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This review seeks to provide an update of preclinical findings and available clinical data on the chronic persistent inflammation and its direct role on the pulmonary arterial hypertension (PAH) progression. We reviewed the different mechanisms by which the inflammatory and immune pathways contribute to the structural and functional changes occurring in the three vascular compartments: the tunica intima, tunica media, and tunica adventitia. We also discussed how these inflammatory mediator changes may serve as a biomarker of the PAH progression and summarize unanswered questions and opportunities for future studies in this area., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Oncolytic viruses are of growing interest to cancer researchers and clinicians, due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. The immune response to an oncolytic virus plays a critical role in treatment efficacy. However, uncertainty remains regarding the circumstances under which the immune system either assists in eliminating tumor cells or inhibits treatment via rapid viral clearance, leading to the cessation of the immune response. In this work, we develop an ordinary differential equation model of treatment for a lethal brain tumor, glioblastoma, using an oncolytic Herpes Simplex Virus. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy (OVT), and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We focus on the tradeoff between viral clearance by innate immune cells and the innate immune cell-mediated recruitment of antiviral and antitumor adaptive immune cells. Our model suggests that when a tumor is treated with OVT alone, the innate immune cells' ability to clear the virus quickly after administration has a much larger impact on the treatment outcome than the adaptive immune cells' antitumor activity. Even in a highly antigenic tumor with a strong innate immune response, the faster recruitment of antitumor adaptive immune cells is not sufficient to offset the rapid viral clearance. This motivates our subsequent incorporation of an immunotherapy that inhibits the PD-1/PD-L1 checkpoint pathway by blocking PD-1, which we combine with OVT within the model. The combination therapy is most effective for a highly antigenic tumor or for intermediate levels of innate immune localization. Extreme levels of innate immune cell activity either clear the virus too quickly or fail to activate a sufficiently strong adaptive response, yielding ineffective combination therapy of GBM. Hence, we show that the innate and adaptive immune interactions significantly influence treatment response and that combining OVT with an immune checkpoint inhibitor expands the range of immune conditions that allow for tumor size reduction or clearance., (Copyright © 2020 Storey, Lawler and Jackson.)

Photodynamic therapy (PDT) is an anticancer strategy utilizing light-mediated activation of a photosensitizer (PS) which has accumulated in tumor and/or surrounding vasculature. Upon activation, the PS mediates tumor destruction through the generation of reactive oxygen species and tumor-associated vasculature damage, generally resulting in high tumor cure rates. In addition, a PDT-induced immune response against the tumor has been documented in several studies. However, some contradictory results have been reported as well. With the aim of improving the understanding and awareness of the immunological events triggered by PDT, this review focuses on the immunological effects post-PDT, described in preclinical and clinical studies. The reviewed preclinical evidence indicates that PDT is able to elicit a local inflammatory response in the treated site, which can develop into systemic antitumor immunity, providing long-term tumor growth control. Nevertheless, this aspect of PDT has barely been explored in clinical studies. It is clear that further understanding of these events can impact the design of more potent PDT treatments. Based on the available preclinical knowledge, recommendations are given to guide future clinical research to gain valuable information on the immune response induced by PDT. Such insights directly obtained from cancer patients can only improve the success of PDT treatment, either alone or in combination with immunomodulatory approaches. [ABSTRACT FROM AUTHOR]

AU-rich elements (AREs) comprise one of the most widely studied families of regulatory RNA structures met in RNAs engaged in complex immunological reactions. A multitude of genetic, molecular, holistic and functional studies have been utilized for the analyses of the AREs and their interactions to proteins that bind to them. Data stemming from these studies brought forth a world of RNA-related check-points against infection, chronic inflammation, tumor associated immunity, and autoimmunity; and the interest to capitalize the interactions of AREs for clinical management and therapy. They also provided lessons on the cellular capabilities of post-transcriptional control. Originally thought as transcript-restricted regulators of turnover and translation, ARE-binding proteins do in fact harbor great versatility and interactivity across nuclear and cytoplasmic compartments; and act as functional coordinators of immune-cellular programs. Harnessing these deterministic functions requires extensive knowledge of their synergies or antagonisms at a cell-specific level; but holds great promise since it can provide the efficacy of combinatorial therapies with single agents. • AU-rich elements are a prototypical class of Regulatory RNA structures of relevance to immune physiology and pathology. • Aberrant AREBPs support pathological inflammation and autoimmunity rendering them as targets for clinical management. • AREBPs emerge as highly versatile and integrate many nuclear and cytoplasmic events to a world of coding and non-coding RNAs. • New concepts suggest that AREBPs and other regulatory systems act via cell-specific RNPs to direct immune-cellular reactions. • Therapies targeting post-transcriptional regulators must consider the physiological and pathological remodeling of RNPs. [ABSTRACT FROM AUTHOR]

Sows (PIC-29) with litter size > 10 (n = 20) were blocked by BW and parity and assigned to litters either managed conventionally in farrowing crates (C) or exposed to topsoil (S) from d 4 postpartum to early weaning (d21), when 5 unisex littermates were penned together. Pigs were fed common antibiotic-free corn-SBM-DDGS diets (NRC 2012). Intake and BW were recorded by phase throughout nursery and grow-finish periods to determine ADG, ADFI, and G:F. Backfat (BF) and longissimus muscle (LM) area at the 10th rib were evaluated at the end of nursery (d39) and each subsequent phase in the grow-finish periods. Peripheral blood mononuclear cells (PBMCs) were collected on d4, d15, d20, d36, d56, and d95 for immunophenotyping. Data were analyzed using SAS MIXED procedure for RCBD. Despite lower BW at weaning (6.87 vs. 7.40 kg, P < 0.05), S pigs had higher ADG throughout the nursery period (0.42 vs. 0.35 kg/d, P < 0.01), resulting in a 2.21-kg difference between S- and C-pigs at end of nursery (P < 0.05). At study completion, S pigs tended (P > 0.10) to be 4.6 kg heavier than C pigs. Moreover, S pigs had greater ADFI than C pigs for overall nursery (0.62 vs. 0.51 kg/d; P < 0.01) and grow-finish periods (2.90 vs. 2.74 kg/d; P < 0.05). G:F at combined nursery phases 1-2 was greater in S pigs (0.68 vs. 0.58; P = 0.02), but greater in C pigs at overall grow-finish (0.38 vs. 0.36; P < 0.05). Carcass composition (P = 0.26) and BF (P = 0.10) were not different, but a larger LM area (18.04 vs. 16.24 cm2; P < 0.01) in S pigs resulted in 1.47 kg heavier lean tissue (P > 0.05) in S- compared to C-pigs at end of grower phase 1. Percentages of T-helper cells, Foxp3+ regulatory T cells, dendritic cells, neutrophils, monocytes and NK cells varied (P < 0.01) with time. Time × treatment effects were evident on PBMC (P < 0.01) and granulocyte (P < 0.05) concentrations. PBMC concentrations were greater in S pigs on d4 and d15 but peaked in C pigs on d20 when levels decreased in S pigs (221 vs. 97 × 106 cells/mL). Granulocyte concentrations were greater in S pigs on d4 and d15, but greater in C pigs on d56 when concentrations peaked in both groups (132 vs. 118 × 106 cells/mL). Findings in this study suggest that dirt exposure during lactation may explain improved performance in outdoor-reared pigs observed in previous studies. [ABSTRACT FROM AUTHOR]

The cancer tissue exists not as a single entity, but as a combination of different cellular phenotypes which, taken together, dramatically contribute to the entirety of their ecosystem, collectively termed as the tumor microenvironment (TME). The TME is composed of both immune and nonimmune cell types, stromal components, and vasculature-all of which cooperate to promote cancer progression. Not all immune cells, however, are immune-suppressive; some of them can promote the immune microenvironment to fight the invading and uncontrollably dividing cell populations at the initial stages of tumor growth. Yet, many of these processes and cellular phenotypes fall short, and the immune ecosystem more often than not ends up stabilizing in favor of the "resistant" resident cells that begin clonal expansion and may progress to metastatic forms. Stromal components, making up the extracellular matrix and basement membrane, are also not the most innocuous: CAFs embedded throughout secrete proteases that allow the onset of one of the most invasive processes-angiogenesis-through destruction of the ECM and the basement membrane. Vasculature formation, because of angiogenesis, is the largest invader of the TME and the reason metastasis happens. Vasculature is so sporadic and omnipresent in the TME that most drug therapies are mainly focused on stopping this uncontrollable process. As the tumor continues to grow, different processes are constantly supplying it with the ingredients favorable for tumor progression and eventual metastasis. For example, angiogenesis promotes blood vessel formation that will allow the bona fide escape of tumor cells to take place. Another process like hypoxia will present itself in several forms throughout the tumor (mild or acute, cycling or permanent), starting mechanisms such as epithelial to mesenchymal transitions (EMT) of resident cells and inadvertently placing the cells in such a stressful condition that production of ROS and DNA damage is unavoidable. DNA damage can induce mutagenicity while allowing resistant cells to survive. This is where drugs and treatments can subsequently suffer in effectiveness. Finally, another molecule has just surfaced as being a very important player in the TME: nitric oxide. Often overlooked and equated with ROS and initially assigned in the category of pathogenic molecules, nitric oxide can definitely do some damage by causing metabolic reprogramming and promotion of immunosuppressive phenotypes at low concentrations. However, its actions seem to be extremely dose-dependent, and this issue has become a hot target of current treatment goals. Shockingly, nitric oxide, although omnipresent in the TME, can have a positive effect on targeting the TME broadly. Thus, while the TME is a myriad of cellular phenotypes and a combination of different tumor-promoting processes, each process is interconnected into one whole: the tumor microenvironment.

In this Chapter we discuss the various mechanisms that are available for the possible transfer of cosmic microbial living systems from one cosmic habitat to another. With the 100 or so habitable planets that are now known to exist in our galaxy alone transfers of cometary dust carrying life including fragments of icy planetoids/asteroids would be expected to occur on a routine basis. It is thus easy to view the galaxy as a single connected "biosphere" of which our planet Earth is a minor component. The Hoyle-Wickramasinghe Panspermia paradigm provides a cogent biological rationale for the actual widespread existence of Lamarckian modes of inheritance in terrestrial systems (which we review here). Thus the Panspermia paradigm provides the raison d'etre for Lamarckian Inheritance. Under a terrestrially confined neoDarwinian viewpoint such an association may have been thought spurious in the past. Our aim here is to outline the main evidence for rapid terrestrial-based Lamarckian-based evolutionary hypermutation processes dependent on reverse transcription-coupled mechanisms among others. Such rapid adaptation mechanisms would be consistent with the effective cosmic spread of living systems. For example, a viable, or cryo-preserved, living system traveling through space in a protective matrix will of necessity need to adapt rapidly and proliferate on landing in a new cosmic niche. Lamarckian mechanisms thus come to the fore and supersede the slow (blind and random) genetic processes expected under neoDarwinian Earth centred theories., (© 2020 Elsevier Inc. All rights reserved.)

Anthracenedione is a derivative of anthraquinone aromatic organic natural pigments found in senna, aloe latex, rhubarb, cascara, lichens, and fungi having broad range of bioactivity, including anti-cancer, anti-inflammatory, anti-microbial, anti-fungal, anti-oxidant, anti-viral activities suggesting potential for clinical purpose of many diseases. The effect of anthracenedione enriched diet on growth, hematology, innate and adaptive immune parameters as well as protection from Aeromonas hydrophila in Mystus vittatus was reported. The weight gain, feed intake, specific growth rate (SGR), and feed conversion ratio (FCR) were significantly increased in uninfected groups fed with 5 mg kg -1 diet. The red blood cells (RBC) and white blood cells (WBC) count and the percentage of lymphocytes were significantly augmented in both infected and uninfected groups feeding with any diet. The percentage of monocytes, eosinophils, neutrophils and the biochemical profile such as total protein, albumin, and globulin also were significantly increased in the infected and uninfected groups fed with 5 mg kg -1 enriched diet. The innate and adaptive immune parameters such as phagocytic activity, immunoglobulin M (IgM), respiratory burst activity, complement activity, and lysozyme activity were significantly increased in uninfected and infected groups fed with 5 or 10 mg kg -1 diets but not with 1 mg kg -1 diet. The serum superoxide dismutase (SOD) activity is significantly increased in the uninfected and infected fish fed with 5 mg kg -1 diet but the increase was not significantly observed in 1 or 10 mg kg -1 diets. The nitric oxide (NO) production is significantly elevated in both uninfected and infected groups fed with 5 mg kg -1 diet. On the other hand, the lymphocyte proliferation and myeloperoxidase (MPO) activity were significantly increased the infected and uninfected groups fed with 5 and 10 mg kg -1 diets. The cumulative mortality was found 5% with 1 and 5 mg kg -1 diet groups while it was observed 10% mortality with 10 mg kg -1 diet group. Based on the results, it is observed that feeding the uninfected and infected groups with 5 mg kg -1 anthracenedione diet resulted in better improvement of growth, hematological, biochemical, and innate as well as adaptive immune parameters in M. vittatus against A. hydrophila., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Cutaneous melanoma is the most common skin cancer with an incidence that has been rapidly increasing in the past decades. Melanomas are among the most immunogenic tumors and, as such, have the greatest potential to respond favorably to immunotherapy. However, like many cancers, melanomas acquire various suppressive mechanisms, which generally act in concert, to escape innate and adaptive immune detection and destruction. Intense research into the cellular and molecular events associated with melanomagenesis, which ultimately lead to immune suppression, has resulted in the discovery of new therapeutic targets and synergistic combinations of immunotherapy, targeted therapy and chemotherapy. Tremendous effort to determine efficacy of single and combination therapies in pre-clinical and clinical phase I-III trials has led to FDA-approval of several immunotherapeutic agents that could potentially be beneficial for aggressive, highly refractory, advanced and metastatic melanomas. The increasing availability of approved combination therapies for melanoma and more rapid assessment of patient tumors has increased the feasibility of personalized treatment to overcome patient and tumor heterogeneity and to achieve greater clinical benefit. Here, we review the evolution of the immune system during melanomagenesis, mechanisms exploited by melanoma to suppress anti-tumor immunity and methods that have been developed to restore immunity. We emphasize that an effective therapeutic strategy will require coordinate activation of tumor-specific immunity as well as increased recognition and accessibility of melanoma cells in primary tumors and distal metastases. This review integrates available knowledge on melanoma-specific immunity, molecular signaling pathways and molecular targeting strategies that could be utilized to envision therapeutics with broader application and greater efficacy for early stage and advanced metastatic melanoma., (Published by Elsevier Ltd.)

Genetic alleles that contribute to enhanced susceptibility or resistance to viral infections and virally induced diseases have often been first identified in mice before humans due to the significant advantages of the murine system for genetic studies. Herein we review multiple discoveries that have revealed significant insights into virus-host interactions, all made using genetic mapping tools in mice. Factors that have been identified include innate and adaptive immunity genes that contribute to host defense against pathogenic viruses such as herpes viruses, flaviviruses, retroviruses, and coronaviruses. Understanding the genetic mechanisms that affect infectious disease outcomes will aid the development of personalized treatment and preventive strategies for pathogenic infections.

Autophagy and inflammasomes are shown to interact in various situations including infectious disease, cancer, diabetes and neurodegeneration. Since multiple layers of molecular regulators contribute to the interplay between autophagy and inflammasome activation, the detail of such interplay remains largely unknown. Non-coding RNAs (ncRNAs), which have been implicated in regulating an expanding list of cellular processes including immune defense against pathogens and inflammatory response in cancer and metabolic diseases, may join in the crosstalk between inflammasomes and autophagy in physiological or disease conditions. In this review, we summarize the latest research on the interlink among ncRNAs, inflammasomes and autophagy and discuss the emerging role of these three in multiple signaling transduction pathways involved in clinical conditions. By analyzing these intriguing interconnections, we hope to unveil the mechanism inter-regulating these multiple processes and ultimately discover potential drug targets for some refractory diseases., (© The Author(s) 2019. Published by Oxford University Press on behalf of West China School of Medicine & West China Hospital of Sichuan University.)

Evolving technologies and increasing understanding of human physiology over the past century have afforded our ability to intervene on human diseases using implantable bio-materials. These bio-electronic devices present a unique challenge through the creation of an interface between the native tissue and implantable bio-materials: the generation of host immune response surrounding such devices. While recent developments in cancer immunology seek to stimulate the immune system against cancer, successful long-term application of implantable bio-material devices need to durably minimize reactive immune processes at involved anatomical sites. Peripheral immune system response has been studied extensively for implanted bio-materials at various body sites. Examples include tooth composites (Gitalis et al., 2019), inguinal hernia repair (Heymann et al., 2019), and cardiac stents and pacemaker leads (Slee et al., 2016). Studies have also been extended to less well-studied immune reactivity in response to CNS neural-electronic implant devices. Recent technological advances in 2-Photon Laser Scanning Microscopy (2P-LSM) have allowed novel insights into in vivo immune response in a variety of tissue microenvironments. While imaging of peripheral tissues has provided an abundance of data with regards to immune cell dynamics, central nervous system (CNS) imaging is comparatively complicated by tissue accessibility and manipulation. Despite these challenges, the results of dynamic intravital neuro-immune imaging thus far have provided foundational insights into basic CNS biology. Utilizing a combination of intravital and ex vivo 2P-LSM, we have observed novel pathways allowing immune cells, stromal cells, cancer cells and proteins to communicate between the CNS parenchyma and peripheral vasculature. Similar to what has been reported in the intestinal tract, we have visualized myeloid cells extend dendritic processes across the blood brain barrier (BBB) into pial blood vessels. Furthermore, transient vessel leaks seen during systemic inflammation provide opportunities for cellular protein to be exchanged between the periphery and CNS. These insights provide new, visual information regarding immune surveillance and antigen presentation within the CNS. Furthermore, when combining intravital 2P-LSM and microfluidic devices complexed with mathematical modeling, we are gaining new insights into the intravascular behavior of circulating immune cells. This new knowledge into the basic mechanisms by which cells migrate to and interact with the CNS provide important considerations for the design of neuro-electronic biomaterials that have the potential to connect the peripheral-neural microenvironments into a unique, artificial interface.

Macrophages play an important role in tissue development and homeostasis. They serve as a nexus between adaptive and innate immunity, and employ considerable plasticity. In cancer, they play a pivotal role in chronic inflammation and tumor growth either by directly stimulating the proliferation of cancer cells or by producing angiogenic and lymphangiogenic factors. Although numerous immune cells play an important role in the tumor microenvironment, tumor-associated macrophages (TAMs) are by far the most extensively studied. A better understanding of the role of TAMs in mediating chemo- and radiotherapy resistance and suppressing immunosurveillance has led to numerous strategies targeting TAMs as an anticancer therapy either by targeting them directly or by polarizing TAMs toward a tumoricidal phenotype.

Lymphocytes and heterophils are the two most abundant leucocyte types, which play a major role in adaptive and innate immune defence, respectively. The ratio of heterophils to lymphocytes (H/L ratio) may reflect a readiness to cope with infection through injury (via heterophils) rather than with a communicable disease (via lymphocytes). Since elevated H/L ratio constitutes a corticosterone-mediated response to external stressors, this trait is generally acknowledged as the robust measure of physiological stress in vertebrates. Here, I hypothesized that baseline H/L ratios of birds (as measured under normal physiological function) could be an important evolutionary trait shaped by species' ecology and life history. I predicted that H/L ratios should be determined by traits related to pathogen exposure (migratoriness, sociality, breeding latitude) and trade-offs between investment in reproduction (clutch size) and self-maintenance (longevity). I compiled published data on leucocyte profiles for nearly 250 bird species representing over half of all extant avian orders and nearly 30% of all extant avian families. Phylogenetically informed comparative methods were used to assess evolutionary associations of H/L ratios with ecological and life-history traits across the avian tree of life. Relatively strong phylogenetic signal and phylogenetic autocorrelation in avian H/L ratios indicated that most diversification in this trait occurred relatively early in bird radiation. Fluctuating selection and drift were identified as the major forces responsible for the evolution of H/L ratios in birds, while low H/L ratios were identified as an ancestral state in birds. Finally, phylogenetically informed Bayesian models showed that H/L ratios correlated negatively with longevity and positively with sociality and breeding latitude. This study was the first to describe the patterns of avian H/L ratio evolution in a broad phylogenetic framework. The results indicate that H/L ratios should not be merely recognized as a proxy for the intraspecific variation in physiological stress, but also as an important evolutionary trait, which probably have adaptive significance visible in a wider phylogenetic perspective., (© 2019 The Authors. Journal of Animal Ecology © 2019 British Ecological Society.)

One cause of sepsis is systemic maladaptive immune response of the host to bacteria and specifically, to Gram-negative bacterial outer-membrane glycolipid lipopolysaccharide (LPS). On the host myeloid cell surface, proinflammatory LPS activates the innate immune system via Toll-like receptor-4/myeloid differentiation factor-2 complex. Intracellularly, LPS is also sensed by the noncanonical inflammasome through caspase-11 in mice and 4/5 in humans. The minimal functional determinant for innate immune activation is the membrane anchor of LPS called lipid A. Even subtle modifications to the lipid A scaffold can enable, diminish, or abolish immune activation. Bacteria are known to modify their LPS structure during environmental stress and infection of hosts to alter cellular immune phenotypes. In this review, we describe how mass spectrometry-based structural analysis of endotoxin helped uncover major determinations of molecular pathogenesis. Through characterization of LPS modifications, we now better understand resistance to antibiotics and cationic antimicrobial peptides, as well as how the environment impacts overall endotoxin structure. In addition, mass spectrometry-based systems immunoproteomics approaches can assist in elucidating the immune response against LPS. Many regulatory proteins have been characterized through proteomics and global/targeted analysis of protein modifications, enabling the discovery and characterization of novel endotoxin-mediated protein translational modifications., (Published by Elsevier Ltd.)

The 11-member APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of zinc-dependent cytidine deaminases bind to RNA and single-stranded DNA (ssDNA) and, in specific contexts, modify select (deoxy)cytidines to (deoxy)uridines. In this review, we describe advances made through high-resolution co-crystal structures of APOBECs bound to mono- or oligonucleotides that reveal potential substrate-specific binding sites at the active site and non-sequence-specific nucleic acid binding sites distal to the active site. We also discuss the effect of APOBEC oligomerization on functionality. Future structural studies will need to address how ssDNA binding away from the active site may enhance catalysis and the mechanism by which RNA binding may modulate catalytic activity on ssDNA., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

To maintain health, the immune system must maintain a delicate balance between eliminating invading pathogens and avoiding immune disorders such as autoimmunity and allergies. The gut microbiota provide essential health benefits to the host, particularly by regulating immune homeostasis. Dysbiosis, an alteration and imbalance of the gut microbiota, is associated with the development of several autoimmune diseases in both mice and humans. In this review, we discuss recent advances in understanding how certain factors, such as age and gender, affect the gut microbiota, which in turn can influence the development of autoimmune diseases. The age factor in microbiota-dependent immune disorders indicates a window of opportunity for future diagnostic and therapeutic approaches. We also discuss unique commensal bacteria with strong immunomodulatory activity. Finally, we provide an overview of the potential molecular mechanisms whereby gut microbiota induce autoimmunity, as well as the evidence that gut microbiota trigger extraintestinal diseases by inducing the migration of gut-derived immune cells. Elucidating the interaction of gut microbiota and the host immune system will help us understand the pathogenesis of immune disorders, and provide us with new foundations to develop novel immuno- or microbe-targeted therapies., (© 2017 New York Academy of Sciences.)

Summary Within the human gut reside diverse microbes coexisting with the host in a mutually advantageous relationship. Evidence has revealed the pivotal role of the gut microbiota in shaping the immune system. To date, only a few of these microbes have been shown to modulate specific immune parameters. Herein, we broadly identify the immunomodulatory effects of phylogenetically diverse human gut microbes. We monocolonized mice with each of 53 individual bacterial species and systematically analyzed host immunologic adaptation to colonization. Most microbes exerted several specialized, complementary, and redundant transcriptional and immunomodulatory effects. Surprisingly, these were independent of microbial phylogeny. Microbial diversity in the gut ensures robustness of the microbiota’s ability to generate a consistent immunomodulatory impact, serving as a highly important epigenetic system. This study provides a foundation for investigation of gut microbiota-host mutualism, highlighting key players that could identify important therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Despite the relatively high efficacy of antifungal drugs, invasive fungal infections (IFIs) are still associated with tremendous morbidity and mortality, since late diagnosis makes an antifungal drug therapy inefficient. Therefore, antifungal immunotherapies to specifically strengthen the host´s own immune mechanisms constitute an additional promising strategy in taking action against fungal pathogens. Areas covered: The authors summarize efforts in research and clinical trials to provide safe and efficient immunotherapeutic options against invasive fungal diseases. Treatment of IFIs is challenging as the number of available antifungals is limited and further complications include: toxicity, drug interactions and the emergence of drug resistance. Susceptibility is determined by the impaired immune status of the host. Hence, augmenting immunity by immunotherapeutic interventions may offer future directions to treat IFI. Expert opinion: A much better understanding of fungus and host cell interactions is essential for the development of safe and successful immunotherapeutic strategies. Indeed, there is encouraging preliminary data available that such approaches are possible; however, current data is too limited to allow solid conclusions on the risks and benefits in the clinical setting. Clinical trials focusing on the role of adjuvant immunotherapeutics with or without a combination of antifungals are highly needed for further evaluation.

The immune system is important to protect the host from fungal infections. Diverse cell types belonging to the innate or adaptive branch of the immune system act in a tightly coordinated and tissue-specific manner. Experimental mouse models of fungal infections have proved essential for assessing the protective principles against different fungal pathogens. Besides pathological, histological, biochemical and molecular parameters, the analysis of phenotypic and functional aspects of immune cells in infected tissues is key for understanding the mechanisms of antifungal defense. In this chapter, we describe a method based on flow cytometry to assess innate and adaptive immune cells isolated from an in vivo context in a qualitative and quantitative manner.

For decades, immunologists have considered the complement system as a paradigm of a proteolytic cascade that, acting cooperatively with the immune system, enhances host defense against infectious organisms. In recent years, advances made in thrombosis research disclosed a functional link between activated neutrophils, monocytes, and platelet-driven thrombogenesis. Forging a physical barrier, the fibrin scaffolds generated by synergism between the extrinsic and intrinsic (contact) pathways of coagulation entrap microbes within microvessels, limiting the systemic spread of infection while enhancing the clearance of pathogens by activated leukocytes. Insight from mice models of thrombosis linked fibrin formation via the intrinsic pathway to the autoactivation of factor XII (FXII) by negatively charged "contact" substances, such as platelet-derived polyphosphates and DNA from neutrophil extracellular traps. Following cleavage by FXIIa, activated plasma kallikrein (PK) initiates inflammation by liberating the nonapeptide bradykinin (BK) from an internal domain of high molecular weight kininogen (HK). Acting as a paracrine mediator, BK induces vasodilation and increases microvascular permeability via activation of endothelial B2R, a constitutively expressed subtype of kinin receptor. During infection, neutrophil-driven extravasation of plasma fuels inflammation via extravascular activation of the kallikrein-kinin system (KKS). Whether liberated by plasma-borne PK, tissue kallikrein, and/or microbial-derived proteases, the short-lived kinins activate immature dendritic cells via B2R, thus linking the infection-associated innate immunity/inflammation to the adaptive arm of immunity. As inflammation persists, a GPI-linked carboxypeptidase M removes the C-terminal arginine from the primary kinin, converting the B2R agonist into a high-affinity ligand for B1R, a GPCR subtype that is transcriptionally upregulated in injured/inflamed tissues. As reviewed here, lessons taken from studies of kinin receptor function in experimental infections have shed light on the complex proteolytic circuits that, acting at the endothelial interface, reciprocally couple immunity to the proinflammatory KKS., (© 2017 Elsevier Inc. All rights reserved.)

Introduction Metastatic pancreatic Ca leads to fatalities due to resistance in conventional anticancer therapies. By activation of immunological mechanisms we aim to circumvent the chemoresistant mechanisms. Methods Animal models characterized by metastatic pancreatic Ca refractory to conventional treatment were developed and treated with IV administration of the Gene-Modified Cellular Vaccine(GMCV) termed as SV/AS (under patent),which is composed of Autologous Adipose-derived Mesenchymal Stem Cells (AADMSCs), which were transfected with lipid-cation imunodominant molecule Hsp70. Results Post-treatment, we observed molecular remission in all tumour/metastatic sites, and activation of CD4+ T-cells by antigen presenting cells (APC), enhancement of MHC class I expression, generation of tumor-specific cytotoxicity with CTLs induced by the antigenic fingerprint/repertoire, activation of natural-killer (NK) cells, generation of peptide-specific tumour immunity induced by CD91 and C19 overexpression on dendritic cells (DCs),CD40 on macrophages, and LOX-1,CD14 and TLR2–4 on monocytes. Furthermore, hsp70 induced Th1-type immune response inducing secondary necrosis, which is the most potent immunogenic mode of cell death, and phagocytosis of tumour cells by activated macrophages leading to a lethal bystander effect. Finally, we observed repair of damaged tissue and organs by renewal of injured cells. Conclusion The Gene Modified Cellular Vaccine (GMCV) consisting of autologous adipose mesenchymal stem cells expressing Hsp70 activated the innate and adaptive immunity leading to eradication of metastatic pancreatic Ca cells, while there was stem cell renewal of injured cells. [ABSTRACT FROM PUBLISHER]

Apoptosis is a programmed form of cell death whereby characteristic internal cellular dismantling is accompanied by the preservation of plasma membrane integrity. Maintaining this order during apoptosis prevents the release of cellular contents and ensures a noninflammatory death. Here, we consider examples of apoptosis in different contexts and discuss how the same form of cell death could have different immunological consequences. Multiple parameters such as cell death as a result of microbial infection, the nature of the inflammatory microenvironment, the type of responding phagocytic cells and the genetic background of the host organism all differentially influence the immunological consequences of apoptosis., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

During evolution, organisms were confronted with different environmental pressures leading to selective evolution of different intracellular pathways. Autophagy, an ancestral cellular mechanism involved in cell homeostasis and survival, provides an interesting example of this biologic concept. The constant dialog between viral infections and mechanisms of host protection has scripted the evolving relationship between autophagy and viruses, with some infectious agents being controlled by autophagy; whereas others, perhaps more opportunistic viruses, have adapted to manipulate autophagy for their own benefit.

Campylobacter jejuni is among the most frequently reported bacterial pathogens causing diarrhea in humans worldwide. We recently reported a murine infection model mimicking key features of human campylobacteriosis. Six days following oral C. jejuni infection immediately after weaning, infant mice developed acute enterocolitis resolving within 2 weeks. Thereafter, C. jejuni could still be isolated from the intestines of asymptomatic mice at low levels accompanied by distinct immune responses, both at intestinal and extra-intestinal locations. We here show that, at day 103 post infection (p.i.), long-term C. jejuni-infected mice exhibited higher numbers of T lymphocytes in liver, lung, kindneys, and cardiac muscle as compared to uninfected controls. In addition, B lymphocytes were slightly higher, but macrophage numbers were significantly lower in liver and lung of C. jejuni-infected versus naive mice. As compared to uninfected control animals, proliferating cells were significantly lower in liver, lung, kidneys, cardiac muscle, and spleen at day 103 p.i., whereas more apoptotic cells were abundant in the spleen with predominance in the red pulp. This study underlines that post-infectious, immunological sequelae at extra-intestinal locations are of importance even in asymptomatic long-term C. jejuni carriers and need to be further studied in order to unravel the underlying molecular mechanisms.