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Crustaceans such as shrimps and crabs, hold significant ecological significance and substantial economic value within marine ecosystems. However, their susceptibility to disease outbreaks and pathogenic infections has posed major challenges to production in recent decades. As invertebrate, crustaceans primarily rely on their innate immune system for defense, lacking the adaptive immune system found in vertebrates. Mucosal immunity, acting as the frontline defense against a myriad of pathogenic microorganisms, is a crucial aspect of their immune repertoire. This review synthesizes insights from comparative immunology, highlighting parallels between mucosal immunity in vertebrates and innate immune mechanisms in invertebrates. Despite lacking classical adaptive immunity, invertebrates, including crustaceans, exhibit immune memory and rely on inherent "innate immunity factors" to combat invading pathogens. Drawing on parallels from mammalian and piscine systems, this paper meticulously explores the complex role of mucosal immunity in regulating immune responses in crustaceans. Through the extrapolation from well-studied models like mammals and fish, this review infers the potential mechanisms of mucosal immunity in crustaceans and provides insights for research on mucosal immunity in crustaceans. • Mucosal immunity parallels cellular and humoral immunity and interacts closely with the lymphatic system. • Vertebrate mucosal immunity shows significant convergence with invertebrate innate immunity. • Mucosal immunity probably exists in crustaceans. [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]

Abstract: Three years ago, the Journal of Autoimmunity and Autoimmunity Reviews launched a series of special issues devoted to the contributions of outstanding scholars in autoimmunology. The special issues are devoted not only to recognize achievements, but also to include a series of dedicated papers that reflect the scholar’s work, but also are cutting-edge research and reviews in immunology. This special issue is devoted to Haralampos M. Moutsopoulos of the National University of Athens. His contributions to patient care, teaching, and original research are legion. The papers that are included reflect not only a wide range of scholarship in autoimmunology, but importantly are written by his colleagues and friends, and by former students. They encompass original scholarship in Sjögren’s syndrome, but also in a number of effector pathways in both adult and pediatric autoimmunology. [ABSTRACT FROM AUTHOR]

Abstract: We have shown in two accompanying papers that TNF induces oscillations in (1) ∼13% of the genome, and (2) the activation of MAP kinase and NF-κB signaling pathways. Here we aim to bridge oscillations in signal transduction activation to oscillations in genetic output. Specifically, we sought to study how these oscillations can combine in a ligand-specific manner at the level of the promoter to initiate gene transcription. We utilize the late onset gene CD38 as a model gene since it has previously been shown that TNF, but not the related cytokine RANK-L, induces its expression. We find that TNF-induced oscillations in p65 and p50 recruitment to the CD38 promoter correlated with recruitment of MAPK-induced AP-1 recruitment, as analyzed by quantitative ChIP analysis. Through re-ChIP analysis we show that a unique transcriptional complex is seen on the promoter at 3h post-TNF addition, corresponding to the onset of CD38 transcription, which is not seen in the basal state. Moreover, we show that RANK-L was unable to combinatorially recruit AP-1 and NF-κB transcription factors to the CD38 promoter, despite inducing the activation of both signaling pathways. These results, in sum with the two accompanying papers, constitute a new paradigm through which cells dynamically orchestrate signaling molecules to coordinate time-resolved gene transcription by the formation of novel time-specific transcriptional complexes. [Copyright &y& Elsevier]

Abstract: The first line of defense against microbial infections in animals is innate immune response which triggers diverse humoral and cellular activities via signal transduction pathways. Toll, IMD and JAK/STAT pathways are regarded as the main pathways regulating the immune response of invertebrates. This paper reviews the main progress of the investigation on the immune response to pathogen''s infection in shrimp and supposes that these three signal pathways exist in shrimp. Most of the components (proteins or genes) involved in Toll pathway of Drosophila have been cloned also in shrimp which suggested the existence of Toll pathway in shrimp. The data update shows that the Toll pathway of shrimp is responsive not only to Gram-positive bacteria, Gram-negative bacteria, but also to WSSV. Challenge of WSSV can lead to the variation of transcription level of all identified components in shrimp Toll pathway, which supported that Toll pathway in shrimp played important roles during WSSV infection. Two major homologs to the components of IMD pathway of Drosophila, IMD and Relish, have been identified in shrimp, which indicated that IMD pathway should be existed in shrimp and might play important roles in regulating the immune response of shrimp to bacteria and virus infection. Relish in IMD pathway and dorsal in Toll pathway of shrimp were both involved in the immune response of shrimp to bacteria and virus infection, which implied that these two pathways are not completely separated during the immune response of shrimp. The transcription of STAT in shrimp was modulated after WSSV infection, which suggested that a putative JAK/STAT pathway might exist in shrimp and be very important to virus infection. Study on the signaling pathway regulating the immune response in shrimp could help us to understand the innate immune system, and would provide instructions to shrimp disease control. Obviously, to get more clear ideas about the innate immunological pathways in shrimp, more solid functional studies should be done in the future. [Copyright &y& Elsevier]

Abstract: Stable RNA–DNA hybrids formed by invasion of an RNA strand into duplex DNA, termed R-loops, are notorious for provoking genome instability especially when they arise during transcription. However, in some instances (DNA replication and class switch recombination), R-loops are useful so long as their existence is carefully managed to avoid them persisting. A recent flow of research papers establishes a newly discovered use for R-loops as key intermediates in a prokaryotic immune system called CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats). Structures and mechanism of ribonucleoprotein complexes (“Cascades”) that form CRISPR R-loops highlight precision targeting of duplex DNA that has sequence characteristics marking it as foe, enabling nucleolytic destruction of DNA and recycling the Cascade. We review these significant recent breakthroughs in understanding targeting/interference stages of CRISPR immunity and discuss questions arising, including a possible link between targeting and adaptive immunity in prokaryotes. [Copyright &y& Elsevier]

Abstract: In this paper, we investigate global dynamics for a system of delay differential equations which describes a virus-immune interaction in vivo. The model has two distributed time delays describing time needed for infection of cell and virus replication. Our model admits three possible equilibria, an uninfected equilibrium and infected equilibrium with or without immune response depending on the basic reproduction number for viral infection and for CTL response such that . It is shown that there always exists one equilibrium which is globally asymptotically stable by employing the method of Lyapunov functional. More specifically, the uninfected equilibrium is globally asymptotically stable if , an infected equilibrium without immune response is globally asymptotically stable if and an infected equilibrium with immune response is globally asymptotically stable if . The immune activation has a positive role in the reduction of the infection cells and the increasing of the uninfected cells if . [Copyright &y& Elsevier]

Abstract: Predicting the individual vulnerability to immune mediated disease is one of the main challenges of modern biomedical research. However, the question of individual behavioral and physiological characteristics that might predict this vulnerability has been subject of research and debate for a long time. This paper will argue that animal models aimed at individual vulnerability should consider the biological function of variation in nature. An increasing number of studies show the ecological significance of variation within a species. Based on behavioral studies in several vertebrate species two coping style can be distinguished. Variation in coping style appears to play a role in the population dynamics and the evolutionary fitness of the species. Coping styles are reflected in a stable differentiation in the behavioral and physiological stress responsiveness over time and across situations. Based on the observations that the individual level of offensive aggressive behavior (i.e., the tendency to defend the home territory) is strongly related to the way animals react to various other environmental challenges, it is argued that the individual’s level of offensiveness is an important indicator and component of a more trait-like behavioral and physiological response pattern (coping style) to environmental demands. The coping style of aggressive animals is principally aimed at a (pro)active prevention or manipulation of a stressor whereas the non-aggressive individuals tend to passively accept or react to it. Proactive coping is associated with high sympathetic reactivity to stressors whereas the more passive or reactive coping style generally has a higher HPA axis reactivity. In view of the immune modulating nature of these major neuroendocrine stress systems, one might expect that coping styles will be reflected in a differential vulnerability to immune mediated disease as well. Indeed, several studies have demonstrated such a relationship, indicating that the functional variation in coping style and related neuroendocrine stress reactivity, as it occurs in nature, might be a good standard for studies aimed at understanding individual vulnerability. This is in agreement with more recent views that also in humans stress reactivity may be the best predictor for the individual vulnerability to immune mediated diseases. This asks for a more fundamental and translational approach of individual disease vulnerability based on a common biological basis of individual differentiation in behavior and physiology in humans and animals. [Copyright &y& Elsevier]

Abstract: Behavioral characteristics closely associated with specific physiological profiles present an important area of research in understanding health disparities. In particular, glucocorticoid overproduction may be an important factor moderating disease progression; natural variance in production of this steroid has been proposed as one mechanism underlying individual differences in health and disease. In the current paper, we examined immune parameters in female rats of two different behavioral types previously shown to have differential glucocorticoid production and life spans. We categorized young female rats according to their behavioral response to novelty (high- or low-locomotion), and compared their glucocorticoid production, adrenal size, thymus size, tumor necrosis factor-α (TNF-α) production, tumor development and life span. As expected, high-locomotion females produced more glucocorticoids and had larger adrenal glands during young adulthood than did low-locomotion females. High-locomotion females had significantly smaller thymuses and reduced TNF-α levels compared to low-locomotion, suggesting altered immune function in young adulthood. Finally, high-locomotion females had shorter life spans than did low-locomotion females, and this was particularly true in females that developed pituitary tumors, but not in those that developed mammary tumors. These results, along with other published findings, suggest that high-locomotion rodent females experience life-long elevations in glucocorticoid responses to novelty, and that these elevated levels may be comparable to chronic stress. This naturally occurring endocrine profile may influence immune responses which in turn could affect disease susceptibility. Variance in immune function across personality types may be partially moderated by natural variance in glucocorticoid production. [Copyright &y& Elsevier]

Abstract: The epithelial-to-mesenchymal transition (EMT) is a crucial process, occurring both during development and tumor progression, by which an epithelial cell undergoes a conversion to a mesenchymal phenotype, dissociates from initial contacts and migrates to secondary sites. We recently reported that in hepatocytes the multifunctional cytokine TGFβ induces a full EMT characterized by (i) Snail induction, (ii) E-cadherin delocalization and down-regulation, (iii) down-regulation of the hepatocyte transcriptional factor HNF4α and (iv) up-regulation of mesenchymal and invasiveness markers. In particular, we showed that Snail directly causes the transcriptional down-regulation of E-cadherin and HNF4, while it is not sufficient for the up-regulation of mesenchymal and invasiveness EMT markers. In this paper, we show that in hepatocytes TGFβ induces a Src-dependent activation of the focal adhesion protein FAK. More relevantly, we gathered results indicating that FAK signaling is required for (i) transcriptional up-regulation of mesenchymal and invasiveness markers and (ii) delocalization of membrane-bound E-cadherin. Our results provide the first evidence of FAK functional role in TGFβ-mediated EMT in hepatocytes. [Copyright &y& Elsevier]

Abstract: Studies investigating the influence of psychosocial factors on immunity played a critical and formative role in the field of psychoneuroimmunology (PNI), and have been a major component of articles published in Brain, Behavior and Immunity (BBI). An analysis of papers during the first two decades of BBI from 1987–2006 revealed three behavior-related topics were most prominent: (1) stress-induced changes in immune responses, (2) immune correlates of psychopathology and personality, and (3) behavioral conditioning of immunity. Important subthemes included the effect of early rearing conditions on immune maturation in the developing infant and, subsequently, psychosocial influences affecting the decline of immunity in the senescent host. The responsiveness of cell functioning in the young and elderly helped to validate the view that our immune competence is malleable. Many technical advances in immune methods were also evident. Initially, there was a greater reliance on in vitro proliferative and cytolytic assays, while later studies were more likely to use cell subset enumerations, cytokine quantification, and indices of latent virus reactivation. The reach of PNI extended from the traditional clinical entities of infection, autoimmunity, and cancer to attain a broader relevance to inflammatory physiology, and thus to asthma, cardiovascular and gastrointestinal disease. There continue to be many theoretical and applied ramifications of these seminal findings. Fortunately, the initial controversies about whether psychological processes could really impinge upon and modify immune responses have now receded into the pages of history under the weight of the empirical evidence. [Copyright &y& Elsevier]

Abstract: The host response to adenovirus (Ad) infection involves induction of cytokines in lung epithelia. We have demonstrated induction of the lung neutrophil chemokine interleukin-8 (IL-8) by Ad7, a major lung pathogen, in A549 lung epithelial cells and lung tissue through activation of the Erk signaling pathway. However, the mechanism of IL-8 induction is still unclear. In this paper, we first showed that Ad7 viral gene expression is not essential for IL-8 induction as psoralen-UV inactivation of Ad7 did not affect IL-8 mRNA induction or IL-8 protein induction in A549 cells. We then inhibited internalization of Ad7 by treatment of A549 cells with EGTA in calcium-free medium during exposure to Ad7. We verified that this treatment inhibited Ad internalization by confocal microscopy, FACS analysis and Ad E1A and fiber mRNA expression. Preventing internalization by calcium depletion did not inhibit Erk activation by Ad7. However, calcium-dependent internalization was required for IL-8 protein production in Ad7 exposed cells. This is not likely due to an effect of calcium depletion on downstream Erk signaling or IL-8 protein production since calcium depletion did not block IL-8 protein production stimulated by PMA, and because addition of EGTA subsequent to Ad7 internalization also did not prevent Ad induction of IL-8. These studies indicate that Ad7 internalization is calcium-dependent and is required for IL-8 protein induction upon Ad7 infection. Ad7 induction of Erk is independent of calcium and does not require virus internalization. [Copyright &y& Elsevier]

Abstract: Human granulocyte-colony stimulating factor (hG-CSF), a human cytokine, was expressed in transgenic rice cell suspension culture. The hG-CSF gene was cloned into the rice expression vector containing the promoter, signal peptide, and terminator derived from a rice α-amylase gene Amy3D. Using particle bombardment-mediated transformation, hG-CSF gene was introduced into the calli of rice (Oryza sativa) cultivar Dong-jin. Expression of the hG-CSF gene was confirmed by ELISA and Northern blot analysis. The amount of recombinant hG-CSF accumulated in culture medium from transgenic rice cell suspension culture on the sugar starvation was determined by time series ELISA. Biological activity of the plant derived hG-CSF was confirmed by measuring the proliferation of the AML-193 cells, and was similar to that of the commercial Escherichia coli-derived hG-CSF. In this paper, we discuss the attractive attributes of using rice cell suspension system for the expression of therapeutic recombinant hG-CSF. [Copyright &y& Elsevier]

Abstract: In this paper we evaluated the influence of the protein concentration and a formulation vehicle on the stability of recombinant human Interferon alpha 2b (rhIFN-α2b) in solution. The effect of the protein content (from 1 to 100MIU/ml) at 37°C, showed that higher concentration of this cytokine protected against the loss of bioactivity (antiviral titration) better than the lower concentrations. In contrast, rhIFN-α2b at 50 and 100MIU/ml decreased the SDS/PAGE- and RP-HPLC-determined purity faster than samples at 1 or 10MIU/ml. According to these results, 10MIU/ml rhIFN-α2b was the best choice to evaluate the influence of a formulation on the stability of this cytokine. Taking this into consideration, we studied the stability of a liquid and albumin-free formulation of this protein at the recommended storage temperature (5±3°C) and under accelerated conditions (28±2°C). Accelerated storage results showed an acceptable biochemical stability of the active ingredient throughout 2 months. Real-time storage data confirmed the good biochemical stability of this formulation for 30 months. [Copyright &y& Elsevier]

Abstract: Antigen recognition by T cells is a key event in the adaptive immune response. T cells scan the surface of antigen-presenting cells (APCs) or target cells for specific peptides bound to MHC molecules. In the physiological setting, a typical APC presents tens of thousands of diverse endogenous self-derived peptides complexed to MHC (pMHC complexes). When ‘foreign’ peptides are presented, they constitute a small fraction of the total surface peptide repertoire. As T cells seem to be capable of discerning minute amounts of ‘foreign’ peptides among a complex background of self-peptides, endogenous peptides are generally assumed to play no role in recognition. However, recent results suggest that these background peptides may alter the sensitivity of T cells to foreign peptides. Current experimental limitations preclude analysis of peptide mixtures approaching physiological complexity, making it difficult to further address the role of complex background peptides. In this paper, we present a computational model to test how complex, varied peptide populations on an APC could potentially modulate a T cell''s ability to detect the presence of small numbers of agonist peptides among a diverse population. We use the model to investigate the notion that under physiological conditions, T cell recognition of foreign peptides is context dependent, that is, T cells process signals gathered from all pMHC interactions, not just from a few agonist peptides while ignoring all others. [Copyright &y& Elsevier]

Abstract: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine whose circulating levels have been detected in the lesions of several diseases such as pulmonary fibrosis, rheumatoid arthritis and atherosclerosis. However, the factors involved in the regulation of its production remain largely unknown. The main aim of the present paper was to ascertain the contribution of the familial/genetic factors on the production of MCP-1 in apparently healthy individuals. We also tested the possible relationships between the plasma levels of MCP-1 and other cytokines involved in bone metabolism (receptor activator NF-kB ligand (RANKL), osteoprotegerin (OPG), interleukin-6, macrophage-colony stimulating factor, tumor necrosis factor-α). Using ELISA assays the cytokine levels were measured in 570 apparently healthy individuals belonging to ethnically homogeneous Caucasian families. We found that MCP-1 levels were significantly (P <0.01) correlated with RANKL (in both sexes) and with OPG only in women. The study showed that adjusted for potential covariates, 72% of the MCP-1 variance, was attributable to familial effects. About 49% was due to potential genetic factors and the rest was explained by common environmental sources shared by spouses within each family. In conclusion, our data provide reliable evidence for the substantial role of genetic factors in the determination of the phenotypic variability of MCP-1 plasma levels. The association between the osteoclastogenic cytokines and MCP-1 levels in healthy pedigrees is of special interest and might shed light on MCP-1 involvement in bone remodeling. [Copyright &y& Elsevier]

Abstract: Several proinflammatory cytokines can induce periodontal tissue destruction and are thought to be useful indicators or diagnostic markers for periodontitis. Here, we aimed to investigate whether oncostatin M (OSM) was present in gingival crevicular fluid (GCF) and to clarify the correlation of GCF OSM and interleukin-6 (IL-6) levels with the severity of periodontitis. Sixty-two sites in 14 patients were divided into 4 groups based on probing depth (PD) and bleeding on probing (BOP). GCF was collected using paper strips from clinically health sites (PD≤3mm, CAL: 1–3mm, without BOP, n =31), mildly diseased sites (PD≤3mm, CAL: 3–5mm, with BOP, n =11), moderately diseased sites (PD=4–6mm, CAL: 5–8mm, with BOP, n =11), and severely diseased sites (PD>6mm, CAL: 8–12mm, with BOP, n =9). IL-6 and OSM in GCF were quantified by enzyme-linked immunosorbent assay and are expressed as concentrations (pg/ml) and total amounts (pg/site). Correlations of OSM and IL-6 levels with the severity of periodontitis in all groups were determined using Spearman rank correlation (r s). Our results showed that OSM and IL-6 were detected in most GCF samples. The total amounts of OSM and IL-6 were significantly positive correlated with severity of diseased sites (OSM: r s =0.526, p &#60;0.01; IL-6: r s =0.729, p &#60;0.01). No correlations of OSM or IL-6 concentration in GCF were found with disease severity. OSM and IL-6 levels in GCF were positively correlated to each other when expressed as either concentrations or total amounts (concentrations: r =0.485, p &#60;0.01; total amounts r =0.490, p &#60;0.01). In conclusion, our findings suggest that IL-6 and OSM may play a role in modulating the inflammatory cascade of chronic periodontitis. [Copyright &y& Elsevier]

Abstract: Programmed cell death, or apoptosis, is a genetically controlled process of cell suicide that is a common fate during an animal''s life. In metazoans, apoptotic cells are rapidly removed from the body through the process of phagocytosis. Genetic analyses probing the mechanisms controlling the engulfment of apoptotic cells were pioneered in the nematode Caenorhabditis elegans. So far, at least seven genes have been identified that are required for the recognition and engulfment of apoptotic cells and have been shown to function in two partially redundant signaling pathways. Molecular characterization of their gene products has lead to the finding that similar genes act to control the same processes in other organisms, including mammals. In this paper, we review these exciting findings in C. elegans and discuss their implications in understanding the clearance of apoptotic cells in mammals. [Copyright &y& Elsevier]