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In this paper, we study a delayed HIV infection model with nonmonotonic immune response and perform stability and bifurcation analysis. Our results show that the delayed HIV infection system with nonmonotonic immune response has bistability and stable periodic solution appear. We find that both the uninfected and immune-free equilibria are globally asymptotically stable under certain conditions which are not affected by time delay. However, the time delay makes one immune equilibrium always unstable for τ ≥ 0 and also makes another immune equilibrium appear stability switches; meanwhile, the system will exhibit local Hopf bifurcation, global Hopf bifurcation, and saddle-node-Hopf bifurcation. Numerical simulations are carried out to verify our results. [ABSTRACT FROM AUTHOR]

Background: Sexual dimorphism is observed in the occurrence, course, and severity of human disease. The difference in immune response between males and females can in part be attributed to sexual genotype. However, immunological differences can also be explained by endocrine–immune interactions. Specifically, androgens possess the ability of directly modulating the development and function of immune cells. Although androgens generally contribute to immunosuppressive effects, this is not necessarily always the case. Aim: The aim of the review is to uncover the role of androgens in shaping the innate immune response. Material & Methods: Authors included papers in this review which discussed the impact of androgens on specific innate immune cells. Results: Androgens modulate the innate immune response through various mechanisms. However, there is conflicting evidence in the literature regarding the interplay betwen androgens and the innate immune system. Discussion: Conflicting evidence presented in this review could in part be explained by the limitations present in interpreting results. Conclusion: This review is of great importance for our understanding of occurence and mechanism of human inflammatory disease. [ABSTRACT FROM AUTHOR]

In this paper, we proposed a multidelayed in‐host HIV model to represent the interaction between human immunodeficiency virus and immune response. One delay was considered to incorporate the time required by the virus for various intracellular events to make a host cell productively infective, and the second delay was introduced to take into account the time required for adaptive immune system to respond against infection. We extensively analyzed this multidelayed model analytically and numerically. We show that delay may have both destabilizing and stabilizing effects even when the system contains a single immune response delay. It happens when there exists two sequences of critical values of this delay. If the system starts with stable state in absence of delay, then the smallest value of these critical delays causes instability and the next higher value causes stability. The system may also show stability switching for different values of the virus replication factor. These results demonstrate the possible reasons of intrapatients and interpatients variability of CD4+ T cells and virus counts in HIV‐infected patients. [ABSTRACT FROM AUTHOR]

In this paper, we consider a tumor growth mathematical model that includes an immune system and drug therapies. Immuno- and chemodrug administration as well as periodic administration of radiation are integrated in the model. We have set an optimal control (OC) problem relative to the model so that the average number of tumor cells and immuno- and chemotherapeutic drug administration are simultaneously minimized in a multiobjective context. The external injection of two immunostimulators and a chemotherapeutic drug has been considered as control, and the objective functionals aim to reflect the severity of both types of drug administration. The multiobjective approach to the OC of the tumor growth model provides good-quality approximate solutions and has shown to be a valuable procedure to identify good trade-offs between conflicting objectives. [ABSTRACT FROM AUTHOR]

Many of the reviews include discussion of diffusible molecules involved in cell-cell communication during the evolution of innate and adaptive responses (eg, interferons) and how these mediators influence the outcome of the dynamic processes visualized by optical methods. New data on tissue-resident T cells also fall in this category, as do recent observations of perivascular co-localization of effector lymphocytes and presenting cells at sites of effector function within tissues. Technologies are now emerging that will permit combining the protein and cell-based optical imaging methods used to date with recent advances in nucleic acid/genomic methods, especially single-cell sequencing. [Extracted from the article]

Innate immune adaptor proteins are critical components of the innate immune system that propagate pro‐inflammatory responses from their upstream receptors, and lead to pathogen clearance from the host. Bacterial pathogens have developed strategies to survive inside host cells without triggering the innate immune surveillance in ways that are still not fully understood. Here, it is reported that Pseudomonas aeruginosa induces its quorum sensing mechanism after macrophage engulfment. Further investigation of its secretome identified a quorum sensing regulated product, LasB, is responsible for innate immune suppression depending on the MyD88‐mediated signaling. Moreover, it is showed that this specific type of pathogen‐mediated innate immune suppression is due to the enzymatic digestion of the death domains of the innate immune adaptors, mainly MyD88, and attributed to LasB's large substrate binding groove. Lastly, it is demonstrated that the secretion of LasB from P. aeruginosa directly contributed to MyD88 degradation within macrophages. Hence, it is discovered an example of bacterial quorum sensing‐regulated cellular innate immune suppression by direct cleavage of immune adaptors. [ABSTRACT FROM AUTHOR]

We are frequently exposed to potentially harmful microbes of various types on a daily basis. Our immune system is an amazing collection of unique organs and cells that defends us from hazardous germs as well as certain diseases. It plays a crucial role in protecting the body against external invaders, including bacteria, viruses, and parasites. Maintaining a healthy immune system requires consuming a balanced diet that provides a variety of macro‐ and micronutrients. By consuming sufficient amounts of water, minerals such as zinc and magnesium, micronutrients, herbs, and foods rich in vitamins C, D, and E, and adopting a healthy lifestyle, one can enhance their health and immunity, and prevent infections. This article provides a comprehensive review of the scientific literature on common foods known for their potential to boost human immunity. The review begins by discussing the various components of the immune system and their functions. It then delves into the current understanding of how nutrition can influence immune response, highlighting the importance of a well‐balanced diet in supporting optimal immune function. The article presents an extensive analysis of a range of common foods that have been studied for their immune‐boosting properties. These foods include fruits, vegetables, whole grains, and animal‐based foods. Each food category is explored in terms of its specific nutrients and bioactive compounds that contribute to immune support. Foods such as milk, eggs, fruits, leafy greens, and spices like onion, garlic, and turmeric contain beneficial compounds that can enhance the immune system's function, activate and inhibit immune cells, and interfere with multiple pathways that eventually lead to improved immune responses and defense. The available literature on the issue was accessed via online resources and evaluated thoroughly as a methodology for preparing this manuscript. [ABSTRACT FROM AUTHOR]

Summary: Polymorphonuclear neutrophils are no longer considered as a homogeneous population of terminally differentiated and short‐lived cells that belong to the innate immune system only. In fact, data from the past decades have uncovered that neutrophils exhibit large phenotypic heterogeneity and functional versatility that render them more plastic than previously thought. Hence, their precise role as effector cells in inflammation, in immune response and in other pathophysiological processes, including tumors, needs to be better evaluated. In such a complex scenario, common knowledge of the differentiation of neutrophils in bone marrow refers to lineage precursors, starting from the still poorly defined myeloblasts, and proceeding sequentially to promyelocytes, myelocytes, metamyelocytes, band cells, segmented neutrophils, and mature neutrophils, with each progenitor stage being more mature and better characterized. Thanks to the development and utilization of cutting‐edge technologies, novel information about neutrophil precursors at stages earlier than the promyelocytes, hence closer to the hematopoietic stem cells, is emerging. Accordingly, this review discusses the main findings related to the very early precursors of human neutrophils and provides our perspectives on human neutropoiesis. [ABSTRACT FROM AUTHOR]

Recently, evidence has shown that variations in the cuticular hydrocarbons (CHCs) profile allow healthy honeybees to identify diseased nestmates, eliciting agonistic responses in the former. Here, we determined whether these 'immunologic cues' emitted by diseased nestmates were only detected by workers, who consequently took hygienic measures and excluded these individuals from the colony, or whether queens were also able to detect these cues and respond accordingly. Healthy honeybee queens were exposed to (i) healthy, (ii) Ringer-injected and (iii) lipopolysaccharide (LPS)-injected nestmates by allowing direct body contact. Quantitative differences in the CHC profiles of these three groups were measured using GC-MS. The transcript levels of the products of four genes that encode for antimicrobial peptides (AMPs), which are part of the queen's immune response, were measured in bees exposed to direct contact using qPCR. A significant increase in the transcript levels of these AMP genes over baseline levels in queens was observed when body contact was allowed between the queens and the Ringer- and LPS-injected nestmates. These results provide the first evidence that the detection of CHCs contributes to the initiation of an immune response in insects. In an additional experiment, CHCs were extracted from diseased workers and directly presented to queens, which also evoked a similar immune response. A potential mechanism that relied on volatile compounds could be ruled out by conducting a distance experiment. The study helps to expand our knowledge of chemical communication in insects and sheds light on a likely new mechanism of social immunity. [ABSTRACT FROM AUTHOR]

Background: So far, limited studies have focused on the role of Macrophages (MQs) in the development or progression of celiac disease (CD). Researchers believe that increasing knowledge about the function of MQs in inflammatory disorders plays a critical role in finding a new treatment for these kinds of diseases. Main body: CD is a permanent autoimmune intestinal disorder triggered by gluten exposure in predisposed individuals. This disorder happens due to the loss of intestinal epithelial barrier integrity characterized by dysregulated innate and adaptive immune responses. MQs are known as key players of the innate immune system that link innate and adaptive immunity. MQs of human intestinal lamina propria participate in maintaining tissue homeostasis, and also intestinal inflammation development. Previous studies suggested that gliadin triggers a proinflammatory phenotype (M1 MQ) in human primary MQs. Moreover, M2‐related immunosuppressive mediators are also present in CD. In fact, CD patients present an impaired transition from pro‐inflammatory to anti‐inflammatory responses due to inappropriate responses to gliadin peptides. Conclusion: The M1/M2 MQs polarization balancing regulators can be considered novel therapeutic targets for celiac disease. [ABSTRACT FROM AUTHOR]

Immunoprotection and oxygen supply are vital in implementing a cell therapy for type 1 diabetes (T1D). Without these features, the transplanted islet cell clusters will be rejected by the host immune system, and necrosis will occur due to hypoxia. The use of anti‐rejection drugs can help protect the transplanted cells from the immune system; yet, they also may have severe side effects. Cell delivery systems (CDS) have been developed for islet transplantation to avoid using immunosuppressants. CDS provide physical barriers to reduce the immune response and chemical coatings to reduce host fibrotic reaction. In some CDS, there is architecture to support vascularization, which enhances oxygen exchange. In this review, we discuss the current clinical and preclinical studies using CDS without immunosuppression as a cell therapy for T1D. We find that though CDS have been demonstrated for their ability to support immunoisolation of the grafted cells, their functionality has not been fully optimized. Current advanced methods in clinical trials demonstrate the systems are partly functional, physically complicated to implement or inefficient. However, modifications are being made to overcome these issues. [ABSTRACT FROM AUTHOR]

COVID‐19, caused by SARS‐CoV‐2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of NK cells in COVID‐19 remains less well understood. Here, we characterized NK cell‐mediated SARS‐CoV‐2 antibody‐dependent cellular cytotoxicity (ADCC) against SARS‐CoV‐2 spike‐1 (S1) and nucleocapsid (NC) protein. Serum samples from SARS‐CoV‐2 resolvers induced significant CD107a‐expression by NK cells in response to S1 and NC, while serum samples from SARS‐CoV‐2‐negative individuals did not. Furthermore, serum samples from individuals that received the BNT162b2 vaccine induced strong CD107a expression by NK cells that increased with the second vaccination and was significantly higher than observed in infected individuals. As expected, vaccine‐induced responses were only directed against S1 and not against NC protein. S1‐specific CD107a responses by NK cells were significantly correlated to NK cell‐mediated killing of S1‐expressing cells. Interestingly, screening of serum samples collected prior to the COVID‐19 pandemic identified two individuals with cross‐reactive antibodies against SARS‐CoV‐2 S1, which also induced degranulation of NK cells. Taken together, these data demonstrate that antibodies induced by SARS‐CoV‐2 infection and anti‐SARS‐CoV‐2 vaccines can trigger significant NK cell‐mediated ADCC activity, and identify some cross‐reactive ADCC‐activity against SARS‐CoV‐2 by endemic coronavirus‐specific antibodies. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionised oncology and are now standard‐of‐care for the treatment of a wide variety of solid neoplasms. However, tumour responses remain unpredictable, experienced by only a minority of ICI recipients across malignancy types. Therefore, there is an urgent need for better predictive biomarkers to identify a priori the patients most likely to benefit from these therapies. Despite considerable efforts, only three such biomarkers are FDA‐approved for clinical use, and all rely on the availability of tumour tissue for immunohistochemical staining or genomic assays. There is emerging evidence that host factors – for example, genetic, metabolic, and immune factors, as well as the composition of one's gut microbiota – influence the response of a patient's cancer to ICIs. Tantalisingly, some of these factors are modifiable, paving the way for co‐therapies that may enhance the therapeutic index of these treatments. Herein, we review key host factors that are of potential biomarker value for response to ICI therapy, with a particular focus on the proposed mechanisms for these influences. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

During the last 15 years, a significant amount of data related to the crustacean immune system has been generated, mainly led by the advances made in the field of transcriptomic analysis through massive mRNA sequencing technology. In order to shed new light on the genes and metabolic pathways associated with the immune system in shrimp species, we have carried out a meta‐analysis using the current literature and the Sequence Read Archive (SRA) database of the National Center for Biotechnology Information (NCBI), which has 1195 published transcriptomic data sets until 31 December 2020, from different tissues and 14 Penaeus species. The transcriptomic analyses published so far have explored the effects of the challenge from viral and bacterial pathogens, as well as abiotic stressors, such as ammonia, temperature, salinity, oxygen deprivation and pH. They have also explored the effect of dietary factors and beneficial microbes (pre‐ and probiotics) in the immune response. In order to harness the vast amount of information available, multidisciplinary efforts have to generate better genomic tools to overcome the complexity of the genome and to implement the knowledge gained into commercial applications for the improvement of the culture conditions, adaptation of more sustainable feeds and producing strains showing more resilience/tolerance to diseases. [ABSTRACT FROM AUTHOR]

Microsporidia are a group of obligate, intracellular, spore‐forming eukaryotic pathogens, which predominantly infects immunocompromised individuals worldwide. Encephalitozoon spp. is one of the most prevalent microsporidia known to infect humans. Host immune system plays a major role in combating pathogens including Encephalitozoon spp. infecting humans. Both innate and adaptive arms of host immune system work together in combating Encephalitozoon infection. Researchers are conducting studies to elucidate the role of both arms of immune system against Encephalitozoon infection. In addition to cell‐mediated adaptive immunity, role of innate immunity is also being highlighted in clearance of Encephalitozoon spp. from host body. Therefore, the current review will give a clear and consolidated update on the role of innate as well as adaptive immunity in protection against Encephalitozoon spp. [ABSTRACT FROM AUTHOR]

The development of donor‐specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post‐transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor‐specific antibodies post‐transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet‐based donor:recipient matching, including unavailability of allele‐level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long‐read genotyping methods, compilation of large data sets with allele‐level genotypes, and standardization of methods to verify eplets as determinants of immune‐mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes. [ABSTRACT FROM AUTHOR]

Immunotherapy—treatments that target a patient's immune system—has attracted considerable attention in cancer research. Its recent success has led to generation of novel immunotherapeutic agents that need to be evaluated in clinical trials. Two unique features of immunotherapy are the immune response and the fact that some patients may achieve long‐term durable response. In this article, we propose a two‐arm Bayesian adaptive randomized phase II clinical trial design for immunotherapy that jointly models the longitudinal immune response and time‐to‐event efficacy (BILITE), with a fraction of patients assumed to be cured by the treatment. The longitudinal immune response is modeled using hierarchical nonlinear mixed‐effects models with possibly different trajectory patterns for the cured and susceptible groups. Conditional on the immune response trajectory, the time‐to‐event efficacy data for patients in the susceptible group is modeled via a time‐dependent Cox‐type regression model. We quantify the desirability of the treatment using a utility function and propose a two‐stage design to adaptively randomize patients to treatments and make treatment recommendations at the end of the trial. Simulation studies show that compared with a conventional design that ignores the immune response, BILITE yields superior operating characteristics in terms of the ability to identify promising agents and terminate the trial early for futility. [ABSTRACT FROM AUTHOR]

Longevity patterns in most vertebrates suggest that females benefit most from maintenance investment. A reversed longevity pattern in loggerhead musk turtles (Sternotherus minor) allowed us to test trade‐offs between maintenance and survivorship. We tested the hypothesis that the sex with greater longevity has greater maintenance than the sex with shorter longevity. We also compared the following parameters between sexes: Bactericidal ability (BA) and heterophil:lymphocyte ratios (HLR). Baseline blood samples were collected from turtles in the field; a subset of turtles was returned to a laboratory for experiments of acquired immune responses to sheep red blood cells (SRBC). We found no support for the original hypothesis of reversal in sex‐dependent immune trade‐offs (difference between sex SRBC titers: p =.102; interaction between treatment and sex: p =.177; difference between treatments: p <.001; effect of sex on BA: p =.830; effect of sex on HLR: p =.717). However, we did find support for sex‐dependent differences in immunity in the relationship between HLR and body condition (BCI) (effect of BCI on HLR: p =.015). In field conditions, we found that males with higher body condition indices express stressed phenotypes more than males with lower body condition indices (p =.002). However, females expressed similar stress loads across all body conditions (p =.900). Testosterone concentrations were assayed in free‐living turtles and were not related to any of the immune parameters. Our results suggest that the immune systems play an important role in balancing sex‐specific responses to different selective pressures in S. minor. Research Highlights: In male Sternotherus minor, heterophil:lymphocyte ratios (HLR) were positively correlated to body condition index (BCI); females expressed equal HLR across BCI. Male and female turtles had similar innate and acquired immunity. [ABSTRACT FROM AUTHOR]

The detection and elimination of pathogens in an organism are the main tasks of its immune system. The most important cells involved in these processes are neutrophils and macrophages. These processes might have two resolutions: The first is the possibility of pathogen elimination, and the other the possibility of the inflammation resolution. In this work, we present several mathematical models involving immune cell densities and inflammation levels. Our general goal is to exhibit the possible pathogen eradication or the inflammation resolution. We use bifurcation techniques in order to analyze how parameter variations may change the system evolution. Our results indicate that the elimination of apoptotic neutrophils by macrophages has a dichotomy effect: It contributes to the decrease of the inflammation level, but it may hinder the pathogen elimination. Also, an increment of the average neutrophil life can improve healthy outcomes. Moreover, we find scenarios when pathogens cannot be eliminated, as well as conditions for their successful eradication. [ABSTRACT FROM AUTHOR]

Recent years have seen a dramatic increase in the range of applications of virus‐like nanoparticle (VNP)‐ and liposome‐based antigen delivery systems for the treatment of allergies. These platforms rely on a growing number of inert virus‐backbones or distinct lipid formulations and intend to engage the host's innate and/or adaptive immune system by virtue of their co‐delivered immunogens. Due to their particulate nature, VNP and liposomal preparations are also capable of breaking tolerance against endogenous cytokines, Igs, and their receptors, allowing for the facile induction of anti‐cytokine, anti‐IgE, or anti‐FcεR antibodies in the host. We here discuss the "pros and cons" of inducing such neutralizing autoantibodies. Moreover, we cover another major theme of the last years, i.e., the engineering of non‐anaphylactogenic particles and the elucidation of the parameters relevant for the specific trafficking and processing of such particles in vivo. Finally, we put the various technical advances in VNP‐ and liposome‐research into (pre‐)clinical context by referring and critically discussing the relevant studies performed to treat allergic diseases. [ABSTRACT FROM AUTHOR]

The activation of Toll‐like receptors (TLRs) leads to proinflammatory cytokine production, which is responsible for activating the innate immune system. Thus, TLR signaling is subject to multilayer regulatory control mechanisms that aim to prevent a protective response from causing injury. In the present study, we report that the E3 ubiquitin ligase RNF182 is highly expressed in macrophages and is specifically upregulated by TLR stimuli (TLR4, TLR3 and TLR9 agonists). Knockdown of RNF182 selectively amplifies TLR signaling by promoting the production of proinflammatory cytokines but not type I interferons in macrophages. Mechanistically, RNF182 promotes the degradation of p65 via K48‐linked ubiquitination, resulting in the inhibition of TLR‐triggered innate immune responses. Our findings highlight a feedback‐negative mechanism for terminating TLR‐induced inflammation and maintaining the immunological balance. [ABSTRACT FROM AUTHOR]

Arterial hypertension represents a serious public health problem, being a major cause of morbidity and mortality worldwide. The availability of many antihypertensive therapeutic strategies still fails to adequately treat around 20% of hypertensive patients, who are considered resistant to conventional treatment. In the pathogenesis of hypertension, immune system mechanisms are activated and both the innate and adaptive immune responses play a crucial role. However, what, when and how the immune system is triggered during hypertension development is still largely undefined. In this context, this review highlights scientific advances in the manipulation of the immune system in order to attenuate hypertension and end-organ damage. Here, we discuss the potential use of immunosuppressants and immunomodulators as pharmacological tools to control the activation of the immune system, by non-specific and specific mechanisms, to treat hypertension and improve end-organ damage. Nevertheless, more clinical trials should be performed with these drugs to establish their therapeutic efficacy, safety and risk-benefit ratio in hypertensive conditions. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc. [ABSTRACT FROM AUTHOR]

Mindin has a broad spectrum of roles in the innate immune system, including in macrophage migration, antigen phagocytosis and cytokine production. Mindin functions as a pattern‐recognition molecule for microbial pathogens. However, the underlying mechanisms of mindin‐mediated phagocytosis and its exact membrane receptors are not well established. Herein, we generated mindin‐deficient mice using the CRISPR‐Cas9 system and show that peritoneal macrophages from mindin‐deficient mice were severely defective in their ability to phagocytize E  coli. Phagocytosis was enhanced when E  coli or fluorescent particles were pre‐incubated with mindin, indicating that mindin binds directly to bacteria or non‐pathogen particles and promotes phagocytosis. We defined that 131I‐labelled mindin binds with integrin Mac‐1 (CD11b/CD18), the F‐spondin (FS)‐fragment of mindin binds with the αM‐I domain of Mac‐1 and that mindin serves as a novel ligand of Mac‐1. Blockade of the αM‐I domain of Mac‐1 using either a neutralizing antibody or si‐Mac‐1 efficiently blocked mindin‐induced phagocytosis. Furthermore, mindin activated the Syk and MAPK signalling pathways and promoted NF‐κB entry into the nucleus. Our data indicate that mindin binds with the integrin Mac‐1 to promote macrophage phagocytosis through Syk activation and NF‐κB p65 translocation, suggesting that the mindin/Mac‐1 axis plays a critical role during innate immune responses. [ABSTRACT FROM AUTHOR]

The neuropathological hallmarks of Parkinson's disease (PD) are the degeneration and death of dopamine‐producing neurons in the ventral midbrain, the widespread intraneuronal aggregation of alpha‐synuclein (α) in Lewy bodies and neurites, neuroinflammation, and gliosis. Signs of microglia activation in the PD brain postmortem as well as during disease development revealed by neuroimaging, implicate immune responses in the pathophysiology of the disease. Intensive research during the last two decades has advanced our understanding of the role of these responses in the disease process, yet many questions remain unanswered. A transformative finding in the field has been the confirmation that in vivo microglia are able to respond directly to pathological a‐syn aggregates but also to neuronal dysfunction due to intraneuronal a‐syn toxicity well in advance of neuronal death. In addition, clinical research and disease models have revealed the involvement of both the innate and adaptive immune systems. Indeed, the data suggest that PD leads not only to a microglia response, but also to a cellular and humoral peripheral immune response. Together, these findings compel us to consider a more holistic view of the immunological processes associated with the disease. Central and peripheral immune responses aimed at maintaining neuronal health will ultimately have consequences on neuronal survival. We will review here the most significant findings that have contributed to the current understanding of the immune response in PD, which is proposed to occur early, involve peripheral and brain immune cells, evolve as neuronal dysfunction progresses, and is likely to influence disease progression. Clinical and basic research has revealed the involvement of both the innate and adaptive immune systems in Parkinson's disease (PD). PD leads not only to a microglia response in brain, but also to a cellular and humoral peripheral immune response. This has resulted into the current understanding of the immune response in PD, which is proposed to occur early, involve peripheral and brain immune cells, evolve as neuronal dysfunction progresses, and is likely to influence disease progression. [ABSTRACT FROM AUTHOR]

In animals, sex differences in immunity are proposed to shape variation in infection prevalence and intensity among individuals in a population, with females typically expected to exhibit superior immunity due to life‐history trade‐offs. We performed a systematic meta‐analysis to investigate the magnitude and direction of sex differences in immunity and to identify factors that shape sex‐biased immunocompetence. In addition to considering taxonomic and methodological effects as moderators, we assessed age‐related effects, which are predicted to occur if sex differences in immunity are due to sex‐specific resource allocation trade‐offs with reproduction. In a meta‐analysis of 584 effects from 124 studies, we found that females exhibit a significantly stronger immune response than do males, but the effect size is relatively small, and became non‐significant after controlling for phylogeny. Female‐biased immunity was more pronounced in adult than immature animals. More recently published studies did not report significantly smaller effect sizes. Among taxonomic and methodological subsets of the data, some of the largest effect sizes were in insects, further supporting previous suggestions that testosterone is not the only potential driver of sex differences in immunity. Our findings challenge the notion of pervasive biases towards female‐biased immunity and the role of testosterone in driving these differences. [ABSTRACT FROM AUTHOR]

Sulphur mustard (SM) is an incapacitating chemical warfare agent which causes acute and chronic toxicities in different body organs of affected individuals. The aim of this study was to investigate the innate immune status of the Iranian veterans who were exposed to SM around 30 years earlier and had more than 25% disabilities. In this regard, most functional and non‐functional parameters of innate immunity were evaluated in 35 veterans. Phagocytic activity, nitroblue tetrazolium (NBT) reduction assay and haemolytic complement activity (HCA) in addition to routine haematological parameters, serum protein electrophoresis, complements C3 and C4 levels were studied. Measures of haematological parameters, serum proteins, C3 and C4 were almost within the normal range. Functional experiments such as phagocytic activity, NBT reduction assay and HCA were normal as well. However, serum protein analysis revealed a fair decrease in percentages of α1‐globulin. Mean values of the parameters of innate immune system of the veterans three decades after SM poisoning were almost within the upper and lower normal limits. Reduced α1‐globulin – maybe subsequent to a chain of SM‐induced genetic disorders – may have been the result of α1‐antitrypsin deficiency which may result in prevalent respiratory complications among these veterans. As a supplementary study, measurement of serum α1‐antitrypsin in SM‐poisoned veterans could be beneficial. Further studies are required to prove this hypothesis. Further investigations on the evaluation of the acquired immunity parameters as the second line of defence may reveal a better understanding of SM veterans' immune system status. [ABSTRACT FROM AUTHOR]

Background: Growth hormone (GH) has been identified as an important regulator of the immune response. We have previously shown that adults with isolated GH deficiency (IGHD) due to a mutation in the GH releasing hormone receptor (GHRHR) gene, have a greater chance of having periodontitis. However, the interaction of GH with periodontal tissues is still unknown, and this population has emerged as a unique model to investigate this issue. Therefore, we evaluated the microbiological and immunological periodontal profiles of such individuals.Methods: Nineteen IGHD and 19 controls matched by age, sex, diabetes, and smoking status, were enrolled in this case-control study. Periodontal clinical parameters (probing depth [PD] and clinical attachment loss [AL]) were measured at six sites per tooth. Immune mediators (C-reactive protein, matrix metalloproteinase [MMP]-8, MMP-9, interleukin [IL]-1α, IL-6, IL-8, tumor necrosis factor [TNF]-α, adiponectin, and leptin) were analyzed by enzyme-linked immunosorbent assay (ELISA) in the gingival crevicular fluid (GCF) in four non-adjacent sites for each participant (two with PD ≤3 mm [shallow sites] and two with PD ≥7 mm or the worst PD found in the mouth [deep sites]). Bacterial quantification (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) of subgingival biofilm samples collected from these same sites was performed by quantitative real-time polymerase chain reaction (qPCR).Results: IGHD individuals presented higher values of PD and AL, and increased levels of CRP, IL-8, MMP-8, and adiponectin in the GCF. Bacterial quantification did not identify differences between the two groups.Conclusion: IGHD alters the local immune response in periodontal pockets leading to greater attachment loss, and GH stands out as an important hormone to be evaluated in the pathogenesis of periodontitis. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) are a diverse family of cells that play a crucial role in linking our innate and adaptive immune system to initiate adequate T‐cell responses. They respond to pathogens by triggering the appropriate adaptive immune response that is required to clear invaders while balancing the need to limit tissue damage as a result of inflammation. Perturbation in DC regulation results in abnormal T‐cell homeostasis, leading to development of autoimmune diseases and aberrant responses to pathogens. In recent years, it has become clear that the DC family is more complex than initially thought in terms of their identification, homeostasis and functions. In this review, we discuss recent findings that improve our understanding of development, and functional specializations of conventional and plasmacytoid DCs. [ABSTRACT FROM AUTHOR]

Abstract: Background: Lupus is an autoimmune disease with complex syndrome. Rodent models have limitations for recapitulating the spectrum of the disease. A more powerful translational model is desirable. Method: Lupus‐associated model in cynomolgus monkeys was induced by two intraperitoneal injections of 2, 6, 10, 14‐tetramethylpentadecane (PRISTANE). Lupus‐specific biomarkers and manifestations over a 246‐day period were observed at multilevel. To visualize and quantify kidney function in real time, contrast‐enhanced ultrasound was used. Results: The indicative biomarkers and manifestations fulfilled major diagnosis criteria according to the “Criteria of Lupus” of the American College of Rheumatology. Significant changes in time‐intensity curve parameters were observed, indicating impaired renal function and the method as a feasible, non‐invasive diagnostic method in primate model. Conclusions: We successfully induced lupus‐associated model with systemic lupus syndrome. This primate model can be a valuable translational model for further pathogenesis and symptomology studies and for exploring therapeutic candidates. [ABSTRACT FROM AUTHOR]

Introduction Innate immunity rapidly defends the host against infectious insults. These reactions are of limited specificity and exhaust without providing long-term protection. Functional fluids and effector molecules contribute to the defence against infectious agents, drive the immune response, and direct the cellular players. Aim To review the literature and present a summary of current knowledge about the function of tissues, cellular players and soluble mediators of innate immunity relevant to caries and periodontitis. Methods Historical and recent literature was critically reviewed based on publications in peer-reviewed scientific journals. Results The innate immune response is vital to resistance against caries and periodontitis and rapidly attempts to protect against infectious agents in the dental hard and soft tissues. Soluble mediators include specialized proteins and lipids. They function to signal to immune and inflammatory cells, provide antimicrobial resistance, and also induce mechanisms for potential repair of damaged tissues. Conclusions Far less investigated than adaptive immunity, innate immune responses are an emerging scientific and therapeutic frontier. Soluble mediators of the innate response provide a network of signals to organize the near immediate molecular and cellular response to infection, including direct and immediate antimicrobial activity. Further studies in human disease and animal models are generally needed. [ABSTRACT FROM AUTHOR]

Treatment for chronic hepatitis C virus ( HCV) infection has rapidly evolved into interferon-free directly acting antiviral regimens ( DAA) that result in high sustained virologic response. DAAs primarily work by suppressing HCV replication and rely less on the immune system than interferon-based therapies. However, it is unclear whether the immune system recovers with suppression of HCV replication and contributes to HCV clearance with DAA therapy. We previously demonstrated HCV clearance is associated with increased HCV-specific immunity in CHCV- GT-1-infected patients during treatment with sofosbuvir ( SOF)+ribavirin ( RBV). Here, we aimed to analyse changes in HCV-specific immunological responses associated with viral clearance with combination DAA therapy of SOF+ledipasvir ( LDV) for 12 weeks in CHCV- GT1 (N=14) patients who relapsed without augmentation of HCV-specific immunity during treatment with SOF+RBV. Phenotypic and functional changes within the T-cell compartment of PBMCs pre- and post-treatment were analysed. Retreatment of relapsers with LDV/ SOF resulted in all patients attaining SVR12. Suppression of HCV was associated with a decline in T-cell exhaustion markers ( CD57; Tim3; PD1) along with augmented of HCV-specific T-cell IFN-gamma responses post-treatment. Addition of LDV to SOF was associated with augmentation of HCV-specific immunity and SVR in patients who previously failed SOF+ RBV therapy without increased immunity. These findings demonstrate a novel effect of DAA in inducing host immune responses to aid HCV clearance and achieve SVR. [ABSTRACT FROM AUTHOR]

Sepsis, a complex and dynamic syndrome resulting from microbial invasion and immune system dysregulation, is associated with an increased mortality, reaching up to 35% worldwide. Cholesterol metabolism is often disturbed during sepsis, with low plasma cholesterol levels being associated with poor prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of the low-density lipoprotein receptor (LDLR), thus regulating intracellular and plasma cholesterol levels. PCSK9 is often upregulated during sepsis and might have a detrimental effect on immune host response and survival. Accordingly, PCSK9 reduces lipopolysaccharide uptake and clearance by human hepatocytes. Moreover, PCSK9 upregulation exacerbates organ dysfunction and tissue inflammation during sepsis, whereas a protective effect of PCSK9 deficiency has been documented in septic patients. Although a possible detrimental impact of PCSK9 on survival has been described, some beneficial effects of PCSK9 on immune response may be hypothesized. First, PCSK9 is associated with increased plasma cholesterol levels, which might be protective during sepsis. Second, PCSK9, by stimulating LDLR degradation and inhibiting reverse cholesterol transport (RCT), might promote preferential cholesterol accumulation in macrophages and other immune cells; these events might improve lipid raft composition and augment toll-like receptor function thus supporting inflammatory response. Hence, a more clear definition of the role of PCSK9 in septic states might provide additional insight in the understanding of the sepsis-associated immune dysregulation and enhance therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Aim To systematically review the evidence regarding immune senescence in the pathogenesis of periodontitis and dental caries. Methods A systematic search of electronic databases utilizing medical subject headings (Me SH terms) supplemented by screening of review articles and other relevant texts was undertaken. Results Seventy-three articles were included (43 for periodontitis, 30 for caries). Study results were found to be generally heterogeneous. Regarding periodontitis, human studies suggest evidence for altered neutrophil function and increased production of pro-inflammatory mediators (e.g. interleukin-1 β, interleukin-6 and prostaglandin E2) in older compared to younger subjects, and animal experiments suggest increased expression of genes that contribute to a pro-inflammatory state in older compared to younger animals. Regarding dental caries, research relating to changes in immune functioning and the impact of ageing is in its infancy. A small number of studies have reported components of innate and adaptive immunity that affect the composition of saliva and dental biofilms with possible impacts on caries progression. Conclusion There is evidence that immune functioning related to periodontitis and (less investigated) dental caries alters with increasing age. In both conditions, age-associated mechanistic changes in immune functioning are complex and incompletely understood and it is not clear how these relate to disease susceptibility. [ABSTRACT FROM AUTHOR]

To analyze the pathogenesis at both physiological and molecular level using the model organism, Caenorhabditis elegans at different developmental stages in response to Shigella spp. and its pathogen associated molecular patterns such as lipopolysaccharide. The solid plate and liquid culture-based infection assays revealed that Shigella spp. infects C. elegans and had an impact on the brood size and pharyngeal pumping rate. LPS of Shigella spp. was toxic to C. elegans. qPCR analysis revealed that host innate immune genes have been modulated upon Shigella spp. infections and its LPS challenges. Non-destructive analysis was performed to kinetically assess the alterations in LPS during interaction of Shigella spp. with C. elegans. The modulation of innate immune genes attributed the surrendering of host immune system to Shigella spp. by favoring the infection. LPS appeared to have a major role in Shigella-mediated pathogenesis and Shigella employs a tactic behavior of modifying its LPS content to escape from the recognition of host immune system. [ABSTRACT FROM AUTHOR]

An optimal control problem for a mathematical model of tumour-immune dynamics under the influence of chemotherapy is considered. The toxicity effect of the chemotherapeutic agent on both tumour and immunocompetent cells is taken into account. A standard linear pharmacokinetic equation for the chemotherapeutic agent is added to the system. The aim is to find an optimal strategy of treatment to minimize the tumour volume while keeping the immune response not lower than a fixed permissible level as far as possible. Sufficient conditions for the existence of not more than one switching and not more than two switchings without singular regimes are obtained. The surfaces in the extended phase space, on which the last switching appears, are constructed analytically.Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The human immune system is capable of learning. To investigate how it communicates with the brain during learning processes, researchers employ the paradigm of classical conditioning. Their aim is to achieve a better understanding of immune responses and to establish learning protocols as supportive therapy for the treatment of diseases. [ABSTRACT FROM AUTHOR]