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Platelets as immune cells in physiology and immunopathology

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197408 Year: Pages: 111 DOI: 10.3389/978-2-88919-740-8 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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Are platelets cells? (Not everyone agrees, since they are non-nucleate). And if platelets are cells - which all specialists consider at the time being - are they immune cells? The issue that platelets participate in immunity is no longer debated; however, the issue that they are key cells in immunity is challenged. It has even been proposed a couple of years ago that platelets can present antigen to T-lymphocytes by using their HLA class I molecules. No one has the same functional definition of platelets. The ‘Frontiers Research Topic’- coordinators’ own view is that platelets are primarily repairing cells, what they do in deploying tools of physiological inflammation. This function is better acknowledged as primary hemostasis, i.e. platelet adherence to injured or wounded vessels, followed by activation, aggregation, and constitution of the initial clot. Platelets would thus repair damaged vascular endothelium; so doing, as they patrol to detect damages, they sense danger along the vascular arborescence. As the latter is immense, platelets get close to tissues, which are not allowed to them under ‘physiological’ conditions but are readily accessible in pathology. Platelets are equipped with a variety of Pathogen Recognition Receptors such as TLRs; they have a complete signalosome, which is functional until the phosphorylation of NFkB; they have been proved to retro-transcribe RNA and synthesize de novo proteins; etc. Platelets participate to inflammation along the whole spectrum: from physiological (tissue repair, healing) to acute/severe inflammation (as can be seen in e.g. sepsis). In general, platelets engage complex interactions with most infectious pathogens. We propose there to cover those topics - from physiology to pathology, that put platelets within cells that not only take place in-, but also are key players of-, innate immunity. The relation of platelets with adaptive immunity is even more complex. Not everyone is convinced that platelets present antigens; however, platelets influence adaptive immunity since they have mutual interactions with Dendritic cells, Monocytes/Macrophages, and B-lymphocytes (the key players of antigen presentation); they also have mutual interactions with T-lymphocytes, though is issue is less clearly deciphered. We propose to also cover these topics - or to present the forum. There is another issue which is medically relevant - speaking of physiology/physiopathology-: this is fetal maternal incompatibility of platelet specific antigens (the HPA system) and the likely formation of maternal antibodies that often injure the newborn with risks of severe thrombocytopenia and intracranial hemorrhage. We propose an update on this issue as well. Last, platelets are very special because they can be directly therapeutic (by transfusion), even when being offered by a generous blood donor displaying given genetic and phenotypic parameters to a patient/recipient in need, who also display his/her own genetic and phenotypic parameters, which - for a large part - differ from the donor's ones. Besides immunization - via mechanisms probably close to the fetal maternal platelet incompatibility, but likely not similar -, transfusion has allowed the identification of the tremendous capacity of platelets to mediate inflammation: we propose to conclude the Topics with this item/forum.

Keywords

platelets --- Infection --- Inflammation --- immunity

Dual role of microglia in health and disease: pushing the balance towards repair

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194926 Year: Pages: 101 DOI: 10.3389/978-2-88919-492-6 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2015-11-16 15:44:59
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Microglial cells play a vital role in the innate immune response occurring in the Central Nervous System (CNS). Under physiologic conditions, microglia dynamically patrol the brain parenchyma and participate in the remodeling of active neuronal circuits. Accordingly, microglia can boost synaptic plasticity by removing apoptotic cells and by phagocytizing axon terminals and dendritic spines that form inappropriate neural connections. Upon brain and spinal cord injury or infection, microglia act as the first line of immune defense by promoting the clearance of damaged cells or infectious agents and by releasing neurotrophins and/ or proneurogenic factors that support neuronal survival and regeneration.Recently, two main pathways were suggested for microglia activation upon stimuli. Classical activation is induced by Toll-like receptor agonists and Th1 cytokines and polarizes cells to an M1 state, mainly leading to the release of TNF-alpha, IL-6 and nitric oxide and to grave neural damage. Alternative activation is mediated by Th2 cytokines and polarizes cells to an M2a state inducing the release of antiinflammatory factors. These findings have further fueled the discussion on whether microglia has a detrimental or beneficial action (M1 or M2-associated phenotypes, respectively) in the diseased or injured CNS and, more importantly, on whether we can shift the balance to a positive outcome.Although microglia and macrophages share several common features, upon M1 and M2 polarizing conditions, they are believed to develop distinct phenotypic and functional properties which translate into different patterns of activity. Moreover, microglia/macrophages seem to have developed a tightly organized system of maintenance of CNS homeostasis, since cells found in different structures have different morphology and specific function (e.g. meningeal macrophages, perivascular macrophages, choroid plexus macrophages). Nevertheless, though substantial work has been devoted to microglia function, consensus around their exact origin, their role during development, as well as the exact nature of their interaction with other cells of the CNS has not been met.This issue discusses how microglial cells sustain neuronal activity and plasticity in the healthy CNS as well as the cellular and molecular mechanisms developed by microglia in response to injury and disease. Understanding the mechanisms involved in microglia actions will enforce the development of new strategies to promote an efficient CNS repair by committing microglia towards neuronal survival and regeneration.

Endoplasmic Reticulum Stress Response and Transcriptional Reprogramming

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194360 Year: Pages: 97 DOI: 10.3389/978-2-88919-436-0 Language: English
Publisher: Frontiers Media SA
Subject: Genetics --- Science (General)
Added to DOAB on : 2016-01-19 14:05:46
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Endoplasmic reticulum (ER) is an intracellular organelle responsible for protein folding and assembly, lipid and sterol biosynthesis, and calcium storage. A number of biochemical, physiological, or pathological stimuli can interrupt protein folding process, causing accumulation of unfolded or misfolded proteins in the ER lumen, a condition called “ER stress”. To cope with accumulation of unfolded or misfolded proteins, the ER has evolved a group of signaling pathways termed “Unfolded Protein Response (UPR)” or “ER stress response” to align cellular physiology. To maintain ER homeostasis, transcriptional regulation mediated through multiple UPR branches is orchestrated to increase ER folding capacity, reduce ER workload, and promote degradation of misfolded proteins. In recent years, accumulating evidence suggests that ER stress-triggered transcriptional reprogramming exists in many pathophysiological processes and plays fundamental roles in the initiation and progression of a variety of diseases, such as metabolic disease, cardiovascular disease, neurodegenerative disease, and cancer. Understanding effects and mechanisms of ER stressassociated transcriptional reprogramming has high impact on many areas of molecular genetics and will be particularly informative to the development of pharmacologic avenues towards the prevention and treatment of modern common human diseases by targeting the UPR signaling. For these reasons, ER stress response and transcriptional reprogramming are a timely and necessary topic of discussion for Frontiers in Genetics.The important topics in this area include but not limited to:(1) ER-resident transcription factors and their involvements in ER stress response and cell physiology; (2) Physiologic roles and molecular mechanisms of ER stress-associated transcriptional regulation in lipid and glucose metabolism; (3) In vitro and in vivo models for ER stress-associated transcriptional reprogramming; (4) ER stress-associated transcriptional regulation in human disease; (5) Therapeutic potentials by targeting ER stress response pathways.

Chronic inflammation in conditions associated with a deficient clearance of dying and dead cells, their remnants, and intracellular constituents

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196012 Year: Pages: 73 DOI: 10.3389/978-2-88919-601-2 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-08-16 10:34:25
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In multicellular organisms, states with a high degree of tissue turnover like embryogenesis, development, and adult tissue homeostasis need an instantaneous, tightly regulated and immunologically silent clearance of these dying cells to ensure appropriate development of the embryo and adult tissue remodelling. The proper and swift clearance of apoptotic cells is essential to prevent cellular leakage of damage associated molecular patterns (DAMPs) which would lead to the stimulation of inflammatory cytokine responses. In addition to the clearance of apoptotic cells (efferocytosis), backup mechanisms are required to cope with DAMPs (HMGB-1, DNA, RNA, S100 molecules, ATP and adenosine) and other intracellular material (uric acid, intracellular proteins and their aggregates) released from cells, that were not properly cleared and have entered the stage of secondary necrosis. Furthermore, under certain pathologic conditions (e.g. gout, cancer, diabetes) non-apoptotic cell death may transiently occur (NETosis, necroptosis, pyroptosis) which generates material that also has to be cleared to avoid overloading tissues with non-functional cellular waste. Efficient efferocytosis is therefore indispensable for normal tissue turnover and homeostasis. The characterization of various signalling pathways that regulate this complex and evolutionary conserved process has shed light on new pathogenetic mechanisms of many diseases. Impaired clearance promotes initiation of autoimmunity as well as the perpetuation of chronic inflammation, but may also foster anti-tumor immunity under certain microenvironmental conditions. Immunological tolerance is continuously being challenged by the presence of post-apoptotic remnants in peripheral lymphoid tissues. Besides the autoimmune phenotype of chronic inflammatory rheumatoid disorders a plethora of pathologies have been associated with defects in genes involved in clearance, e.g. atherosclerosis, cancer, gout, diabetes, some forms of blindness, neuropathy, schizophrenia and Alzheimer’s disease. The main goal of this research topic is to collect contributions from various disciplines committed to studying pathogenetic mechanisms of the aforementioned disorders and dealing with alterations in the clearance of dying and dead cells, their remnants, and their constituents that leak out after membrane rupture. Integrating the combined collection of knowledge on efferocytosis and clearance of dead cells and their derived waste from different fields of research in physiology and pathophysiology could improve the molecular understanding of these increasingly prevalent diseases and may ultimately result in new therapeutic strategies.

Antimicrobial Peptides

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ISBN: 9783038420729 9783038420736 Year: Pages: 336 DOI: 10.3390/books978-3-03842-073-6 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Added to DOAB on : 2015-10-22 10:29:38
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Antimicrobial peptides (AMPs) are gene-encoded, ancient (and important) mediators of innate host defense that exert direct or indirect antimicrobial action as well as possessing other important biologic activities (e.g., neutralization of endotoxin and anti-biofilm action) that help to protect vertebrates, invertebrates and plants from invading pathogens. While the emergence of multi-antibiotic resistant pathogens (and the desperate need to develop new anti-infectives) has been a recent force driving the field, interest in AMPs has an earlier origin in studies of how phagocytes kill bacteria by oxygen-independent processes. AMPs responsible for such killing of microbes by rabbit and human neutrophils were later purified by Ganz, Selsted and Lehrer, which they termed defensins; at the time of this writing, literally thousands of defensin-based publications can be found in the scientific literature! The initial reports on defensins and the earlier report by Boman’s group on the purification and action of an insect AMP represented a historical and defining point for the AMP field as they, in hindsight, demanded the recognition of AMP research as a unique discipline that has important linkages to other important fields of medicine, especially those of microbiology, infectious diseases and immunology. On a personal note, I remember conferences on phagocytes and host defense in the early 1980s where the topic of AMPs was relegated to one short session in a five day period! Now, we have hundreds of international “AMPologists” with expertise in chemistry, biochemistry, molecular and structural biology, cell biology, microbiology, pharmacology, or medicine who have built their research careers around AMPs and can now attend international conferences dedicated to advances in AMP research.

Brain-immune interactions in health and disease

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195145 Year: Pages: 109 DOI: 10.3389/978-2-88919-514-5 Language: English
Publisher: Frontiers Media SA
Subject: Internal medicine --- Medicine (General) --- Neurology --- Science (General)
Added to DOAB on : 2015-12-10 11:59:06
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Brain-immune interactions are essential to maintain health and their dysfunction contributes to diverse human diseases. Recent data show that haematopoietic processes and immune organs are under central autonomic control. Deficient regulation of inflammatory events contributes to brain diseases, whereas acute or chronic brain injury is linked with the development of systemic inflammatory conditions or immunosuppression. At present, common disorders with high socio-economic burden such as cancer, cardiovascular-, neuroinflammatory- and neurodegenerative diseases, asthma, allergies, autism, psychiatric conditions and sepsis are believed to be influenced, at least in part, by the dysfunction of brain-immune communication. Since the median age of the world's population is increasing rapidly, it is expected that the burden of common non-communicable diseases will further increase, which represents a huge challenge to the health care systems worldwide. Thus, there is an increasing demand to understand and treat complex diseases, many of which are age-related, and this is not possible unless the fine-tuned communication between large systems -such as the nervous and the immune system- is comprehensively understood. Although it is impossible to cover all areas of relevant research in this field, papers in this eBook give some insight to a few important aspects of brain-immune interactions and their contribution to disease. We hope that this collection could stimulate further relevant research and facilitate discussions to support the understanding of the highly complex interactions between the immune system and the brain in health and disease.

Diverse functions of mucosal resident memory T cells

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195398 Year: Pages: 86 DOI: 10.3389/978-2-88919-539-8 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-01-19 14:05:46
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Early studies recognized the unique phenotype and attributes of T cells found in mucosal tissues, such as the intestines, skin, lung and female reproductive tract. This special topic issue will cover many aspects of mucosal-resident T cell biology during infection and disease and is dedicated to Leo Lefrancois, a pioneer in this field who recently passed away. A major proportion of these mucosal T cells are memory T cells, now recognized as a major constituent of memory T cells referred to as tissue-resident memory T cells. Unlike central and effector memory T cell subsets, tissue-resident memory T cells exhibit tissue specificity with minimal systemic migration. Nonetheless, tissue-resident memory T cells share a similar origin and display some overlapping phenotypes with their other memory T cell counterparts. Articles in this issue will describe the different types of memory T cells residing in mucosal tissues, their origins and functions as well as how they vary among discrete mucosal sites. Manuscripts will consider the unique physiological environments and cellular constituents which facilitate tissue residency while preserving tissue function. Additionally, there will be descriptions of the various mechanisms responsible for the migration and segregation of tissue resident memory CD8 T cells from the peripheral T cell pool. Although the mechanisms facilitating the sequestration of tissue-resident memory T cells within a respective tissue has not well characterized, various theories will also be discussed. Lastly, how these T cells contribute to immunity to pathogens, cancer, and autoimmunity and could be modified through vaccination or therapeutic intervention will be described. As mucosal tissues are the major portals of pathogen entry and frequent transformation, the activities and persistence of tissue resident memory T cells is crucial for mediating protection at these sites.

30 years old: O-GlcNAc Reaches Age of Reason - Regulation of Cell Signaling and Metabolism by O-GlcNAcylation

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195916 Year: Pages: 113 DOI: 10.3389/978-2-88919-591-6 Language: English
Publisher: Frontiers Media SA
Subject: Internal medicine --- Medicine (General)
Added to DOAB on : 2016-03-10 08:14:32
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Hundreds post-translational modifications (PTM) were characterized among which a large variety of glycosylations including O-GlcNAcylation. Since its discovery, O-GlcNAcylation has emerged as an unavoidable PTM widespread in the living beings including animal and plant cells, protists, bacteria and viruses. In opposition to N- and O-glycosylations, O-GlcNAcylation only consists in the transfer of a single N-acetylglucosamine moiety through a beta-linkage onto serine and threonine residues of proteins confined within the cytosol, the nucleus and the mitochondria. The O-GlcNAc group is provided by UDP-GlcNAc, the end-product of the hexosamine biosynthetic pathway located at the crossroad of cell metabolisms making O-GlcNAcylation a PTM which level tightly reflects nutritional status; therefore regulation of cell homeostasis should be intimately correlated to lifestyle and environment. Like phosphorylation, with which it can compete, O-GlcNAcylation is reversible. This versatility is managed by OGT (O-GlcNAc transferase) that transfers the GlcNAc group and OGA (O-GlcNAcase) that removes it. Also, like its unsweetened counterpart, O-GlcNAcylation controls fundamental processes, e.g. protein fate, chromatin topology, DNA demethylation and, as recently revealed, circadian clock. Deregulation of O-GlcNAc dynamism may be involved in the emergence of cancers, neuronal and metabolic disorders such as Alzheimer's or diabetes respectively. This Research Topic in Frontiers in Endocrinology is the opportunity to celebrate the thirtieth anniversary of the discovery of "O-GlcNAc" by Gerald W. Hart.

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194681 Year: Pages: 115 DOI: 10.3389/978-2-88919-468-1 Language: English
Publisher: Frontiers Media SA
Subject: Physiology --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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Pancreatic Cancer has been and still is one of the deadliest types of human malignancies. The annual mortality rates almost equal incidence rates making this disease virtually universally fatal. The 5-year survival of patients with pancreatic cancer is a dismal 5% or less. Therapeutic strategies are extremely limited with gemcitabine extending the survival by a disappointing few weeks. The failure of several randomized clinical trials in the past decade investigating the therapeutic efficacy of different mono- and combination therapies reflects our limited knowledge of pancreatic cancer biology. In addition, biomarkers for early detection are sorely missing. Several pancreatic cancer risk factors have been identified. Unfortunately, the underlying mechanisms linking these risk factors to cancer development are poorly understood. Well known possible and probable risk factors for the development of pancreatic cancer are age, smoking, chronic pancreatitis, obesity, and type-2 diabetes mellitus. Age is certainly of the most important risk factors as most cases of pancreatic cancer occur in the elderly population. Smoking ten cigarettes a day increases the risk by 2.6 times and smoking a pack per day increases it by 5 folds. Chronic pancreatitis increases the risk of pancreatic cancer by up to 13 times. Patients with hereditary forms of chronic pancreatitis have an even higher risk. Obesity, a growing global health problem, increases the risk of pancreatic cancer by about 1.5 fold. Type-2 diabetes mellitus is also associated with an increased risk of pancreatic cancer by at least two-fold. The more recent the onset of diabetes, the stronger the correlation with pancreatic cancer is. In addition, heavy alcohol drinking, a family history of the disease, male gender and African American ethnicity are other risk factors for pancreatic cancer. Pancreatic cancer is characterized by several genetic alterations including mutations in the Kras proto-oncogene and mutations in the tumor suppressor genes p53 and p16. While Kras mutations are currently thought as early events present in a certain percentage of pancreatic intraepithelial neoplasias (PanINs), known precursor lesions of pancreatic ductal adenocarcinomas, mutations in tumor suppressor genes, e.g. p53, seem to accumulate later during progression. In addition, several intracellular signaling pathways are amplified or enhanced, including the MAPK/ERK and PI3K/AKT signaling modules. Overall, these genetic alterations lead to enhanced and sustained proliferation, resistance to cell death, invasive and metastatic potential, and angiogenesis, all hallmarks of cancers. The scope of this Research Topic is to collect data and knowledge of how risk factors increase the risk of initiation/progression of pancreatic cancer. Of particular interest are potential underlying molecular mechanisms. Understanding the molecular mechanisms and driving signaling pathways will ultimately allow the development of targeted interventions to disrupt the risk factor-induced cancer development. This Research Topic is interested in a broad range of risk factors, including genetic and environmental, and welcomes original papers, mini and full reviews, and hypothesis papers. Manuscripts that address the effect of combination of risk factors on pancreatic cancer development and progression are of great interest as well.

Toll-Like Receptor Activation in Immunity vs. Tolerance

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196364 Year: Pages: 75 DOI: 10.3389/978-2-88919-636-4 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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The innate immune system has evolved means to recognize and react suitably to foreign entities such as infectious agents. In many cases infectious microorganisms threaten the integrity and function of the target organs or tissues; therefore, consequent to their recognition the immune system becomes activated to ensure their elimination. Toll-like receptors (TLR) constitute a family of receptors specialized in the recognition of molecular patterns typically associated with infectious agents. Different TLRs exist, each selective for molecular entities and motifs belonging to a specific pathogen group. Consequently, it is thought that the molecular nature of invading microorganisms activates specific TLRs to drive adequate anti-infectious immunity. For instance, nucleic acid-specific, intracellular receptors (TLR3/7/8/9) are used to sense viruses and drive antiviral immunity, while other receptors (such as TLR2 and TLR4) recognize and promote immunity against bacteria, yeast, and fungi. Yet, it is becoming evident that activation of TLR pathways trigger mechanisms that not only stimulate but also regulate the immune system. For instance, TLR stimulation by viruses will drive antiviral interferon but also immunoregulatory cytokine production and regulatory T cell activation. Stimulation of TLRs by bacteria or using molecular agonists can also trigger both immune stimulatory and regulatory responses. TLR stimulation by infectious agents likely serves to activate but also control anti-infectious immunity, for instance prevent potential immunopathological tissue damage which can be caused by acute immune defense mechanisms. Previous work by us and others has shown that the immunoregulatory arm of TLR stimulation can additionally help control autoreactive processes in autoimmune disease. Hence, it is becoming established that gut commensals, which also play a crucial part in the control of autoimmune disease, establish immune regulatory mechanisms through activation of particular TLRs. In sum, it appears that TLRs are key immune players that not only stimulate but also regulate immune processes in health and disease. In this Research Topic, we wish to review the dual role of TLRs as activators and regulators of immune responses. We aim to motivate data-driven opinions as to the importance of context of TLR agonism for determining immune activation vs. regulation. The presentation of ongoing original works, as well as data and opinions around other innate immune receptors pertaining to this topic, are also encouraged.

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