Showing papers in "Clinical & Developmental Immunology in 2016"

An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment

Abstract: Inflamm-aging is a challenging and promising new branch of aging-related research fields that includes areas such as immunosenescence. Increasing evidence indicates that inflamm-aging is intensively associated with many aging diseases, such as Alzheimer's disease, atherosclerosis, heart disease, type II diabetes, and cancer. Mounting studies have focused on the role of inflamm-aging in disease progression and many advances have been made in the last decade. However, the underlying mechanisms by which inflamm-aging affects pathological changes and disease development are still unclear. Here, we review studies of inflamm-aging that explore the concept, pathological features, mechanisms, intervention, and the therapeutic strategies of inflamm-aging in disease progression.

Sirtuins Link Inflammation and Metabolism.

Abstract: Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1-7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to "defend and mend" against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to "defend" against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to "mend," leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis.

Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance

Abstract: Neutrophils (also named polymorphonuclear leukocytes or PMN) are essential components of the immune system, rapidly recruited to sites of inflammation, providing the first line of defense against invading pathogens. Since neutrophils can also cause tissue damage, their fine-tuned regulation at the inflammatory site is required for proper resolution of inflammation. Annexin A1 (AnxA1), also known as lipocortin-1, is an endogenous glucocorticoid-regulated protein, which is able to counterregulate the inflammatory events restoring homeostasis. AnxA1 and its mimetic peptides inhibit neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. AnxA1 also promotes monocyte recruitment and clearance of apoptotic leukocytes by macrophages. More recently, some evidence has suggested the ability of AnxA1 to induce macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. The combination of these mechanisms results in an effective resolution of inflammation, pointing to AnxA1 as a promising tool for the development of new therapeutic strategies to treat inflammatory diseases.

Adjuvants: Classification, Modus Operandi, and Licensing

Abstract: Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations.

An Introduction to B-Cell Epitope Mapping and In Silico Epitope Prediction

Abstract: Identification of B-cell epitopes is a fundamental step for development of epitope-based vaccines, therapeutic antibodies, and diagnostic tools. Epitope-based antibodies are currently the most promising class of biopharmaceuticals. In the last decade, in-depth in silico analysis and categorization of the experimentally identified epitopes stimulated development of algorithms for epitope prediction. Recently, various in silico tools are employed in attempts to predict B-cell epitopes based on sequence and/or structural data. The main objective of epitope identification is to replace an antigen in the immunization, antibody production, and serodiagnosis. The accurate identification of B-cell epitopes still presents major challenges for immunologists. Advances in B-cell epitope mapping and computational prediction have yielded molecular insights into the process of biorecognition and formation of antigen-antibody complex, which may help to localize B-cell epitopes more precisely. In this paper, we have comprehensively reviewed state-of-the-art experimental methods for B-cell epitope identification, existing databases for epitopes, and novel in silico resources and prediction tools available online. We have also elaborated new trends in the antibody-based epitope prediction. The aim of this review is to assist researchers in identification of B-cell epitopes.

Roles of Zinc Signaling in the Immune System

Abstract: Zinc (Zn) is an essential micronutrient for basic cell activities such as cell growth, differentiation, and survival Zn deficiency depresses both innate and adaptive immune responses However, the precise physiological mechanisms of the Zn-mediated regulation of the immune system have been largely unclear Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the transport, distribution, and storage of Zn There is growing evidence that Zn behaves like a signaling molecule, facilitating the transduction of a variety of signaling cascades in response to extracellular stimuli In this review, we highlight the emerging functional roles of Zn and Zn transporters in immunity, focusing on how crosstalk between Zn and immune-related signaling guides the normal development and function of immune cells

Effector, Memory, and Dysfunctional CD8+ T Cell Fates in the Antitumor Immune Response

Abstract: The adaptive immune system plays a pivotal role in the host's ability to mount an effective, antigen-specific immune response against tumors. CD8+ tumor-infiltrating lymphocytes (TILs) mediate tumor rejection through recognition of tumor antigens and direct killing of transformed cells. In growing tumors, TILs are often functionally impaired as a result of interaction with, or signals from, transformed cells and the tumor microenvironment. These interactions and signals can lead to transcriptional, functional, and phenotypic changes in TILs that diminish the host's ability to eradicate the tumor. In addition to effector and memory CD8+ T cells, populations described as exhausted, anergic, senescent, and regulatory CD8+ T cells have been observed in clinical and basic studies of antitumor immune responses. In the context of antitumor immunity, these CD8+ T cell subsets remain poorly characterized in terms of fate-specific biomarkers and transcription factor profiles. Here we discuss the current characterization of CD8+ T cell fates in antitumor immune responses and discuss recent insights into how signals in the tumor microenvironment influence TIL transcriptional networks to promote CD8+ T cell dysfunction.

Dengue Fever: Causes, Complications, and Vaccine Strategies

Abstract: Dengue is a highly endemic infectious disease of the tropical countries and is rapidly becoming a global burden. It is caused by any of the 4 serotypes of dengue virus and is transmitted within humans through female Aedes mosquitoes. Dengue disease varies from mild fever to severe conditions of dengue hemorrhagic fever and shock syndrome. Globalization, increased air travel, and unplanned urbanization have led to increase in the rate of infection and helped dengue to expand its geographic and demographic distribution. Dengue vaccine development has been a challenging task due to the existence of four antigenically distinct dengue virus serotypes, each capable of eliciting cross-reactive and disease-enhancing antibody response against the remaining three serotypes. Recently, Sanofi Pasteur's chimeric live-attenuated dengue vaccine candidate has been approved in Mexico, Brazil, and Philippines for usage in adults between 9 and 45 years of age. The impact of its limited application to the public health system needs to be evaluated. Simultaneously, the restricted application of this vaccine candidate warrants continued efforts in developing a dengue vaccine candidate which is additionally efficacious for infants and naive individuals. In this context, alternative strategies of developing a designed vaccine candidate which does not allow production of enhancing antibodies should be explored, as it may expand the umbrella of efficacy to include infants and naive individuals.

Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications.

Abstract: Today, potential immunogenicity can be better evaluated during the drug development process, and we have rational approaches to manage the clinical consequences of immunogenicity. The focus of the scientific community should be on developing sensitive diagnostics that can predict immunogenicity-mediated adverse events in the small fraction of subjects that develop clinically relevant anti-drug antibodies. Here, we discuss the causes of immunogenicity which could be product-related (inherent property of the product or might be picked up during the manufacturing process), patient-related (genetic profile or eating habits), or linked to the route of administration. We describe various posttranslational modifications (PTMs) and how they may influence immunogenicity. Over the last three decades, we have significantly improved our understanding about the types of PTMs of biotherapeutic proteins and their association with immunogenicity. It is also now clear that all PTMs do not lead to clinical immunogenicity. We also discuss the mechanisms of immunogenicity (which include T cell-dependent and T cell-independent responses) and immunological tolerance. We further elaborate on the management of immunogenicity in preclinical and clinical setting and the unique challenges raised by biosimilars, which may have different immunogenic potential from their parent biotherapeutics.

Comparative In Vitro Immune Stimulation Analysis of Primary Human B Cells and B Cell Lines.

Abstract: B cell specific immunomodulatory drugs still remain an unmet medical need. Utilisation of validated simplified in vitro models would allow readily obtaining new insights in the complexity of B cell regulation. For this purpose we investigated which human B lymphocyte stimulation assays may be ideally suited to investigate new B lymphocyte immunosuppressants. Primary polyclonal human B cells underwent in vitro stimulation and their proliferation, production of immunoglobulins (Igs) and of cytokines, and expression of cell surface molecules were analysed using various stimuli. ODN2006, a toll-like receptor 9 (TLR9) agonist, was the most potent general B cell stimulus. Subsequently, we investigated on which human B cell lines ODN2006 evoked the broadest immunostimulatory effects. The Namalwa cell line proved to be the most responsive upon TLR9 stimulation and hence may serve as a relevant, homogeneous, and stable B cell model in an in vitro phenotypic assay for the discovery of new targets and inhibitors of the B cell activation processes. As for the read-out for such screening assay, it is proposed that the expression of activation and costimulatory surface markers reliably reflects B lymphocyte activation.

The Immune System in Cancer Pathogenesis: Potential Therapeutic Approaches.

Abstract: Interplay among immune activation and cancer pathogenesis provides the framework for a novel subspecialty known as immunooncology. In the rapidly evolving field of immunooncology, understanding the tumor-specific immune response enhances understanding of cancer resistance. This review highlights the fundamentals of incorporating precision medicine to discover new immune biomarkers and predictive signatures. Using a personalized approach may have a significant, positive impact on the use of oncolytics to better guide safer and more effective therapies.

CAR T Cell Therapy: A Game Changer in Cancer Treatment

Abstract: The development of novel targeted therapies with acceptable safety profiles is critical to successful cancer outcomes with better survival rates. Immunotherapy offers promising opportunities with the potential to induce sustained remissions in patients with refractory disease. Recent dramatic clinical responses in trials with gene modified T cells expressing chimeric antigen receptors (CARs) in B-cell malignancies have generated great enthusiasm. This therapy might pave the way for a potential paradigm shift in the way we treat refractory or relapsed cancers. CARs are genetically engineered receptors that combine the specific binding domains from a tumor targeting antibody with T cell signaling domains to allow specifically targeted antibody redirected T cell activation. Despite current successes in hematological cancers, we are only in the beginning of exploring the powerful potential of CAR redirected T cells in the control and elimination of resistant, metastatic, or recurrent nonhematological cancers. This review discusses the application of the CAR T cell therapy, its challenges, and strategies for successful clinical and commercial translation.

Neutrophils: Their Role in Innate and Adaptive Immunity

Abstract: Polymorphonuclear neutrophils (PMNs) are the most abundant leukocytes in the blood and constitute the first line of host defense against numerous infectious pathogens, including bacteria, fungi, and protozoa. Neutrophils are the first leukocytes to migrate from the blood to injured or infected sites for killing pathogens and removing cellular debris. Neutrophils migrate to sites of inflammation and infection where they recognize and phagocytose invading microorganisms, in order to kill them via different cytotoxic mechanisms. This process involves molecular mechanisms that coordinate cell polarization, delivery of receptors, and activation of integrins at the leading edge of neutrophils migrating toward chemoattractants. Once at sites of infection, neutrophils actively phagocytose microorganisms or form neutrophil extracellular traps (NETs) to trap and kill pathogens. Association of the nicotinamide adenine dinucleotide phosphate (NADPH) reduced oxidase complex at the phagosomal membrane for the production of reactive oxygen species (ROS) and delivery of proteolytic enzymes into the phagosome initiate pathogen killing and removal. In recent years, it has become evident that neutrophils not only have a fundamental role in the acute phase of inflammation when they actively eliminate pathogens, but also are capable of modifying the overall immune response. Neutrophils can do this by exchanging information with macrophages, dendritic cells, and other cells of the adaptive immune system through either soluble mediators or direct cell-cell contact. To illuminate the complex role of neutrophils in infection, inflammation, and immunity, this special issue has gathered original and review articles that will help us expand our knowledge on neutrophil biology. As stated before, any neutrophil response begins with migration of these leukocytes to the site of infection or inflammation. Chemotaxis, the directional movement of the cell guided by extracellular chemoattractant gradients, plays an essential role in the recruitment of neutrophils to sites of inflammation. Chemotaxis is mediated by G protein-coupled receptor (GPCR) signaling pathway. The article by X. Xu and T. Jin describes the novel functions of the PLC/PKC/PKD signaling axis in GPCR-mediated chemotaxis of neutrophils. Similarly, the review by J. Gamara et al. explains how the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) participate in GPCR signaling cascades regulating several neutrophil functional responses. The various cell responses to different chemoattractants are highlighted by the studies of R. Vaivoda et al. and M. A. Hidalgo et al. R. Vaivoda et al. describe how the deficiency of CYP4F18, an enzyme that catalyzes hydroxylation of leukotriene B4 (LTB4), does not alter the chemotactic response to LTB4 but causes a twofold increase response to complement component C5a. M. A. Hidalgo et al. describe that although N-formyl-methionyl-leucyl-phenylalanine (fMLF) and Platelet Activating Factor (PAF) induce similar intracellular signaling profiles, only fMLF induces interleukin-8 (IL-8) release and NADPH oxidase activity in neutrophils. Several microbicidal functions of neutrophils involve the activation of the NADPH oxidase complex for production of reactive oxygen species (ROS) to mediate pathogen killing. The interesting review by R. C. Allen describes the principles of particle physics and quantum mechanics to develop a fundamental explanation of neutrophil microbicidal metabolism based on ROS atomic properties. Myeloperoxidase, the most abundant neutrophil-granule protein, is known to have potent microbicidal properties. But, recently it has become apparent that myeloperoxidase also participates in regulating adaptive immune responses. The review by D. Odobasic et al. presents an overview on how this enzyme has key roles in various functions of neutrophils in innate and adaptive immunity. When neutrophils cannot kill microorganisms by the classical phagocytosis or degranulation mechanisms, they can also form neutrophil extracellular traps (NETs) to kill microbes. NETs are fibers composed of chromatin and neutrophil-granule proteins and are induced by several pathogens and also some pharmacological stimuli. Antigen-antibody complexes can also induce NET formation. The paper by O. R. Aleman et al. explores direct stimulation of individual Fcγ receptors to induce NET formation and finds that only FcγRIIIb cross-linking induced NET formation in a NADPH oxidase-, PKC-, and ERK-dependent fashion. An intriguing observation on the microbicidal function of neutrophils of older women is reported by J. Bartholomeu-Neto et al. They find that phagocytic and oxidative activities of neutrophils of healthy older women that exercise regularly are higher than those of sedentary older women. The physical condition of each individual was a significant predictor of phagocytosis potential. Clearly, regular exercise contributes to a better innate immune system. However, no mechanism for this beneficial effect is known. This should be an interesting line of future neutrophil research. Neutrophils are potent regulators of inflammation via the release of proinflammatory factors and several cytokines. The paper by M. R. Tardif et al. describes an alternative secretion pathway in neutrophils for the release of the S100A8/A9 (calprotectin) and S100A12, proinflammatory mediators. The secretion of these cytoplasmic proteins was dependent on the production of ROS and required K+ exchanges through ATP-sensitive K+ channels. Because neutrophils can also cause tissue damage, their downregulation at the inflammatory site is required for proper resolution of inflammation. The paper by M. A. Sugimoto et al. describes how Annexin A1, an endogenous glucocorticoid-regulated protein, inhibits neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. Annexin A1 also induced macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. Similarly, the paper by M. Cohen-Mazor et al. describes how heparin binds to activated neutrophils and induces apoptosis. These results provide an explanation for the long-known anti-inflammatory effects of heparin. Neutrophils seem to have dual roles in promoting and controlling inflammation. The mechanisms that control the final outcome are not completely described, but these opposite functions must be tightly balanced. During sepsis, neutrophils are responsible for both the release of cytokines and the phagocytosis of pathogens. But, in SIRS (systemic inflammatory response syndrome), neutrophils contribute to maintaining of a whole-body inflammatory state. In the review by H. Fang et al., the role of neutrophils in these two clinical conditions is described and the therapeutic effect of G-CSF in sepsis is discussed in relation to its function of regulating neutrophil blood levels. Moreover, because neutrophil-derived products can regulate the action of other immune cells and can contribute to the development and chronicity of inflammatory diseases, I. Naegelen et al. propose in their article an original strategy based on linear fitting, to analyze the link between cytokine release and degranulation time. This method could find correlations between granule proteins and cytokines secreted to the inflammatory site. The idea is to be able in the future to predict the type of inflammatory response that neutrophils could induce under certain conditions. In addition, C. F. M. Morris et al. describe in their review how two apparent opposite models of inflammation may be compatible in the outcome of inflammation. The two-hit model states that a first injury (i.e., hit) can serve as a priming event which sequential insults can build on, culminating in a disproportioned inflammatory response to injury. On the other hand, the ischemic preconditioning (IPC) model states that a mild ischemic event, either remote or local, can be protective and can actually attenuate the inflammatory response to the following insults. This article tries to reconcile both models and presents evidence that each of them brings its own unique perspective onto the biology of inflammation. Finally, the dual role of neutrophil function during inflammation is emphasized again in the review by E. Uribe-Querol et al., where the protumor or antitumor character of the tumor-associated neutrophils (TANs) is revised. Recent findings on the mechanisms for neutrophil recruitment to the tumor, for neutrophils supporting tumor progression, and for neutrophil activation to enhance their antitumor functions are presented. These articles together represent the fascinating flexible functions of neutrophils not only in fighting infections, but also in shaping the immune response and the consequences this may have to important health issues such as resolution of inflammation, autoimmunity, and cancer. Carlos Rosales Nicolas Demaurex Clifford A. Lowell Eileen Uribe-Querol

Neutrophil-Mediated Regulation of Innate and Adaptive Immunity: The Role of Myeloperoxidase

Abstract: Neutrophils are no longer seen as leukocytes with a sole function of being the essential first responders in the removal of pathogens at sites of infection. Being armed with numerous pro- and anti-inflammatory mediators, these phagocytes can also contribute to the development of various autoimmune diseases and can positively or negatively regulate the generation of adaptive immune responses. In this review, we will discuss how myeloperoxidase, the most abundant neutrophil granule protein, plays a key role in the various functions of neutrophils in innate and adaptive immunity.

Recent Advances of the NLRP3 Inflammasome in Central Nervous System Disorders

Abstract: Inflammasomes are multiprotein complexes that trigger the activation of caspases-1 and subsequently the maturation of proinflammatory cytokines interleukin-1β and interleukin-18. These cytokines play a critical role in mediating inflammation and innate immunity response. Among various inflammasome complexes, the NLRP3 inflammasome is the best characterized, which has been demonstrated as a crucial role in various diseases. Here, we review recently described mechanisms that are involved in the activation and regulation of NLRP3 inflammasome. In addition, we summarize the recent researches on the role of NLRP3 inflammasome in central nervous system (CNS) diseases, including traumatic brain injury, ischemic stroke and hemorrhagic stroke, brain tumor, neurodegenerative diseases, and other CNS diseases. In conclusion, the NLRP3 inflammasome may be a promising therapeutic target for these CNS diseases.

Corrigendum to "New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy"

Abstract: The majority of basic and clinical studies have shown a protumor function of tumor-associated macrophages (TAMs), which represent a large proportion of matrix cells. TAMs promote tumorigenesis, and their number is related to the malignancy degree and poor prognosis of many kinds of tumors. Macrophage plasticity makes it possible to change the tumor microenvironment and remodel antitumor immunity during cancer immunotherapy. Increasing numbers of studies have revealed the effects of TAMs on the tumor microenvironment, for example, via promotion of tumor growth and tumorigenesis and through an increase in the number of cancer stem cells or via facilitation of angiogenesis, lymphangiogenesis, and metastasis. Investigators also proposed tumor-immunological treatments targeting TAMs by inhibiting TAM recruitment and differentiation, by regulating TAM polarization, and by blocking factors and pathways associated with the protumor function of TAMs. This comprehensive review presents recent research on TAMs in relation to prediction of poor outcomes, remodeling of the tumor immune microenvironment, and immunological targeted therapies.

Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases

Abstract: Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases.

Monocyte Heterogeneity: Consequences for Monocyte-Derived Immune Cells.

Abstract: Blood monocytes are precursors of dendritic cells, macrophages, and osteoclasts. They are a heterogeneous cell population with differences in size, phenotype, and function. Although monocytes maintain several tissue-specific populations of immune cells in homeostasis, their contribution to populations of dendritic cells, macrophages, and osteoclasts is significantly increased in inflammation. Identification of a growing number of functionally different subsets of cells within populations of monocyte-derived immune cells has recently put monocyte heterogeneity into sharp focus. Here, we summarize recent findings in monocyte heterogeneity and their differentiation into dendritic cells, macrophages, and osteoclasts. We also discuss these advances in the context of the formation of functionally different monocyte-derived subsets of dendritic cells, macrophages, and osteoclasts.

Recent Advances in Our Understanding of HLA-G Biology: Lessons from a Wide Spectrum of Human Diseases.

Abstract: HLA-G is a HLA-class Ib molecule with potent immunomodulatory activities, which is expressed in physiological conditions, where modulation of the immune response is required to avoid allograft recognition (i.e., maternal-fetal interface or transplanted patients). However, HLA-G can be expressed de novo at high levels in several pathological conditions, including solid and hematological tumors and during microbial or viral infections, leading to the impairment of the immune response against tumor cells or pathogens, respectively. On the other hand, the loss of HLA-G mediated control of the immune responses may lead to the onset of autoimmune/inflammatory diseases, caused by an uncontrolled activation of the immune effector cells. Here, we have reviewed novel findings on HLA-G functions in different physiological and pathological settings, which have been published in the last two years. These studies further confirmed the important role of this molecule in the modulation of the immune system.

Immunomodulatory Effects Mediated by Dopamine.

Abstract: Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.

How Neutrophil Extracellular Traps Become Visible

Abstract: Neutrophil extracellular traps (NETs) have been identified as a fundamental innate immune defense mechanism against different pathogens NETs are characterized as released nuclear DNA associated with histones and granule proteins, which form an extracellular web-like structure that is able to entrap and occasionally kill certain microbes Furthermore, NETs have been shown to contribute to several noninfectious disease conditions when released by activated neutrophils during inflammation The identification of NETs has mainly been succeeded by various microscopy techniques, for example, immunofluorescence microscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) Since the last years the development and improvement of new immunofluorescence-based techniques enabled optimized visualization and quantification of NETs On the one hand in vitro live-cell imaging led to profound new ideas about the mechanisms involved in the formation and functionality of NETs On the other hand different intravital, in vivo, and in situ microscopy techniques led to deeper insights into the role of NET formation during health and disease This paper presents an overview of the main used microscopy techniques to visualize NETs and describes their advantages as well as disadvantages

Posttranslational Modifications and the Immunogenicity of Biotherapeutics

Abstract: Whilst the amino acid sequence of a protein is determined by its gene sequence, the final structure and function are determined by posttranslational modifications (PTMs), including quality control (QC) in the endoplasmic reticulum (ER) and during passage through the Golgi apparatus. These processes are species and cell specific and challenge the biopharmaceutical industry when developing a production platform for the generation of recombinant biologic therapeutics. Proteins and glycoproteins are also subject to chemical modifications (CMs) both in vivo and in vitro. The individual is naturally tolerant to molecular forms of self-molecules but nonself variants can provoke an immune response with the generation of anti-drug antibodies (ADA); aggregated forms can exhibit enhanced immunogenicity and QC procedures are developed to avoid or remove them. Monoclonal antibody therapeutics (mAbs) are a special case because their purpose is to bind the target, with the formation of immune complexes (ICs), a particular form of aggregate. Such ICs may be removed by phagocytic cells that have antigen presenting capacity. These considerations may frustrate the possibility of ameliorating the immunogenicity of mAbs by rigorous exclusion of aggregates from drug product. Alternate strategies for inducing immunosuppression or tolerance are discussed.

Mucosal Vaccine Development Based on Liposome Technology

Abstract: Immune protection against infectious diseases is most effective if located at the portal of entry of the pathogen. Hence, there is an increasing demand for vaccine formulations that can induce strong protective immunity following oral, respiratory, or genital tract administration. At present, only few mucosal vaccines are found on the market, but recent technological advancements and a better understanding of the principles that govern priming of mucosal immune responses have contributed to a more optimistic view on the future of mucosal vaccines. Compared to live attenuated vaccines, subcomponent vaccines, most often protein-based, are considered safer, more stable, and less complicated to manufacture, but they require the addition of nontoxic and clinically safe adjuvants to be effective. In addition, another limiting factor is the large antigen dose that usually is required for mucosal vaccines. Therefore, the combination of mucosal adjuvants with the recent progress in nanoparticle technology provides an attractive solution to these problems. In particular, the liposome technology is ideal for combining protein antigen and adjuvant into an effective mucosal vaccine. Here, we describe and discuss recent progress in nanoparticle formulations using various types of liposomes that convey strong promise for the successful development of the next generation of mucosal vaccines.

Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation

Abstract: T regulatory cells play a key role in the control of the immune response, both in health and during illness. While the mechanisms through which T regulatory cells exert their function have been extensively described, their molecular effects on effector cells have received little attention. Thus, this revision is aimed at summarizing our current knowledge on those regulation mechanisms on the target cells from a molecular perspective.

T Helper Cell Subsets in Clinical Manifestations of Psoriasis.

Abstract: Psoriasis is a chronic inflammatory skin disease, which is associated with systemic inflammation and comorbidities, such as psoriatic arthritis and cardiovascular diseases. The autoimmune nature of psoriasis has been established only recently, conferring a central role to epidermal CD8 T cells recognizing self-epitopes in the initial phase of the disease. Different subsets of helper cells have also been reported as key players in the psoriasis pathogenesis. Here, we reviewed the knowledge on the role of each subset in the psoriatic cascade and in the different clinical manifestations of the disease. We will discuss the role of Th1 and Th17 cells in the initiation and in the amplification phase of cutaneous inflammation. Moreover, we will discuss the recently proposed role of tissue resident Th22 cells in disease memory in sites of recurrent psoriasis and the possible involvement of Th9 cells. Finally, we will discuss the hypothesis of a link between T helper cell subsets recirculating from the skin and the systemic manifestations of psoriasis.

Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

Abstract: The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases.

Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link

Abstract: Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.

Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes

Abstract: Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28− T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28− cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation.

IgE-Related Chronic Diseases and Anti-IgE-Based Treatments.

Abstract: IgE is an immunoglobulin that plays a central role in acute allergic reactions and chronic inflammatory allergic diseases. The development of a drug able to neutralize this antibody represents a breakthrough in the treatment of inflammatory pathologies with a probable allergic basis. This review focuses on IgE-related chronic diseases, such as allergic asthma and chronic urticaria (CU), and on the role of the anti-IgE monoclonal antibody, omalizumab, in their treatment. We also assess the off-label use of omalizumab for other pathologies associated with IgE and report the latest findings concerning this drug and other new related drugs. To date, omalizumab has only been approved for severe allergic asthma and unresponsive chronic urticaria treatments. In allergic asthma, omalizumab has demonstrated its efficacy in reducing the dose of inhaled corticosteroids required by patients, decreasing the number of asthma exacerbations, and limiting the effect on airway remodeling. In CU, omalizumab treatment rapidly improves symptoms and in some cases achieves complete disease remission. In systemic mastocytosis, omalizumab also improves symptoms and its prophylactic use to prevent anaphylactic reactions has also been discussed. In other pathologies such as atopic dermatitis, food allergy, allergic rhinitis, nasal polyposis, and keratoconjunctivitis, omalizumab significantly improves clinical manifestations. Omalizumab acts in two ways: by sequestering free IgE and by accelerating the dissociation of the IgE-Fce receptor I complex.

Differential Use of Human Neutrophil Fcγ Receptors for Inducing Neutrophil Extracellular Trap Formation.

Abstract: Neutrophils (PMN) are the most abundant leukocytes in the blood. PMN migrate from the circulation to sites of infection, where they are responsible for antimicrobial functions. PMN use phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to kill microbes. NETs are fibers composed of chromatin and neutrophil-granule proteins. Several pathogens, including bacteria, fungi, and parasites, and also some pharmacological stimuli such as phorbol 12-myristate 13-acetate (PMA) are efficient inducers of NETs. Antigen-antibody complexes are also capable of inducing NET formation. However the particular Fcγ receptor involved in triggering this function is a matter of controversy. In order to provide some insight into what Fcγ receptor is responsible for NET formation, each of the two human Fcγ receptors was stimulated individually by specific monoclonal antibodies and NET formation was evaluated. FcγRIIa cross-linking did not promote NET formation. Cross-linking other receptors such as integrins also did not promote NET formation. In contrast FcγRIIIb cross-linking induced NET formation similarly to PMA stimulation. NET formation was dependent on NADPH-oxidase, PKC, and ERK activation. These data show that cross-linking FcγRIIIb is responsible for NET formation by the human neutrophil.