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In this paper, we formulate a generalized hepatitis B virus (HBV) infection model with two modes of infection transmission and adaptive immunity and investigate its dynamical properties. Both the virus‐to‐cell and cell‐to‐cell infection transmissions are modeled by general functions which satisfy some biologically motivated assumptions. Furthermore, the model incorporates three distributed time delays for the production of active infected hepatocytes, mature capsids, and virions. The well‐posedness of the proposed model is established by showing the non‐negativity and boundedness of solutions. Five equilibria of the model are identified in terms of five threshold parameters R0,R1,R2,R3$$ {R}_0,{R}_1,{R}_2,{R}_3 $$, and R4$$ {R}_4 $$. Further, the global stability analysis of each equilibrium under certain conditions is carried out by employing suitable Lyapunov function and LaSalle's invariance principle. Finally, we present an example with numerical simulations to illustrate the applicability of our study. Nonetheless, the results obtained in this study are valid for a wide class of HBV infection models. [ABSTRACT FROM AUTHOR]

Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre‐symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti‐lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11‐dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell‐dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ‐binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization‐independent T cell‐mediated effects, even against an established CNS infection by a lethal neurotropic virus. Synopsis: Rabies is a fatal viral disease of humans, with uniform mortality once central nervous system (CNS) invasion occurs and symptoms appear. This study demonstrates that a single‐dose monoclonal (mAb) therapy can yield a functional cure for rabies, even after robust CNS replication.Peripheral administration of mAb F11 reduces CNS viral replication and prevents mortality, following infection of mice with a lethal dose of either Australian bat lyssavirus (ABLV) or rabies virus (RABV).Therapeutic efficacy of F11, a human IgG1, requires a functional antibody Fc region, implicating the mechanistic involvement of immune cells bearing FcRγ.F11 efficacy requires an intact host adaptive immune response, particularly CD4 T cells.Administration of F11 alters both the proportions and phenotypes of immune cells in the brains of ABLV‐infected animals.Virus persists chronically at a low level in the brains of F11‐treated animals, but animals remain free of disease signs. [ABSTRACT FROM AUTHOR]

By substituting the heavy chain constant region of IgM and IgD with that of IgG, IgA or IgE, immunoglobulin class switching endows antibodies with novel effector functions that enhance the ability of the immune system to effectively clear invading pathogens. Plasmacytoid dendritic cells critically link innate immunity with adaptive immunity by producing massive amounts of type 1 IFN in response to viruses. We have recently found that type 1 IFN triggers class switching by inducing myeloid dendritic cells to upregulate the expression of BAFF and APRIL, two powerful B cell-activating molecules. In this paper, we propose that IFN-producing plasmacytoid dendritic cells modulate class switching by activating B cells through both T cell-dependent and T cell-independent pathways. A better understanding of these pathways may facilitate the development of novel antiviral vaccine strategies and aid in identifying new therapies for antibody-mediated autoimmune disorders, such as lupus. [ABSTRACT FROM AUTHOR]

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS‐CoV‐2 pandemic. Nirmatrelvir—an orally available inhibitor of the 3‐chymotrypsin‐like cysteine protease—has been shown to reduce the risk of progression to severe COVID‐19. However, the impact of nirmatrelvir treatment on the development of SARS‐CoV‐2‐specific adaptive immune responses is unknown. Here, by using mouse models of SARS‐CoV‐2 infection, we show that nirmatrelvir administration blunts the development of SARS‐CoV‐2‐specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir‐treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals. Synopsis Nirmatrelvir administration to SARS‐CoV‐2‐infected mice blunts the development of SARS‐CoV‐2‐specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir‐treated mice recruited significantly fewer memory T and B cells.Adaptive immune response is impaired across different SARS‐CoV‐2 variants and regardless of the time of treatment.Our results might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals. [ABSTRACT FROM AUTHOR]

T cells act as the puppeteers in the adaptive immune response, and their dysfunction leads to the initiation and progression of pathological conditions. During their lifetime, T cells experience myriad forces that modulate their effector functions. These forces are imposed by interacting cells, surrounding tissues, and shear forces from fluid movement. In this review, a journey with T cells is made, from their development to their unique characteristics, including the early studies that uncovered their mechanosensitivity. Then the studies pertaining to the responses of T cell activation to changes in antigen‐presenting cells' physical properties, to their immediate surrounding extracellular matrix microenvironment, and flow conditions are highlighted. In addition, it is explored how pathological conditions like the tumor microenvironment can hinder T cells and allow cancer cells to escape elimination. [ABSTRACT FROM AUTHOR]

The precise interaction between the immune system and severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is critical in deciphering the pathogenesis of coronavirus disease 2019 (COVID‐19) and is also vital for developing novel therapeutic tools, including monoclonal antibodies, antivirals drugs, and vaccines. Viral infections need innate and adaptive immune reactions since the various immune components, such as neutrophils, macrophages, CD4+ T, CD8+ T, and B lymphocytes, play different roles in various infections. Consequently, the characterization of innate and adaptive immune reactions toward SARS‐CoV‐2 is crucial for defining the pathogenicity of COVID‐19. In this study, we explain what is currently understood concerning the conventional immune reactions to SARS‐CoV‐2 infection to shed light on the protective and pathogenic role of immune response in this case. Also, in particular, we investigate the in‐depth roles of other immune mediators, including neutrophil elastase, serum amyloid A, and syndecan, in the immunopathogenesis of COVID‐19. [ABSTRACT FROM AUTHOR]

Innate and adaptive immune systems are built‐in homeostatic functions of many multicellular organisms and protect the host against foreign pathogens and infections. Dysregulation of the molecular mechanisms of the immune system can result in autoimmune diseases. The immune system can also be harnessed and manipulated to provide targeted cancer therapies, some of them relying on the blockade of immune‐checkpoint receptors. Two prominent immune checkpoints, PD‐1/PD‐L1 and CTLA‐4/CD80, comprise receptor–ligand pairs that prevent the host immune cells from attacking host tissues. However, cancer cells upregulate the respective PD‐L1 and CD80 ligands for PD‐1 and CTLA‐4 and thereby evade the host‐immune response. Therapeutic drugs that block PD‐1/PD‐L1 and CTLA‐4/CD80 interactions re‐enable the immune system to attack cancer cells, but their prognostic biomarker remains challenging. In this review, we discuss how the use of quantitative molecular imaging can be exploited to predict the response to anti‐PD‐1/PD‐L1 therapies and to identify cancer patients who would benefit from them. [ABSTRACT FROM AUTHOR]

Afterward, N SB 52-59 sb -specific T cells were fluorescence-activated cell sorting-based isolated from the spleen and transferred to new hosts bearing the CD45.2 genetic marker, to facilitate discrimination between transferred antigen-specific T cells and I de novo i -generated host antigen-specific T cells. Keywords: adaptive immunity; immune memory; memory T-cell; T-cell EN adaptive immunity immune memory memory T-cell T-cell 374 376 3 05/03/23 20230501 NES 230501 T-cell memory is considered long-lasting, but new evidence recently published in I Nature i by Soerens I et al i . shows that, under certain conditions, mouse memory T-cell immunity can span several mouse lifetimes. Age is just a number: long-lasting T-cell immunity can span several lifetimes. [Extracted from the article]

Chronic lung allograft dysfunction (CLAD) remains the major barrier to long‐term survival after lung transplantation and improved insight into its underlying immunological mechanisms is critical to better understand the disease and to identify treatment targets. We systematically searched the electronic databases of PubMed and EMBASE for original research publications, published between January 2000 and April 2021, to comprehensively assess current evidence on effector immune cells in lung tissue and bronchoalveolar lavage fluid from lung transplant recipients with CLAD. Literature search revealed 1351 articles, 76 of which met the criteria for inclusion in our analysis. Our results illustrate significant complexity in both innate and adaptive immune cell responses in CLAD, along with presence of numerous immune cell products, including cytokines, chemokines and proteases associated with tissue remodelling. A clear link between neutrophils and eosinophils and CLAD incidence has been seen, in which eosinophils more specifically predisposed to restrictive allograft syndrome. The presence of cytotoxic and T‐helper cells in CLAD pathogenesis is well‐documented, although it is challenging to draw conclusions about their role in tissue processes from predominantly bronchoalveolar lavage data. In restrictive allograft syndrome, a more prominent humoral immune involvement with increased B cells, immunoglobulins and complement deposition is seen. Our evaluation of published studies over the last 20 years summarizes the complex multifactorial immunopathology of CLAD onset and progression. It highlights the phenotype of several key effector immune cells involved in CLAD pathogenesis, as well as the paucity of single cell resolution spatial studies in lung tissue from patients with CLAD. [ABSTRACT FROM AUTHOR]

The immune system plays an indispensable role in maintaining human health against the invasion of foreign materials, microorgainisms and pathogens. The autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses resulting in excessive and uncontrolled tissue inflammation, as well as tumour, and others. In recent years, flavonoids are widely recognized as potentially natural polyphenol compounds for the treatment of multiple diseases, given their immunomodulatory activity, antioxidant and antineoplastic activities. However, the exact mechanisms of flavonoids on the immune system and inhibiting tumour remains unclear. This review article provides an overview of the impact and mechanism of flavonoids on innate and adaptive immune system through the analysis of various immune cells. Meanwhile, we also explain the probable therapeutic mechanism of flavonoids on tumour and other chronic diseases. Overall, this review may provide a certain theoretical direction and theoretical basis for the application of flavonoids in the treatment of immune‐related disorders and tumour. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic inflammatory condition that destroys the tooth‐supporting tissues and eventually leads to tooth loss. As one of the most prevalent oral conditions, periodontitis endangers the oral health of 70% of people throughout the world. Periodontitis is also related to various systemic diseases, such as diabetes mellitus, atherosclerosis, and rheumatoid arthritis, which not only has a great impact on population health status and the quality of life but also increases the social burden. Porphyromonas gingivalis (P. gingivalis) is a gram‐negative oral anaerobic bacterium that plays a key role in the pathogenesis of periodontitis. Porphyromonas gingivalis can express various of virulence factors to overturn innate and adaptive immunities, which makes P. gingivalis survive and propagate in the host, destroy periodontal tissues, and have connection to systemic diseases. Porphyromonas gingivalis can invade into and survive in host tissues by destructing the gingival epithelial barrier, internalizing into the epithelial cells, and enhancing autophagy in epithelial cells. Deregulation of complement system, degradation of antibacterial peptides, and destruction of phagocyte functions facilitate the evasion of P. gingivalis. Porphyromonas gingivalis can also suppress adaptive immunity, which allows P. gingivalis to exist in the host tissues and cause the inflammatory response persistently. Here, we review studies devoted to understanding the strategies utilized by P. gingivalis to escape host immunity. Methods for impairing P. gingivalis immune evasion are also mentioned. [ABSTRACT FROM AUTHOR]

Immunoglobulin replacement therapy (IGRT) is an effective treatment to reduce the rate of infections and improve the quality of life.1 While IGRT is effective, the appropriate duration of treatment is not known. An international survey found that the mean duration of IGRT was approximately one year in patients with hematological malignancies (range 1-60 months).2 Long-term outcomes after IGRT discontinuation are lacking. Keywords: adaptive immunity; hematological malignancy; hypogammaglobulinemia; immunodeficiency; immunotherapy; infections EN adaptive immunity hematological malignancy hypogammaglobulinemia immunodeficiency immunotherapy infections 584 588 5 10/08/21 20211001 NES 211001 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2900. [Extracted from the article]

Desert species, especially ectotherms, experience temperature‐related challenges throughout their lives. Temperature affects many aspects of ectotherm physiology, including immune function. The goal of this study was to investigate how temperature affects the immune system of a common desert toad, Anaxyrus punctatus. We used three well‐known eco‐immunological techniques (bacterial lysis, hemagglutination and phytohaemagglutinin assays) to measure aspects of immune performance across temperature. Field and preferred temperatures were used to determine the temperatures utilized in the immunological assays. We found that temperature affects bactericidal and hemagglutination capacity in this species, but not inflammatory response. We also found that bactericidal and hemagglutination capacity are optimal at extremely high temperatures compared to the preferred temperature of this species or extremely low temperatures. These results have implications for disease management in desert amphibians as well as the vulnerability of this species to emerging infectious diseases. [ABSTRACT FROM AUTHOR]

Allergic responses are characterized by the activation of a specific subset of effector CD4+ T cells, the T‐helper type 2 (Th2) cells, that respond to harmless environmental antigens causing inflammation and pathology. Th2 cells are also found in the context of parasite infections, where they can mediate parasite clearance and expulsion, and support tissue repair. The process that leads to the activation of Th2 cells in vivo is incompletely understood: while it has become clear that "conventional" dendritic cells are essential antigen‐presenting cells for the initiation of Th2 immune responses, the molecules that are expressed by dendritic cells exposed to allergens, and the mediators that are produced as a consequence and signal to naïve CD4+ T cells to promote their development into effector Th2, remain to be defined. Here we summarize recent developments in the identification of the dendritic cell subsets involved in Th2 responses, review potential mechanisms proposed to explain the generation of these immune responses, and discuss the direct and indirect signals that condition dendritic cells to drive the development of Th2 responses during allergen or parasite exposure. [ABSTRACT FROM AUTHOR]

We have applied mathematical modeling to investigate the infections of the ongoing coronavirus disease‐2019 (COVID‐19) pandemic caused by SARS‐CoV‐2 virus. We first validated our model using the well‐studied influenza viruses and then compared the pathogenesis processes between the two viruses. The interaction between host innate and adaptive immune responses was found to be a potential cause for the higher severity and mortality in COVID‐19 patients. Specifically, the timing mismatch between the two immune responses has a major impact on disease progression. The adaptive immune response of the COVID‐19 patients is more likely to come before the peak of viral load, while the opposite is true for influenza patients. This difference in timing causes delayed depletion of vulnerable epithelial cells in the lungs in COVID‐19 patients while enhancing viral clearance in influenza patients. Stronger adaptive immunity in COVID‐19 patients can potentially lead to longer recovery time and more severe secondary complications. Based on our analysis, delaying the onset of adaptive immune responses during the early phase of infections may be a potential treatment option for high‐risk COVID‐19 patients. Suppressing the adaptive immune response temporarily and avoiding its interference with the innate immune response may allow the innate immunity to more efficiently clear the virus. [ABSTRACT FROM AUTHOR]

An understudied aspect of vertebrate ecoimmunology has been the relative contributions of environmental factors (E), genetic background (G) and their interaction (G × E) in shaping immune development and function. Environmental temperature is known to affect many aspects of immune function and alterations in temperature regimes have been implicated in emergent disease outbreaks, making it a critical environmental factor to study in the context of immune phenotype determinants of wild animals.We assessed the relative influences of environmental temperature, genetic background and their interaction on first‐year development of innate and adaptive immune defences of captive‐born garter snakes Thamnophis elegans using a reciprocal transplant laboratory experiment. We used a full‐factorial design with snakes from two divergent life‐history ecotypes, which are known to differ in immune function in their native habitats, raised under conditions mimicking the natural thermal regime—that is, warmer and cooler—of each habitat.Genetic background (ecotype) and thermal regime influenced innate and adaptive immune parameters of snakes, but in an immune‐component specific manner. We found some evidence of G × E interactions but no indication of adaptive plasticity with respect to thermal environment. At the individual level, the effects of thermal environment on resource allocation decisions varied between the fast‐ and the slow‐paced life‐history ecotypes. Under warmer conditions, which increased food consumption of individuals in both ecotypes, the former invested mostly in growth, whereas the latter invested more evenly between growth and immune development.Overall, immune parameters were highly flexible, but results suggest that other environmental factors are likely more important than temperature per se in driving the ecotype differences in immunity previously documented in the snakes under field conditions. Our results also add to the understanding of investment in immune development and growth during early postnatal life under different thermal environments. Our finding of immune‐component specific patterns strongly cautions against oversimplification of the highly complex immune system in ecoimmunological studies. In conjunction, these results deepen our understanding of the degree of immunological flexibility wild animals present, information that is ever more vital in the context of rapid global environmental change. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and has one of the highest mortality rates of any cancer type with a 5‐year survival rate of <5%. Recent studies of PDAC have provided several transcriptomic classifications based on separate analyses of individual patient cohorts. There is a need to provide a unified transcriptomic PDAC classification driven by therapeutically relevant biologic rationale to inform future treatment strategies. Here, we used an integrative meta‐analysis of 353 patients from four different studies to derive a PDAC classification based on immunologic parameters. This consensus clustering approach indicated transcriptomic signatures based on immune infiltrate classified as adaptive, innate and immune‐exclusion subtypes. This reveals the existence of microenvironmental interpatient heterogeneity within PDAC and could serve to drive novel therapeutic strategies in PDAC including immune modulation approaches to treating this disease. What's new? While several transcriptomic classifications of pancreatic adenocarcinoma (PDAC) have been proposed, a unified classification would be valuable to inform future treatment strategies. Through an integrative meta‐analysis of 353 patients from four different studies, the authors found that the greatest prognostic value in independent cohorts could be achieved through stratification by gene expression signatures associated with tumour‐infiltrating immune cells across different pancreatic cancer subtypes. Recognising the existence of different tumour escape mechanisms (and indeed phenotypes) in pancreatic cancer may guide immunotherapeutic treatment plans and improve patient stratification for maximization of therapeutics. [ABSTRACT FROM AUTHOR]

In this Annual Review Issue of The Journal of Pathology, we present 15 invited reviews on topical aspects of pathology, ranging from the impacts of the microbiome in human disease through mechanisms of cell death and autophagy to recent advances in immunity and the uses of genomics for understanding, classifying and treating human cancers. Each of the reviews is authored by experts in their fields and our intention is to provide comprehensive updates in specific areas of pathology in which there has been considerable recent progress. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Sustained adaptive immunity to pathogens provides effective protection against infections, and effector cells located at the site of infection ensure rapid response to the challenge. Both are essential for the success of vaccine development. To explore new vaccination approach against Mycobacterium tuberculosis (M.tb) infection, we have shown that Rv3615c, identified as ESX‐1 substrate protein C of M.tb but not expressed in BCG, induced a dominant Th1‐type response of CD4+ T cells from patients with tuberculosis pleurisy, which suggests a potential candidate for vaccine development. But subcutaneous immunization with Rv3615c induced modest T‐cell responses systemically, and showed suboptimal protection against virulent M.tb challenge at the site of infection. Here, we use a mouse model to demonstrate that intranasal immunization with Rv3615c induces sustained capability of adaptive CD4+ T‐ and B‐cell responses in lung parenchyma and airway. Rv3615c contains a dominant epitope of mouse CD4+ T cells, Rv3615c41‐50, and elicits CD4+ T‐cell response with an effector–memory phenotype and multi‐Th1‐type cytokine coexpressions. Since T cells resident at mucosal tissue are potent at control of infection at early stage, our data show that intranasal immunization with Rv3615c promotes a sustained regional immunity to M.tb, and suggests a potency in control of M.tb infection. Our study warranties a further investigation of Rv3615c as a candidate for development of effective vaccination against M.tb infection. [ABSTRACT FROM AUTHOR]

ABSTRACT: We propose an evolutionary perspective to classify and characterize the diverse systems of adaptive immunity that have been discovered across all major domains of life. We put forward a new function‐based classification according to the way information is acquired by the immune systems: Darwinian immunity (currently known from, but not necessarily limited to, vertebrates) relies on the Darwinian process of clonal selection to ‘learn’ by cumulative trial‐and‐error feedback; Lamarckian immunity uses templated targeting (guided adaptation) to internalize heritable information on potential threats; finally, shotgun immunity operates through somatic mechanisms of variable targeting without feedback. We argue that the origin of Darwinian (but not Lamarckian or shotgun) immunity represents a radical innovation in the evolution of individuality and complexity, and propose to add it to the list of major evolutionary transitions. While transitions to higher‐level units entail the suppression of selection at lower levels, Darwinian immunity re‐opens cell‐level selection within the multicellular organism, under the control of mechanisms that direct, rather than suppress, cell‐level evolution for the benefit of the individual. From a conceptual point of view, the origin of Darwinian immunity can be regarded as the most radical transition in the history of life, in which evolution by natural selection has literally re‐invented itself. Furthermore, the combination of clonal selection and somatic receptor diversity enabled a transition from limited to practically unlimited capacity to store information about the antigenic environment. The origin of Darwinian immunity therefore comprises both a transition in individuality and the emergence of a new information system – the two hallmarks of major evolutionary transitions. Finally, we present an evolutionary scenario for the origin of Darwinian immunity in vertebrates. We propose a revival of the concept of the ‘Big Bang’ of vertebrate immunity, arguing that its origin involved a ‘difficult’ (i.e. low‐probability) evolutionary transition that might have occurred only once, in a common ancestor of all vertebrates. In contrast to the original concept, we argue that the limiting innovation was not the generation of somatic diversity, but the regulatory circuitry needed for the safe operation of amplifiable immune responses with somatically acquired targeting. Regulatory complexity increased abruptly by genomic duplications at the root of the vertebrate lineage, creating a rare opportunity to establish such circuitry. We discuss the selection forces that might have acted at the origin of the transition, and in the subsequent stepwise evolution leading to the modern immune systems of extant vertebrates. [ABSTRACT FROM AUTHOR]

Vertebrates differ in their ability to mount an adaptive immune response to novel antigens. Bioenergetic resources available to an organism are finite; investment in reproduction compromises immune function and may therefore affect critical life history trade-offs. We tested whether reproduction impairs the ability to produce an antibody response against a novel antigen in roach ( Rutilus rutilus). The antigen approach has rarely been used in fish studies, and the ability to produce an antibody response during reproductive season has never been tested in cyprinid fish before. The fish in an experimental group were injected with a Brucella abortus (BA) antigen, while the fish in a control group were injected with an isotonic saline solution. Blood samples were extracted from all the fish to obtain the total number and proportion of blood cells such as lymphocytes, neutrophils and antioxidant glutathione. The groups were tested during the spawning season and one week after it had ended. The roach were unable to mount an immune response during spawning but produced a robust response after it. We conclude that reproduction is costly in roach, as indicated by the increased concentration of neutrophils in fish injected with BA during spawning, as well as the negative associations between neutrophil counts and glutathione levels. This study demonstrates the potential of BA antigen as a research tool in experimental research on fish ecological immunology. [ABSTRACT FROM AUTHOR]

CRISPR-Cas are self-/nonself-discriminating systems found in prokaryotic cells. They represent a remarkable example of molecular memory that is hereditarily transmitted. Their discovery can be considered as one of the first fruits of the systematic exploration of prokaryotic genomes. Although this genomic feature was serendipitously discovered in molecular biology studies, it was the availability of multiple complete genomes that shed light about their role as a genetic immune system. Here we tell the story of how this discovery originated and was slowly and painstakingly advanced to the point of understating the biological role of what initially was just an odd genomic feature. [ABSTRACT FROM AUTHOR]

Influenza causes significant morbidity and mortality annually. Although vaccination offers a considerable amount of protection, it is far from perfect, especially in aging populations. This is due to age-related defects in immune function, a process called immunosenescence. To date, there are no assays or methods to predict or explain variations in an individual's level of response to influenza vaccination. In this study, we measured levels of several immune cell subsets at baseline (Day 0) and at Days 3 and 28 post-vaccination using flow cytometry. Statistical modelling was performed to assess correlations between levels of cell subsets and Day 28 immune responses - haemagglutination inhibition ( HAI) assay, virus neutralizing antibody ( VNA) assay, and memory B cell ELISPOT. Changes in several groups of cell types from Day 0 to Day 28 and Day 3 to Day 28 were found to be significantly associated with immune response. Baseline levels of several immune cell subsets, including B cells and regulatory T cells, were able to partially explain variation in memory B-cell ELISPOT results. Increased expression of HLA- DR on plasmacytoid dendritic cells after vaccination was correlated with increased HAI and VNA responses. Our data suggest that the expression of activation markers ( HLA- DR and CD86) on various immune cell subsets, as well as the relative distribution of cell subsets, both have value in predicting immune responses to influenza vaccination in older individuals. [ABSTRACT FROM AUTHOR]

It has been recently shown that Toll-like receptor ( TLR) signalling in murine nonparenchymal liver cells ( NPCs) is suppressed in the presence of Hepatitis B virus surface antigen ( HBs Ag). It is not clear, however, whether this is also relevant for the adaptive immune responses and how this effect is mediated. Peripheral blood mononuclear cells ( PBMCs) from Hepatitis B virus ( HBV) patients and controls were stimulated by TLR ligands in the absence or presence of autologous serum. Interestingly, TLR-mediated cytokine expression ( Interleukin-6 and -10) as well as TLR3-induced interferon ( IFN) expression in PBMCs of HBV patients was significantly higher than in the healthy volunteers, showing a negative correlation with the levels of HBs Ag. In addition, TLR3-mediated IFN-γ production was inhibited in the presence of HBV-containing serum. To mechanistically analyse this observation, murine Kupffer cells ( KCs) and sinusoidal endothelial cells ( LSECs) were stimulated with TLR3 ligands in the presence or absence of HBs Ag. Mixed lymphocyte reactions were performed to study T-cell activation induced by TLR-stimulated NPCs. Gene expression of cytokines and TLR3 was analysed by quantitative rt- PCR, and activation of transcription factors was assessed by Western blot or reporter gene assays. TLR-induced expression of interferon γ, interferon sensitive genes and proinflammatory cytokines in murine KCs and LSECs was efficiently suppressed in the presence of HBs Ag, whereas the expression of anti-inflammatory cytokines was enhanced. Activation of NFκ B, IRF-3 and MAPKs in these liver cells was potently suppressed by HBs Ag. T-cell activation mediated through TLR3-stimulated KCs or LSECs was suppressed by HBs Ag which could be reverted by anti- IL-10 antibodies. These findings may, at least in part, explain how HBV evades innate and adaptive immune responses to maintain a persistent infection. [ABSTRACT FROM AUTHOR]

In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. Also watch the . [ABSTRACT FROM AUTHOR]

We have previously demonstrated that chronic obstructive pulmonary disease ( COPD) patients who do not have Siglec-14 are less prone to exacerbation of the disease. Siglec-14 is a myeloid cell protein that recognizes bacteria and triggers inflammatory responses. Therefore, soluble mediators secreted by myeloid cells responding to Siglec-14 engagement could be involved in the pathogenesis of exacerbation and could potentially be utilized as biomarkers of exacerbation. To find out, we sought genes specifically induced in Siglec-14+ myeloid cells and evaluated their utility as biomarkers of COPD exacerbation. Using DNA microarray, we compared gene expression levels in Siglec-14+ and control myeloid cell lines stimulated with or without nontypeable Haemophilus influenzae to select genes that were specifically induced in Siglec-14+ cells. The expressions of several cytokine and chemokine genes were specifically induced in Siglec-14+ cells. The concentrations of seven gene products were analyzed by multiplex bead array assays in paired COPD patient sera ( n = 39) collected during exacerbation and stable disease states. Those gene products that increased during exacerbation were further tested using an independent set ( n = 32) of paired patient sera. Serum concentration of interleukin-27 ( IL-27) was elevated during exacerbation (discovery set: P = 0.0472; verification set: P = 0.0428; combined: P = 0.0104; one-sided Wilcoxon matched-pairs signed-rank test), particularly in exacerbations accompanied with sputum purulence and in exacerbations lasting more than a week. We concluded that IL-27 might be mechanistically involved in the exacerbation of COPD and could potentially serve as a systemic biomarker of exacerbation. [ABSTRACT FROM AUTHOR]

It has long been believed that there is no immune interaction between mother and conceptus during pregnancy. This concept changed after evidence was provided that the maternal immune system is aware of the semiallogeneic conceptus and develops strategies to tolerate it. Since then, finely regulated mechanisms of active tolerance toward the fetus have been described. This Special Issue of the American Journal of Reproductive Immunology deals with these mechanisms. It begins with the description of minor histocompatibility antigens in the placenta; it further goes through adaptive immune responses toward paternal fetal antigens, mostly concentrating on regulatory T cells and molecules modulating the Th1/Th2 balance. The participation of antibody-producing B cells in normal and pathological pregnancies is also discussed. This introductory chapter resumes the concepts presented throughout the Issue and discusses the clinical applications raised from these concepts. [ABSTRACT FROM AUTHOR]

Mrp8 and Mrp14 are endogenous alarmins amplifying inflammation via Toll-like receptor-4 (TLR-4) activation. Due to their pro-inflammatory properties, alarmins are supposed to enhance adaptive immunity via activation of dendritic cells (DCs). In contrast, analysing a model of allergic contact dermatitis (ACD) we observed a more severe disease outcome in Mrp8/14-deficient compared to wild-type mice. This unexpected phenotype was associated with an enhanced T-cell response due to an accelerated maturation of DCs in Mrp8/14-deficient mice. Accordingly, Mrp8, the active component of the heterocomplex, inhibits early DC maturation and antigen presentation in a TLR-4-dependent manner. Transfer of DCs purified from the local lymph nodes of sensitized Mrp8/14-deficient to wild-type mice determined the outcome of ACD. Our results link a pro-inflammatory role of the endogenous TLR-4 ligand Mrp8/14 to a regulatory function in adaptive immunity, which shows some similarities with the 'hygiene hypothesis' regarding continuous TLR-4 stimulation and decreased risk of allergy. [ABSTRACT FROM AUTHOR]

Patients with multiple myeloma ( MM) undergoing high dose therapy and autologous stem cell transplantation ( SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens ( CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine ( Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza- Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion ( ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow ( n = 4) or CD138+ cells ( n = 2). CTA ( CTAG1 B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT. [ABSTRACT FROM AUTHOR]

The author discusses about the Atlantic cod (Gadus morhua), first vertebrate to loose the antigen presenting major histocompatibility complex (MHC) II system. He states that this system is responsible for adaptive immune response against bacterial and parasitic infections by activating cluster of differentiation 4 (CD4+) T cells.

Desai SV, Love RM, Rich AM, Seymour GJ. Toll-like receptor 2 expression in refractory periapical lesions. International Endodontic Journal, 44, 907-916, 2011. Abstract Aim To investigate the expression of TLR2 in refractory periapical lesions. Methodology Refractory periapical lesion biopsies were histopathologically and clinically categorized into asymptomatic periapical granuloma ( n = 10), symptomatic periapical granuloma ( n = 10) or periapical cyst ( n = 10) and prepared for immunohistochemical staining using antibodies to TLR2, CD3 and CD19 or staining with methyl green pyronin. Sections were viewed under light microscopy and the presence or absence of the target cells was correlated with the histopathological and clinical data. Additionally, TLR2 expression was quantified by counting TLR+ cells. Results Various mononuclear inflammatory cells in the bacteria-induced periapical lesions were reactive to TLR2 antibody, with many showing morphological similarities to lymphocytes and plasma cells. Lymphocytes were the most numerous cells in the inflammatory infiltrate. In refractory periapical granuloma, CD3+ T cells were more numerous, whereas in periapical cysts, CD19+ B cells were more numerous. There was a statistically significant ( P < 0.05) higher expression of TLR2 in symptomatic periapical granuloma than asymptomatic periapical granuloma or periapical cyst. Conclusion The presence of TLR-expressing cells in periapical granulomas and cysts provides further evidence that periapical cysts are likely to be sustained by the immune system via reaction to bacterial antigens. [ABSTRACT FROM AUTHOR]

The article investigates the acceleration of fracture healing in recombination activating gene 1 knockout mice in the absence of the adaptive immune system using micro-computed tomography, biomechanical testing, histologic and messenger ribonucleic acid (mRNA) analyses. Findings revealed the higher fraction of bone and lower fraction of cartilage in the callus of mice, and accelerated endochondral ossification. Results showed the reduced expression of inflammatory cytokines and upregulation of expression of anti-inflammatory interleukin 10 in the mice.

The discovery of cytokines expressed by T-helper 1 (Th1), Th2, Th17 and T-regulatory (Treg) cells has prompted speculation that these types of responses may exist in fish, arising early in vertebrate evolution. In this investigation, we cloned three zebrafish transcription factors, T-box expressed in T cells ( t-bet), signal transducer and activator of transcription 6 ( stat6) and fork-head box p3 ( foxp3), in which two transcripts are present, that are important in the development of a number of these cell types. They were found within the zebrafish genome, using a synteny approach in the case of t-bet and foxp3. Multiple alignments of zebrafish t-bet, stat6 and foxp3 amino acids with known vertebrate homologues revealed regions of high conservation, subsequently identified to be protein domains important in the functioning of these transcription factors. The gene organizations of zebrafish t-bet and foxp3 were identical to those of the human genes, with the second foxp3 transcript lacking exons 5, 6, 7 and 8. Zebrafish stat6 (21 exons and 20 introns) was slightly different from the human gene, which contained 22 exons and 21 introns. Immunostimulation of zebrafish head kidney and spleen cells with phytohaemagglutinin, lipopolysaccharide or Poly I:C, showed a correlation between the expression of t-bet, stat6 and foxp3 with other genes involved in Th and Treg responses using quantitative PCR. These transcription factors, together with many of the cytokines that are expressed by different T-cell subtypes, will aid future investigations into the Th and Treg cell types that exist in teleosts. [ABSTRACT FROM AUTHOR]

Mast cells are still generally viewed as mediators of type I allergic or pseudoallergic reactions. Research over the past 10 years revealed that our view was too small and that mast cells are of key importance in innate immunity and also types II, III and IV adaptive immune reactions. Understanding their role in modulating and amplifying of inflammatory responses provides important insights into the pathogenesis of skin diseases such as psoriasis, atopic dermatitis, bullous pemphigoid or the control of infections. This helps us to understand the course of these diseases, their trigger mechanisms, and, the new role of agents, which can modulate the function of mast cells. These insights will help to develop new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are professional antigen-presenting cells with a unique T-cell stimulatory aptitude that play a crucial role in the instruction of adaptive immune responses upon infection. By controlling the initiation of a diverse set of effector functions, which are suitable for the elimination of a wide range of pathogens, DCs form the pivotal link between the innate and the adaptive immune system. The innate pattern recognition pathways that trigger DC activation are central for skewing of the adaptive immune responses that are subsequently induced. Thus innate activation not only precedes adaptive immune activation, it also controls it and tailors the effector functions to the requirements of the infection. The adaptive immune response has to match the nature of the infection, but this does not only concern the type of pathogen, it is also affected by the localization of the infection. Tissue homeostasis has to be ensured and thus tissue-derived environmental factors influence the functional activity of activated DCs and thereby contribute to shaping of the immune response. Adaptive immune responses are vital for the elimination of pathogens, have the potential to attack tumor cells and play a detrimental role during transplant rejection and in a variety of autoimmune diseases. Better understanding of the mechanisms that control the induction of different T-cell effector functions will enable the development of strategies to manipulate the immune system in the context of vaccination, tumor immunotherapy, transplantation and autoimmunity.Immunology and Cell Biology (2008) 86, 389–397; doi:10.1038/icb.2008.26; published online 1 April 2008 [ABSTRACT FROM AUTHOR]

Tumor-associated immune responses assert varied responses toward developing neoplasms that can either act to eradicate malignant cells via engagement of potent cytotoxic programs or alternatively enhance tumor growth through release of multifunctional pro-tumor mediators. Seemingly paradoxical, these disparate activities reflect a continuum of polarization (or activation) states possible for distinct leukocyte subsets that demonstrate tissue, organ, and tumor selectivity. Herein, we review clinical and experimental studies investigating cellular and molecular mechanisms utilized by neoplastic tissues to alternatively polarize immune responses that favor either pro- or anti-tumor immunity. [ABSTRACT FROM AUTHOR]

1. In many animals immunity is not fully developed until adulthood but the young still need protection against various sets of pathogens. Thus, bird nestlings are highly dependent on antibodies received from their mother (in the eggs) during their rapid early growth period. The relationship between maternal immunity and the development of neonates’ own immunity has been poorly studied. 2. It has been suggested that immune function plays an important part in mediating resource competition between different life-history traits, e.g. growth and reproduction. Maternal investment of antibodies has potentially permanent effects on offspring phenotype. Thus, the trade-offs between the immune function and other important life-history traits in the offspring will also affect the fitness of the mother. 3. Our supplemental feeding experiment in the magpie Pica pica indicates that the immunoglobulin levels of offspring at hatching are dependent on a mother's nutritional condition. In addition, the amount of maternal immunoglobulins transferred to offspring increases along the laying order within a nest. 4. We also found that at the age of 8–10 days the immunoglobulin production of the offspring has already begun. Furthermore, the maternal immunoglobulin levels of the offspring at hatching were positively related to their immunoglobulin levels on day 10. 5. Maternal immunoglobulins did not significantly affect offspring growth, but there was a negative relationship between self-produced immunoglobulins and growth over the first 10 days, indicating a trade-off between these traits. Nestlings’ weight, however, had a positive relationship with immunoglobulin production suggesting that the observed trade-off between growth and immunoglobulin production is due to catch-up growth of nestlings with a low hatching weight. We found that within nests nestlings with higher maternal antibody levels had higher survival rate until day 20, but between nests there was an opposite relationship. 6. Evidently, there is a trade-off, in magpies, between maternal resources, immune function and growth, shaping the evolution of maternal investment in offspring immunity. [ABSTRACT FROM AUTHOR]

Summary One of the most controversial issues in immunology for over a century has been whether an effective immune response can be elicited against malignant tumours. Whether the immunology community has believed cancer immunotherapy is feasible or impossible has been largely determined by the prevailing immunological paradigms at that time. In fact, during the last 110 years it is possible to trace at least five dramatic fluctuations in attitude towards cancer immunotherapy. It now appears, however, that overwhelming evidence is available to support the view that both the innate and adaptive immune responses can recognize and eliminate tumours. On the other hand, it remains to be seen if these immune responses can be harnessed to control cancer as, at the time of diagnosis, many tumours have already been immunoselected to be highly resistant to immune elimination. Based on these observations it is argued that immunotherapy approaches, other than the generation of tumour-specific cytotoxic T lymphocytes, must be explored. Alternative strategies include recruiting tumouricidal myeloid cells into tumours, generating antiangiogenic immune responses and directing innate immunity to hypoxia-induced ligands on tumour cells. [ABSTRACT FROM AUTHOR]

Summary Heavy exertion has acute and chronic influences on systemic immunity. In the resting state, the immune systems of athletes and non-athletes are more similar than disparate with the exception of NK cell activity, which tends to be elevated in athletes. Many components of the immune system exhibit adverse change after prolonged, heavy exertion. These immune changes occur in several compartments of the immune system and body (e.g. the skin, upper respiratory tract mucosal tissue, lung, blood and muscle). Although still open to interpretation, most exercise immunologists believe that during this ‘open window’ of impaired immunity (which may last between 3 and 72 h, depending on the immune measure) viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. The infection risk may be amplified when other factors related to immune function are present, including exposure to novel pathogens during travel, lack of sleep, severe mental stress, malnutrition or weight loss. [ABSTRACT FROM AUTHOR]