gamm-delta antigen receptors.

This paper demonstrates that CD40 is expressed on rheumatoid synovial pannus and primary fibroblast cell lines established from rheumatoid and osteoarthritic synovium as well as normal skin. Among various tested cytokines, interferon-gamma (IFN-γ) and lo a lower extent, tumour necrosis factor-alpha (TNE-α) were found to upregulate CD40 expression on fibroblasts. Synovial and skin fibroblasts cultured over CD40 Ligand transfected L cells (L-CD40L) demonstrate a CD40 specific increase of DNA synthesis as measured by tritiated thymidine incorporation. Cell-cycle analysis and enumeration of viable cells further show that CD40 induced fibroblast proliferation. Costimulation with L-CD40 L and IFN-γ, resulted in maximal proliferation. Engagement of fibroblasts CD40 increased the IL-l-induced production of granulocyte macrophage-colony stimulating factor and macrophage inflammatory protein-Iα MIP-lα, CD40L activated fibroblasts showed decreased levels of CD40, but only marginal alterations of other cell-surface antigens. Taken together, the present results indicate that fibroblasts express functional CD40 and suggest a possible role of CD40L expressing cells, such as activated T cells and mast cells, in the development of synovium hyperplasia. [ABSTRACT FROM AUTHOR]

Thymocytes from mice with experimental Trypanosoma cruzi infection respond poorly to Con-A stimulation. However, the proliferative capacity of these cells is not impaired, as demonstrated by the fact that at high doses, exogenous rIL-2 restores thymidine uptake. This finding could be explained either by insufficient IL-2 production or by the appearance of inhibitory factors during T. cruzi infection. This paper shows that in response to Con A, IL-2 production is decreased in the model. Furthermore, the whole profile of cytokine production is modified, with a striking increase in IL-10, IFN-γ, IL-4, IL-5 and IL-6 production. The results indicate that IL-10 plus IFN-γ are responsible for the decrease in the Con A-induced proliferation since a normal proliferative response as well as normal IL-2 production can be restored if both cytokines are neutralized by adding their monoclonal antibodies (MoAbs). Evidence is provided also for an enhanced non-specific cytotoxicity of thymic cells from infected mice that might involve IL-4, IL-5 and IL-6. This is the first study demonstrating an alteration of thymic cell function by T. cruzi infection which results from overstimulation of IL-10 and IFN-γ production. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by the breakdown of immune tolerance. Impairment of the cellular immunity is primarily evaluated by the levels of the cytokines which can help in predicting the course of ITP. We aimed to assess the levels of IL4 and IL6 in children with ITP and evaluate their role in the pathogenesis and prognosis of this disease. A prospective cohort study was carried on 60 children (15 patients with newly diagnosed ITP, 15 patients with persistent ITP, 15 patients with chronic ITP and 15 healthy children as a control group). Serum IL-4 and serum IL-6 were measured using Human IL-4 and IL-6 ELISA kit in patients and controls. Patients with newly diagnosed and persistent ITP had significantly higher levels of IL4 and IL6 compared to patients with chronic ITP and healthy controls (p < 0.001). The mean serum level of IL4 was 762.0, 741.0, 364.6 and 436.8 pg/ml, and the mean serum level of IL6 was 178.5, 164.4, 57.9 and 88.4 pg/ml for patients with newly diagnosed, persistent, chronic ITP and healthy controls respectively. Serum IL-4 was significantly higher in patients who achieved remission than those who did not improve on first line therapy. Conclusion: Serum IL-4 and IL-6 may have a role in the pathogenesis of primary ITP. IL-4 seems to be a good predictor to treatment response. What Is Known: • There is a delicate balance of specific cytokine levels in immune thrombocytopenia, which has an important role in the immune system and is known to be deregulated in autoimmune diseases. changes in IL-4 and IL-6 might be involved in the pathogenesis of newly diagnosed ITP in both paediatric and adult patients. • We conducted this research study to measure the serum level of IL-4 and IL-6, in newly diagnosed, persistent and chronic ITP patients and study their relation to disease pathogenesis as well as patient's outcome. What Is New: • We found that IL4 seems to be a good predictor to treatment response and it was a very interesting observation in our study, and to the best of our knowledge, there is no published data about this finding. [ABSTRACT FROM AUTHOR]

Objectives: The origin of systemic inflammatory response syndrome and multiple organ dysfunction syndrome is poorly understood but remains a fundamental concern in the ICU. This paper provides a critical appraisal on whether bone failure may represent an unrecognized component of systemic inflammatory response syndrome/multiple organ dysfunction syndrome.Data Sources, Data Selection, and Data Extraction: Search of the PubMed database and manual review of selected articles investigating bone pathophysiology in critical illness.Data Synthesis: Bone hyperresorption is highly prevalent among critically ill patients. Bone breakdown releases numerous systemically active cytokines and bone-sequestered toxins, with the capacity to fuel inflammatory hypercytokinaemia and metabolic toxaemia. Anti-resorptive medication inhibits bone break down and preadmission anti-resorptive use is associated with superior survival among critically ill patients.Conclusions: We propose that hyperresorptive bone failure is an unrecognised component of systemic inflammatory response syndrome/multiple organ dysfunction syndrome that is causal to critical illness progression. If this hypothesis is valid, bone preservative strategies could reduce the risk of osteoporosis/fractures among ICU survivors, as well as decreasing critical illness mortality. [ABSTRACT FROM AUTHOR]

The best method for monitoring cytomegalovirus (CMV)‐specific cell‐mediated immunity (CMV‐CMI) among high‐risk kidney transplant (KT) recipients remains uncertain. We assessed CMV‐CMI by intracellular cytokine staining (ICS) by flow cytometry and a commercial interferon (IFN)‐γ release assay (QuantiFERON®‐CMV [QTF‐CMV]) at posttransplant months 3, 4, and 5 in 53 CMV‐seropositive KT recipients that had received induction therapy with antithymocyte globulin (ATG) and a 3‐month course of valganciclovir prophylaxis. The discriminative capacity (areas under receiver operating characteristics curve [auROCs]) and diagnostic accuracy to predict immune protection against CMV infection from the discontinuation of prophylaxis to month 12 were compared between both methods. There was significant although moderate correlations between CMV‐specific IFN‐γ‐producing CD8+ T‐cell counts enumerated by ICS and IFN‐γ levels by QTF‐CMV at months 3 (rho: 0.493; p = 0.005) and 4 (rho: 0.440; p = 0.077). The auROCs for CMV‐specific CD4+ and CD8+ T‐cells by ICS were nonsignificantly higher than that of QTF‐CMV (0.696 and 0.733 vs. 0.678; p = 0.900 and 0.692, respectively). The optimal cut‐off of ≥0.395 CMV‐specific CD8+ T‐cells yielded a sensitivity of 86.4%, specificity of 54.6%, positive predictive value of 79.2% and negative predictive value of 66.7% to predict protection. The corresponding estimates for QTF‐CMV (IFN‐γ levels ≥0.2 IU/mL) were 78.9%, 37.5%, 75.0%, and 42.9%, respectively. The enumeration of CMV‐specific IFN‐γ‐producing CD8+ T‐cells at the time of cessation of prophylaxis performed slightly better than the QTF‐CMV assay to predict immune protection in seropositive KT recipients previously treated with ATG. [ABSTRACT FROM AUTHOR]

Simple Summary: The current study shows that using cold water under high ambient temperature (CW: 15 ± 1 °C; HT: HT: 35 ± 1 °C) in heat-exposed laying hens is capable of maintaining productive efficiency and immune-suppressing under heat stress. The feed intake and egg production were enhanced after using the cold water under heat stress. Moreover, the cold water restored the decline in the level of B-cell, helper T cells, and the ratio of helper/cytotoxic T cells in peripheral blood mononuclear cells, as well as the concentration of IL-2, IFN-γ, and immunoglobulin G in plasma. Therefore, cold water is one of the mechanisms that can be considered under heat stress. This study aimed to investigate the effects of cold drinking water on cellular and humoral immunity in heat-exposed laying hens. One hundred and eight laying hens at 19 weeks old were placed into three treatments with six replicates of six hens in each group as follows: (1) hens were provided with normal drinking water (NW) under the control of thermoneutral temperature (CT: 25 ± 1 °C; CT + NW), (2) hens were provided with NW under high ambient temperature (HT: 35 ± 1 °C; HT + NW) for 8 h/d for a month, and (3) hens were treated under HT with cold drinking water (CW: 15 ± 1 °C; HT + CW) for 8 h/d for a 4-weeks. Then, the feed consumption, egg production, egg weight, feed conversion ratio, and blood immune parameters were investigated. The results showed that cold drinking water (CW) caused a significant (p < 0.05) recovery in the reduction of food intake and egg production due to heat stress; however, there was no significant effect (p > 0.05) on egg weight and feed conversion ratio. Moreover, CW significantly (p < 0.05) restored the immune-suppressing effects of heat stress on the contents of peripheral blood mononuclear cells, including B-cell (BU-Ia), helper T cell (CD4), and the ratio of helper/cytotoxic T cell (CD4/CD8). In addition, CW significantly (p < 0.05) recovered the reduction on the level of mRNA expression of interleukin-2 (IL-2) and interferon-gamma (IFN-γ), as well as significantly (p < 0.05) restored the reduction of plasma concentration of IL-2, IFN-γ and immunoglobulin G in heat-stressed laying hens. These results prove that CW increased heat dissipation and enhanced feed intake, egg production, and cellular and humoral immunity in heat-exposed laying hens. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has required extensive research on the new coronavirus SARS-CoV-2 and the creation of new highly effective vaccines. The presence of T-cells in the body that respond to virus antigens suggests adequate antiviral immunity. We investigated T-cell immunity in individuals who recovered from mild and moderate COVID-19 and in individuals vaccinated with the Gam-COVID-Vac combined vector vaccine. The ELISPOT method was used to determine the number of T-cells responding with IFN-γ synthesis to stimulation by peptides containing epitopes of the S-protein or N-, M-, ORF3, and ORF7 proteins, using peripheral blood mononuclear cells (PBMCs). At the same time, the multiplex method was used to determine the accumulation of IFN-γ and other cytokines in the culture medium. According to the data obtained, the proportion of positive conclusions about the T-cell immune response to SARS-CoV-2 antigens in control, recovered, and vaccinated individuals was 12%, 70%, and 52%, respectively. At the same time, more than half of the vaccinated individuals with a T-cell response were sensitized to the antigens of N-, M-, ORF3, and ORF7 proteins not produced by Gam-COVID-Vac, indicating a high likelihood of asymptomatic SARS-CoV-2 infection. Increased IFN-γ release by single sensitized T-cells in response to specific stimulation in recovered and vaccinated individuals did not result in the accumulation of this and other cytokines in the culture medium. These findings suggest a balance between cytokine production and utilization by immunocompetent cells as a prerequisite for providing a controlled cytokine signal and avoiding a "cytokine storm". [ABSTRACT FROM AUTHOR]

Background: There is evidence that chemosensory dysfunctions, including smell and taste disorders, are common findings in patients with SARS-CoV-2 infection. However, the underlying biological mechanisms and the role of inflammatory markers are still poorly understood. Aim: To investigate the inflammatory biomarkers levels in patients with COVID-19 presenting chemosensory dysfunctions. Methods: This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. A systematic literature search was performed from January 1, 2020, to May 12, 2022. Observational studies that provided data on hematological, biochemical, infection-related indices and cellular immunity, and coagulation function in patients with COVID-19 experiencing smell and/or taste disorders were considered eligible. Effect sizes were reported as standardized mean difference (SMD) with 95% confidence intervals (CI). A negative effect size indicated that the inflammatory biomarker levels were lower among patients with chemosensory dysfunctions. Results: Eleven studies were included. Patients with chemosensory disturbances had lower levels of leukocytes (SMD − 0.18, 95% CI − 0.35 to − 0.01, p = 0.04), lactate dehydrogenase (SMD − 0.45, 95% CI − 0.82 to − 0.09, p = 0.01), IL-6 (SMD − 0.25, 95% CI − 0.44 to − 0.06, p < 0.01), and C-reactive protein (SMD − 0.33, 95% CI − 0.58 to − 0.08, p < 0.01) than patients without chemosensory disturbances. Conclusion: Patients with SARS-CoV-2 infection who have olfactory and gustatory disorders have a lower inflammatory response than patients who do not have chemosensory alterations. The presence of these symptoms may indicate a more favorable clinical course for COVID-19. [ABSTRACT FROM AUTHOR]

This paper reports the presence of memory T cells in the nasal mucosa of allergic patients. The demonstration of CD4+/CD29+ (CD4+/CD45RO+) T lymphocytes, which are capable of interleukin-4 production, can indicate a complementary cell-mediated regulatory mechanism for mast cell proliferation and IgE synthesis in human nasal allergy. No substantial IgE production can be obtained in the absence of IL-4. Therefore, the existence of IL-4 producing cells on site in the nasal mucosa of allergic subjects probably implies a complementary interaction between cytokines and different immunocompetent nasal cells in the regulation of B cells and IgE synthesis. [ABSTRACT FROM AUTHOR]