Effects of the microwave radiation from the cellular phones on humans and animals

Biological effects of the mobile phone microwave radiation were shown to depend on many factors: the duration of the irradiation, individual characteristics of the CNS and immune systems, and others. The cellular phone microwave radiation can induce reversible unspecific adaptive responses if it is short and the organism is very radiosensitive. A long-term exposure (over one year) combined with the organism weakened immune system may produce a cumulative effect in the form of stress responses, various damages and, in some cases, even cancer. The ultimate result of the microwave exposure depends on the balance between induced damage and the organism reparative ability.     

In vivo flow cytometry: a horizon of opportunities

Flow cytometry (FCM) has been a fundamental tool of biological discovery for many years. Invasive extraction of cells from a living organism, however, may lead to changes in cell properties and prevents studying cells in their native environment. These problems can be overcome by use of in vivo FCM, which provides detection and imaging of circulating normal and abnormal cells directly in blood or lymph flow. The goal of this review is to provide a brief history, features, and challenges of this new generation of FCM methods and instruments. Spectrum of possibilities of in vivo FCM in biological science (e.g., cell metabolism, immune function, or apoptosis) and medical fields (e.g., cancer, infection, and cardiovascular disorder) including integrated photoacoustic-photothermal theranostics of circulating abnormal cells are discussed with focus on recent advances of this new platform.     

The intrinsic immunogenic properties of cancer cell lines,immunogenic cell death,and how these influence host antitumor immune responses

Modern cancer therapies often involve the combination of tumor-directed cytotoxic strategies and generation of a host antitumor immune response. The latter is unleashed by immunotherapies that activate the immune system generating a more immunostimulatory tumor microenvironment and a stronger tumor antigen-specific immune response. Studying the interaction between antitumor cytotoxic therapies, dying cancer cells, and the innate and adaptive immune system requires appropriate experimental tumor models in mice. In this review, we discuss the immunostimulatory and immunosuppressive properties of cancer cell lines commonly used in immunogenic cell death (ICD) studies being apoptosis or necroptosis. We will especially focus on the antigenic component of immunogenicity. While in several cancer cell lines the epitopes of endogenously expressed tumor antigens are known, these intrinsic epitopes are rarely determined in experimental apoptotic or necroptotic ICD settings. Instead by far the most ICD research studies investigate the antigenic response against exogenously expressed model antigens such as ovalbumin or retroviral epitopes (e.g., AH1). In this review, we will argue that the immune response against endogenous tumor antigens and the immunopeptidome profile of cancer cell lines affect the eventual biological readouts in the typical prophylactic tumor vaccination type of experiments used in ICD research, and we will propose additional methods involving immunopeptidome profiling, major histocompatibility complex molecule expression, and identification of tumor-infiltrating immune cells to document intrinsic immunogenicity following different cell death modalities.Subject terms: Cancer models, Antigen-presenting cells, Immune cell death     

Crosstalk between the circadian clock circuitry and the immune system

Various features, components, and functions of the immune system present daily variations. Immunocompetent cell counts and cytokine levels present variations according to the time of day and the sleep-wake cycle. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwork. The biological clocks intrinsic to immune cells and lymphoid organs, together with inputs from the central pacemaker of the suprachiasmatic nuclei via humoral and neural pathways, regulate the function of cells of the immune system, including their response to signals and their effector functions. Consequences of this include, for example, the daily variation in the response to an immune challenge (e.g., bacterial endotoxin injection) and the circadian control of allergic reactions. The circadian-immune connection is bidirectional, because in addition to this circadian control of immune functions, immune challenges and immune mediators (e.g., cytokines) were shown to have strong effects on circadian rhythms at the molecular, cellular, and behavioral levels. This tight crosstalk between the circadian and immune systems has wide-ranging implications for disease, as shown by the higher incidence of cancer and the exacerbation of autoimmune symptoms upon circadian disruption. (Author correspondence: g.mazzoccoli@operapadrepio.it)     

Energy metabolism and rheumatic diseases: from cell to organism

In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. In recent time many new insights have been gained into the control of the immune response through metabolic signals. Activation of immune cells as well as reduced nutrient supply and hypoxia in inflamed tissues cause stimulation of glycolysis and other cellular metabolic pathways. However, persistent cellular metabolic signals can promote ongoing chronic inflammation and loss of immune tolerance. On the organism level, the neuroendocrine immune response of the hypothalamic-pituitary adrenal axis and sympathetic nervous system, which is meant to overcome a transient inflammatory episode, can lead to metabolic disease sequelae if chronically activated. We conclude that, on cellular and organism levels, a prolonged energy appeal reaction is an important factor of chronic inflammatory disease etiology.     

A role for altered phagosome maturation in the long-term persistence of Helicobacter pylori infection

The vigorous host immune response that is mounted against Helicobacter pylori is unable to eliminate this pathogenic bacterium from its niche in the human gastric mucosa. This results in chronic inflammation, which can develop into gastric or duodenal ulcers in 10% of infected individuals and gastric cancer in 1% of infections. The determinants for these more severe pathologies include host (e.g., high IL-1β expression polymorphisms), bacterial [e.g., cytotoxicity-associated gene (cag) pathogenicity island], and environmental (e.g., dietary nitrites) factors. However, it is the failure of host immune effector cells to eliminate H. pylori that underlies its persistence and the subsequent H. pylori-associated disease. Here we discuss the mechanisms used by H. pylori to survive the host immune response and, in particular, the role played by altered phagosome maturation.     

Role of chemokines,innate and adaptive immunity

Polycystic Kidney Disease (PKD) triggers a robust immune system response including changes in both innate and adaptive immunity. These changes involve immune cells (e.g., macrophages and T cells) as well as cytokines and chemokines (e.g., MCP-1) that regulate the production, differentiation, homing, and various functions of these cells. This review is focused on the role of the immune system and its associated factors in the pathogenesis of PKDs as evidenced by data from cell-based systems, animal models, and PKD patients. It also highlights relevant pre-clinical and clinical studies that point to specific immune system components as promising candidates for the development of prognostic biomarkers and therapeutic strategies to improve PKD outcomes.     

Complement components and their autoantibodies

The purpose of the immune system is to defend the host from constantly changing microbial pathogens. Autoimmune diseases develop as a consequence of the production of antibodies and/or cells that react with self-antigens, and may recruit other effector mechanisms that result in tissue damage. Thus, in this context, autoimmunity represents an immune response to self-antigens that is sufficient to cause disease. This article is specifically devoted to autoantibodies directed against complement components.     

When T-helper cells don't help: immunopathology during concomitant infection

Disease directly caused by immune system action is known as immunopathology. Many factors may lead the immune system to cause rather than cure disease, and autoimmune, allergic, and infection-related immunopathological diseases affect millions of people worldwide. This review presents an analysis of T-helper cell mediated, infection-related immunopathology within the framework of evolutionary ecology. A proximate cause of infection-related immunopathology is an error in the type of T-helper response induced. Distinct subsets of T-helper cells enable different effector mechanisms and therefore work optimally against different types of parasites (e.g., extracellular versus intracellular parasites). Immune responses that cure rather than cause disease require that the T-helper subset be tailored to the parasite. It is thus critical for the immunophenotype to match the "environment" of the parasitic infection. As in other cases of adaptive plasticity, a mismatch between an organism's phenotype and the selective environment can decrease fitness. T-helper response induction may be confounded by coinfection of a single host by multiple parasite species. Because of normally adaptive feedback loops that lend to polarize T-helper responses, it can become impossible for the immune system to mount effective, conflicting responses concurrently. Immunophenotype-environment mismatches may thus be inevitable when simultaneous, conflicting immune responses are required. An ultimate cause of infection-related immunopathology in a multiparasite selection regime is the T-helper response polarization that can propagate response errors and constrain the ability of the immune system to resolve conflicting response requirements. A case study is used to illustrate how coinfection can exacerbate immunopathology and to frame testable predictions about optimal responses to coinfection (e.g., is the observed joint response to coinfection accurately predicted by the average of the component single-infection optimal responses, where the single-infection optima are weighted by the contribution of each to fitness). The case study includes immunological and pathological data from mice infected by Schistosoma mansoni alone and by S. mansoni in combination with Toxoplasma gondii. Such data can inform hypothesis tests of evolutionary ecological principles, and ecological analysis can in turn clarify assumptions about responses to coinfection for a greater understanding of the immune system. The synthesis of evolutionary ecology and immunology could therefore be of mutual benefit to the two disciplines.     

A hassle a day may keep the pathogens away: The fight-or-flight stress response and the augmentation of immune function

Stress is known to suppress or dysregulate immune function and increase susceptibility to disease. Paradoxically, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that galvanizes the neuroendocrine, cardiovascular, and musculoskeletal systems into action to enable survival. Therefore, it is unlikely that short-term stress would suppress immune function at a time when it may be critically required for survival (e.g., in response to wounding and infection by a predator or aggressor). In fact, studies have shown that stress can enhance immune function under certain conditions. Several factors influence the direction (enhancing versus suppressive) of the effects of stress on immune function: (1) Duration: acute or short-term stress experienced at the time of activation of an immune response enhances innate and adaptive immune responses. Chronic or long-term stress can suppress or dysregulate immune function. (2) Leukocyte distribution: compartments (e.g., skin), that are enriched with immune cells during acute stress show immuno-enhancement, while those that are depleted of leukocytes (e.g., blood), show immuno-suppression. (3) The differential effects of physiologic versus pharmacologic stress hormones: Endogenous hormones in physiological concentrations can have immuno-enhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immuno-suppressive. (4) Timing: immuno-enhancement is observed when acute stress is experienced during the early stages of an immune response while immuno-suppression may be observed at late stages. The type of immune response (protective, regulatory/inhibitory, or pathological) that is affected determines whether the effects of stress are ultimately beneficial or harmful for the organism. Arguments based on conservation of energy have been invoked to explain potential adaptive benefits of stress-induced immuno-suppression, but generally do not hold true because most mechanisms for immuno-suppression expend, rather than conserve, energy. We propose that it is important to study, and if possible, to clinically harness, the immuno-enhancing effects of the acute stress response that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve.     

Necrosis: a specific form of programmed cell death?

For a long time necrosis was considered as an alternative to programmed cell death, apoptosis. Indeed, necrosis has distinct morphological features and it is accompanied by rapid permeabilization of plasma membrane. However, recent data indicate that, in contrast to necrosis caused by very extreme conditions, there are many examples when this form of cell death may be a normal physiological and regulated (programmed) event. Various stimuli (e.g., cytokines, ischemia, heat, irradiation, pathogens) can cause both apoptosis and necrosis in the same cell population. Furthermore, signaling pathways, such as death receptors, kinase cascades, and mitochondria, participate in both processes, and by modulating these pathways, it is possible to switch between apoptosis and necrosis. Moreover, antiapoptotic mechanisms (e.g., Bcl-2/Bcl-x proteins, heat shock proteins) are equally effective in protection against apoptosis and necrosis. Therefore, necrosis, along with apoptosis, appears to be a specific form of execution phase of programmed cell death, and there are several examples of necrosis during embryogenesis, a normal tissue renewal, and immune response. However, the consequences of necrotic and apoptotic cell death for a whole organism are quite different. In the case of necrosis, cytosolic constituents that spill into extracellular space through damaged plasma membrane may provoke inflammatory response; during apoptosis these products are safely isolated by membranes and then are consumed by macrophages. The inflammatory response caused by necrosis, however, may have obvious adaptive significance (i.e., emergence of a strong immune response) under some pathological conditions (such as cancer and infection). On the other hand, disturbance of a fine balance between necrosis and apoptosis may be a key element in development of some diseases.     

禽坦布苏病毒诱导的宿主免疫应答

禽坦布苏病毒(Avian Tembusu virus,ATMUV)是近年来在我国新发现的一种病毒,可感染多种蛋禽,感染动物临床特征为采食量下降,产蛋量骤减,甚至停产,感染后期呈神经症状,如腿和翅膀麻痹、共济失调等。ATMUV在我国多个省市地区流行,给我国甚至世界养禽业带来严重影响。固有免疫是机体抵抗病原感染的第一道重要防线,是机体与生俱来的抵御病原微生物的能力。适应性免疫是机体免疫系统在抗原刺激下产生特异性抗体及免疫效应细胞的过程,以建立针对某种病原微生物的抵抗力,是机体免疫系统的重要部分。本文将从禽坦布苏病毒诱导宿主固有免疫应答和适应性免疫应答两方面进行综述。     

Metformin rescues cell surface major histocompatibility complex class I (MHC-I) deficiency caused by oncogenic transformation

Active avoidance by tumor cells from attack and elimination by immune cells is an emerging cancer hallmark that is achieved primarily through decreasing the levels of major histocompatibility complex class I (MHC-I) at the cancer cells’ surface. Deficiencies in MHC-I antigen-restricted immunosurveillance may be intertwined with an altered, Warburg-like cancer cell-intrinsic metabolism, another emerging hallmark of cancer that involves a switch from mitochondrial respiration to glycolysis to efficiently support large-scale biosynthetic programs that are required for active cell proliferation. We recently envisioned that intervention strategies aimed at reversing the bioenergetic signature of cancer cells (e.g., the antidiabetic biguanide metformin) should correct oncogene (e.g., HER2)-driven MHC-I defects, thus preventing immune escape of oncogene transformants. First, we explored how metformin treatment impacted mitochondrial biogenesis in cultured breast cancer cells overexpressing the membrane tyrosine kinase receptor HER2, the best-characterized downregulator of MHC-I. Metformin exposure was found to dose-dependently increase the expression levels of cytochrome c oxidase I and mitochondrial succinate dehydrogenase, which are encoded by mitochondrial and nuclear DNA, respectively. Second, we explored whether metformin-enhanced mitochondrial biogenesis might significantly alter the MHC-I status in breast carcinoma cells. MHC-I expression, as assessed by flow cytometry using an anti-HLA-ABC monoclonal antibody, was fully restored (up to ~25-fold upregulation) in MHC-I-negative HER2 gene-amplified carcinoma cells. These findings may help delineate a previously unrecognized mechanism through which metformin (and metformin-like drugs) may enable a cancer patient’s own immune system to mount an efficient anti-metastasis response that can prevent or delay disease recurrence. Restored antigenicity and immunogenicity of tumor cells may represent a previously unrecognized primary mode of action underlying the cancer-preventive effects of metformin.     

An overview of cancer immunotherapy

The survival of patients with cancer has improved steadily but incrementally over the last century, with the advent of effective anticancer treatments such as chemotherapy and radiotherapy. However, the majority of patients with metastatic disease will not be cured by these measures and will eventually die of their disease. New and more effective methods of treating these patients are required urgently. The immune system is a potent force for rejecting transplanted organs or microbial pathogens, but effective spontaneous immunologically induced cancer remissions are very rare. In recent years, much has been discovered about the mechanisms by which the immune system recognizes and responds to cancers. The specific antigens involved have now been defined in many cases. Improved adjuvants are available. Means by which cancer cells overcome immunological attack can be exploited and overcome. Most importantly, the immunological control mechanisms responsible for initiating and maintaining an effective immune response are now much better understood. It is now possible to manipulate immunological effector cells or antigen-presenting cells ex vivo in order to induce an effective antitumour response. At the same time, it is possible to recruit other aspects of the immune system, both specific (e.g. antibody responses) and innate (natural killer cells and granulocytes).     

Radiation-hormesis phenotypes,the related mechanisms and implications for disease prevention and therapy

Humans are continuously exposed to ionizing radiation throughout life from natural sources that include cosmic, solar, and terrestrial. Much harsher natural radiation and chemical environments existed during our planet’s early years. Mammals survived the harsher environments via evolutionarily-conserved gifts a continuously evolving system of stress-induced natural protective measures (i.e., activated natural protection [ANP]). The current protective system is differentially activated by stochastic (i.e., variable) low-radiation-dose thresholds and when optimally activated in mammals includes antioxidants, DNA damage repair, p53-related apoptosis of severely-damaged cells, reactive-oxygen-species (ROS)/reactive-nitrogen-species (RNS)- and cytokine-regulated auxiliary apoptosis that selectively removes aberrant cells (e.g., precancerous cells), suppression of disease promoting inflammation, and immunity against cancer cells. The intercellular-signaling-based protective system is regulated at least in part via epigenetic reprogramming of adaptive-response genes. When the system is optimally activated, it protects against cancer and some other diseases, thereby leading to hormetic phenotypes (e.g., reduced disease incidence to below the baseline level; reduced pain from inflammation-related problems). Here, some expressed radiation hormesis phenotypes and related mechanisms are discussed along with their implications for disease prevention and therapy.     

Tissue engineering tools for modulation of the immune response

Tissue engineering scaffolds have emerged as a powerful tool within regenerative medicine. These materials are being designed to create environments that promote regeneration through a combination of: (i) scaffold architecture, (ii) the use of scaffolds as vehicles for transplanting progenitor cells, and/or (iii) localized delivery of inductive factors or genes encoding for these inductive factors. This review describes the techniques associated with each of these components. Additionally, the immune response is increasingly recognized as a factor influencing regeneration. The immune reaction to an implant begins with an acute response to the injury and innate recognition of foreign materials, with the subsequent chronic immune response involving specific recognition of antigens (e.g., transplanted cells) by the adaptive immune response, which can eventually lead to rejection of the implant. Thus, we also describe the impact of each component on the immune response, and strategies (e.g., material design, anti-inflammatory cytokine delivery, and immune cell recruitment/transplantation) to modulate, yet not eliminate, the local immune response in order to promote regeneration, which represents another important tool for regenerative medicine.     

Cancer as an emergent phenomenon in systems radiation biology

Radiation-induced DNA damage elicits dramatic cell signaling transitions, some of which are directed towards deciding the fate of that particular cell, while others lead to signaling to other cells. Each irradiated cell type and tissue has a characteristic pattern of radiation-induced gene expression, distinct from that of the unirradiated tissue and different from that of other irradiated tissues. It is the sum of such events, highly modulated by genotype that sometimes leads to cancer. The challenge is to determine as to which of these phenomena have persistent effect that should be incorporated into models of how radiation increases the risk of developing cancer. The application of systems biology to radiation effects may help to identify which biological responses are significant players in radiation carcinogenesis. In contrast to the radiation biology paradigm that focuses on genomic changes, systems biology seeks to integrate responses at multiple scales (e.g. molecular, cellular, organ, and organism). A key property of a system is that some phenomenon emerges as a property of the system rather than of the parts. Here, the idea that cancer in an organism can be considered as an emergent phenomenon of a perturbed system is discussed. Given the current research goal to determine the consequences of high and low radiation exposures, broadening the scope of radiation studies to include systems biology concepts should benefit risk modeling of radiation carcinogenesis. Presented at the First International Workshop on Systems Radiation Biology, February 14–16 2007, GSF-Research Centre, Neuherberg, Germany.     

Understanding the connection between platelet-activating factor,a UV-induced lipid mediator of inflammation,immune suppression and skin cancer

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome.     

A special issue on ＂Interferons, Cytokines, and Immunity＂

Vertebrates including human employ both innate and adaptive immune responses to defend against pathogen infections and malignancy. Interferons and cytokines play pivotal roles in mediating and coordinating diverse aspects of the host immune response responsible for the clearance of infection and elimination of malignant cells. In addition, abnormal immune and/or inflammatory responses are closely linked to the pathogenesis of various human diseases such as infections, autoimmune diseases and cancer. Thus, a better understanding of these signaling pathways is essential to our efforts in developing more effective regimes to prevent and treat infectious diseases as well as to combat autoimmune diseases and cancer.