Mechanisms of Immunotoxicity: Stressors and Evaluators.

The immune system defends the body against certain tumor cells and against foreign agents such as fungi, parasites, bacteria, and viruses. One of its main roles is to distinguish endogenous components from non-self-components. An unproperly functioning immune system is prone to primary immune deficiencies caused by either primary immune deficiencies such as genetic defects or secondary immune deficiencies such as physical, chemical, and in some instances, psychological stressors. In the manuscript, we will provide a brief overview of the immune system and immunotoxicology. We will also describe the biochemical mechanisms of immunotoxicants and how to evaluate immunotoxicity.

Epigenome-wide association study reveals methylation pathways associated with childhood allergic sensitization.

Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva-Boston, and the Generation R Study-Rotterdam). We performed covariate-adjusted epigenome-wide association meta-analysis and employed pathway and regional analyses of results. Seven-hundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylation - time interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization.

Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health.

The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine-disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity.

History of chemical sensitivity and diagnosis.

Histories of mold, pollen, dust, food, chemicals, and electromagnetic field (EMF) sensitivities are the major categories of triggers for chemical sensitivity. They are tied together by the coherence phenomenon, where each has its own frequencies and identifiable EMF; therefore, they can be correlated. The diagnosis of chemical sensitivity can be done accurately in a less-polluted, controlled environment, as was done in these studies. The principles of diagnosis and treatment depend on total environmental and total body pollutant loads, masking or adaptation, bipolarity of response, and biochemical individuality, among others. These principles make less-polluted, controlled conditions necessary. The clinician has to use less-polluted water and organic food with individual challenges for testing, including dust, mold, pesticide, natural gas, formaldehyde, particulates, and EMF testing, which needs to be performed in less-polluted copper-screened rooms. The challenge tests for proof of chemical sensitivity include inhaled toxics within a clean booth that is chemical- and particulate-free at ambient doses in parts per million (ppm) or parts per billion (ppb). Individual foods, both organic and commercial (that are contaminated with herbicides and pesticides), are used orally. Water testing and intradermal testing are performed in a less-polluted, controlled environment. These include specific dose injections of molds, dust, and pollen that are preservative-free, individual organic foods, and individual chemicals, i.e. methane, ethane, propane, butane, hexane, formaldehyde, ethanol, car exhaust, jet fuel exhaust, and prosthetic implants (metal plates, pacemakers, mesh, etc.). Normal saline is used as a placebo. EMF testing is performed in a copper-screened room using a frequency generator. In our experience, 80% of the EMF-sensitive patients had chemical sensitivity when studied under less-polluted conditions for particulates, controlled natural gas, pesticides, and chemicals like formaldehyde.

[Individual risks to adolescent health, caused by contaminating the air, and their relationship with the levels of specific autoantibodies].

The high levels of the air pollution create prerequisites for the development of the pathology of target organs exposed to chemical agents. Big enterprises of oil refining and chemical industry of the Irkutsk region are located in the cities of Angarsk and Sayansk. The average level of the air pollution for several years in these cities is assessed as high and moderate, respectively. The use of the personalized approach may allow to more correctly evaluate the risk for the damage to health and the body's response to external impacts. The purpose of this study was to assess the risk offormation ofpathological processes in the body of adolescents in the conditions of inhalation exposure to chemicals, taking into account the individual load and study of the level of specific autoantibodies. The study included 373 adolescents from the city with high levels of air pollution and 188 schoolchildren from the city with a moderate level pollution. There was made an evaluation of the individual chemical hazard load on adolescents ' body due to the air pollution, physiologicalfeatures and the organization of educational process and leisure. There were studied the levels of specific autoantibodies, reflecting the state of the organs - targets for the impact ofpollutants. The calculation of the individual chemical load allows to calculate indices of the hazard for the health problems of each individual and to identify individuals at increased risk of developing diseases of organs and systems, which are targets for exposure to pollutants. The increase in the hazard index of developing respiratory diseases was found to be accompanied by an increase of the relative content of autoantibodies against membrane antigens of the lung tissue. There was revealed the elevation in autoantibodies levels to the proteins of vascular endothelial with increasing hazard index of disturbances in the cardiovascular system in adolescents living in city with high levels of air pollution.

Interactions between zinc deficiency and environmental enteropathy in developing countries.

Zinc deficiency affects one-fifth of the world's population and leads to substantial morbidity and mortality. Environmental enteropathy (EE), a subclinical pathology of altered intestinal morphology and function, is almost universal among people living in developing countries and affects long-term growth and health. This review explores the overlapping nature of these 2 conditions and presents evidence for their interaction. EE leads to impaired zinc homeostasis, predominantly due to reduced absorptive capacity arising from disturbed intestinal architecture, and zinc deficiency exacerbates several of the proposed pathways that underlie EE, including intestinal permeability, enteric infection, and chronic inflammation. Ongoing zinc deficiency likely perpetuates the adverse outcomes of EE by worsening malabsorption, reducing intestinal mucosal immune responses, and exacerbating systemic inflammation. Although the etiology of EE is predominantly environmental, zinc deficiency may also have a role in its pathogenesis. Given the impact of both EE and zinc deficiency on morbidity and mortality in developing countries, better understanding the relation between these 2 conditions may be critical for developing combined interventions to improve child health.

[Application of immuno-biochemical indices for the identification of the chronic pathology of the upper respiratory tract].

A comprehensive survey of organized children aged 14-17 years residing in the industrial centers with moderate and high levels of air pollution was performed. On the base of the examination of otorhinolaryngologist in the each of cities there was selected the group of schoolchildren with chronic pathology of the upper respiratory tract at the stage of remission. In these groups there was performed the assessment of the informativeness of immuno-biochemical indices for the identification of pathology caused by the impact of man-made factors. The most informative (relative content of autoantibodies to ß2-glycoprotein-1, the average individual immunoreactivity, erythrocyte sedimentation rate, level of α1-antitrypsin) were used in the mathematical model, on the based of which it was possible to calculate the diagnostic coefficient, allowing to identify in the groups observed by ourselves, chronic pathology of upper respiratory tract, formed under the influence of ambient air pollution. The above approach can be used in the formation groups for health promotion of children exposed to the negative impact.

[Features of the immune status in the population of urban areas with a high content of heavy metals].

The immune status was studied in of 4000 Aktobe citizens. The findings indicate that cell immunity indicators as the maximally informative parameter are of criteria significance in evaluating the influence of environmental factors on the body. A direct correlation was found between the sensitization to chromium and CD3, CD4, CD8 and the functional response of T lymphocytes to phytohemagglutinin.

[Efficacy of immunomodulators in children with respiratory diseases in environmentally poor areas].

The authors evaluated the clinical efficacy and safety of the antiviral and immunomodulatory drug Isoprinosine (inosine pranobex, Teva Pharmaceutical Industries, Ltd) in the treatment of bronchopulmonary diseases in children. One hundred and fifty-two children with acute respiratory diseases and an exacerbation of recurrent respiratory diseases were followed up. The use of Isoprinosine in their combined treatment showed both positive clinical changes and a better immunogram.

Innate immunity and the pathogenicity of inhaled microbial particles.

Non-infectious inhaled microbial particles can cause illness by triggering an inappropriate immunological response. From the pathogenic point of view these illnesses can be seen to be related to on one hand autoimmune diseases and on the other infectious diseases.In this review three such illnesses are discussed in some detail. Hypersensitivity pneumonitis (HP) is the best known of these illnesses and it has also been widely studied in animal models and clinically. In contrast to HP Pulmonary mycotoxicosis (PM) is not considered to involve immunological memory, it is an acute self-limiting condition is caused by an immediate "toxic" effect. Damp building related illness (DBRI) is a controversial and from a diagnostic point poorly defined entity that is however causing, or attributed to cause, much more morbidity than the two other diseases.In the recent decade there has been a shift in the focus of immunology from the lymphocyte centered, adaptive immunity towards innate immunity. The archetypal cell in innate immunity is the macrophage although many other cell types participate. Innate immunity relies on a limited number of germline coded receptors for the recognition of pathogens and signs of cellular damage. The focus on innate immunity has opened new paths for the understanding of many chronic inflammatory diseases. The purpose of this review is to discuss the impact of some recent studies, that include aspects concerning innate immunity, on our understanding of the pathogenesis of inflammatory diseases associated with exposure to inhaled microbial matter.

[Influence of ambient air pollution on children's health in Krivoi Rog].

The degree and nature of surface air pollution with man-made chemicals were studied in Krivoy Rog in 1996 to 2005. The priorities of pollutants were established in the area with different forms of technogenic emissions and residential areas. Immunological parameters were studied in healthy neonates and 7-10-year-old children. There was a reduction in the major immunological parameters in both healthy neonatal infants and 7-10-year-old children and a rise in pediatric morbidity.

Advances in environmental and occupational disorders in 2008.

Substantial progress in understanding the role of environmental factors in allergic disease and asthma has been made in the past year. A number of new allergens have been described, and the impact of exposure to indoor allergens in the development of allergic respiratory disease is further confirmed. Exposures to environmental pollutants, particularly tobacco smoke in children, have furthered our knowledge of the detrimental effects of these exposures. This review highlights key advances in environmental and occupational exposures that contribute to the burden of allergic respiratory disease.

Immune response among patients exposed to molds.

Macrocyclic trichothecenes, mycotoxins produced by Stachybotrys chartarum, have been implicated in adverse reactions in individuals exposed to mold-contaminated environments. Cellular and humoral immune responses and the presence of trichothecenes were evaluated in patients with mold-related health complaints. Patients underwent history, physical examination, skin prick/puncture tests with mold extracts, immunological evaluations and their sera were analyzed for trichothecenes. T-cell proliferation, macrocyclic trichothecenes, and mold specific IgG and IgA levels were not significantly different than controls; however 70% of the patients had positive skin tests to molds. Thus, IgE mediated or other non-immune mechanisms could be the cause of their symptoms.

Responsiveness of eosinophils to aeroallergens may be independent of atopic status.

It has been reported that extracts from common aeroallergens directly activate eosinophils from non-allergic individuals, eliciting chemotaxis and degranulation. The aims of this study were to compare the reactivity of eosinophils from non-atopic and atopic individuals to airborne allergens, and to assess if this reactivity was modulated by natural exposure to birch pollen. Blood-derived eosinophils were stimulated with allergen extracts from birch pollen, cat dander, house dust mite and timothy grass, and their capacity to degranulate (eosinophil peroxidase, EPO; major basic protein, MBP) and produce T helper type 1 and 2 cytokines were evaluated as well as their capacity to migrate in vitro, in and out of the birch pollen season. Eosinophils from atopic and non-atopic individuals responded similarly to stimulation with allergen extracts with respect to directed migration, EPO and MBP release, which was independent of the season when the samples were collected. Interestingly, eosinophils from both study groups were incapable of producing tumour necrosis factor-alpha (TNF-alpha) during the birch pollen season, but could generate interleukin-4. Innate responsiveness of eosinophils to aeroallergens is independent of the atopic status of the individual. In vivo exposure to birch allergen as seen during the birch pollen season downregulates the capacity of eosinophils to produce the cytokine TNF-alpha.

[Changes of human immunophenotype during adaptation to environmental factors, in different forms of pathology and their specific treatment].

The aim of the study was to elucidate mechanisms underlying variations of human immune phenotype in the course of adaptation to environmental factors, development of different forms of pathology and their specific treatment from dynamics of expression of surface CD-molecules in lymphocyte plasmolemma and immunoglobulin A, M, G levels in blood plasma. 253 assumingly healthy volunteers residing in the Moscow Megapolis exhibited a tendency toward enhanced lymphocyte apoptosis and reduced efficiency of their co-stimulation and cooperative interaction. Pathologies of different etiology were associated with the imbalance of specific and non-specific reactions of immune and biological control. Specifically, expression of CD 95 (Fas/APO-1) molecules triggering apoptosis increased in all patients with postmenopausal osteoporosis, pneumonia, and bronchial asthma but decreased in patients with rheumatic fever, erosive and ulcerative lesions in the digestive tract. Expression of surface receptors by the cells involved in "processing" of unshared antigens, their presentation by T-lymphocytes, inactivation and destruction of pathogens was enhanced only in patients with erosive and ulcerative lesions in the digestive tract. It decreased in rheumatic fever, postmenopausal osteoporosis, pneumonia, and bronchial asthma. Effective specific treatment leading to the normalization of (or tending to normalize) expression of CD molecules in lymphocytes and prevented changes in the immune and biological control system.

Excess dampness and mold growth in homes: an evidence-based review of the aeroirritant effect and its potential causes.

Exposure to fungi produces respiratory disease in humans through both allergic and nonallergic mechanisms. Occupants of homes with excess dampness and mold growth often present to allergists with complaints of aeroirritant symptoms. This review describes the major epidemiological and biological studies evaluating the association of indoor dampness and mold growth with upper respiratory tract symptoms. The preponderance of epidemiological data supports a link between exposure to dampness and excess mold growth and the development of aeroirritant symptoms. In addition, biological and clinical studies evaluating potential causal substances for the aeroirritant effect, notably volatile organic compounds (VOCs), are examined in detail. These studies support the role of VOCs in contributing to the aeroirritant symptoms of occupants of damp and mold-contaminated homes.

Temporal trends of aeroallergen sensitization over twenty-five years.

BACKGROUND: Little is known about time trends of allergic respiratory disease in adults, in particular in older adults. Furthermore, few trend studies have used objective measurements of IgE sensitization against inhalant allergens. OBJECTIVES: To investigate time trends of aeroallergen sensitization in adults over a 25-year period. METHODS: The study includes a total of 7820 persons, aged 30, 40, 50, and 60 years, who participated in three repeated cross-sectional studies of the general population of Copenhagen, Denmark, in 1976-1977, 1982-1984, and 1999-2001, respectively. Respiratory allergy was assessed by determination of specific IgE aeroallergen sensitization in stored serum samples. RESULTS: Over this 25-year period, a marked and statistically significant increase in the prevalence of aeroallergen sensitization had occurred. This increase was seen in all age-groups challenging the notion that the allergy epidemic only affects generations born 1960 onwards. For example, in 40-year-olds the prevalence (with 95% confidence intervals) of aeroallergen sensitization was 14.9% (12.7-17.1), 19.7% (17.1-22.3), and 27.6% (25.1-30.1) in 1976-1977, 1982-1984, and 1999-2001, respectively. CONCLUSIONS: Our results support that the allergy epidemic has spread to older adults resulting in a continuing increase in the overall prevalence of aeroallergen sensitization and an increase in the mean age of allergic patients.

Chronic helminth infections may negatively influence immunity against tuberculosis and other diseases of public health importance.

Tuberculosis (TB) has once again become a major public health threat owing to the combined effects of deteriorating socioeconomic situations and the emergence of the HIV/AIDS pandemic. The only vaccine available against TB, although effective in reducing the burden of childhood TB, shows enormous variability in its efficacy against pulmonary TB, which is the most common form of the disease in adults. Most areas of high TB incidence and poor TB vaccine efficacy have a high prevalence of intestinal helminth infections. Such infections have been shown to cause a range of immunomodulation characterized by enhanced T helper 2-type cytokine profile, high immunoglobulin E levels and upregulated regulatory T-cell activity, as well as chronic immune activation. An altered background immune profile could have adverse effects on the outcome of subsequent infections and vaccinations. In support of this hypothesis, studies conducted in animals and humans living in worm-endemic areas have shown that helminths impair resistance against a number of infections of major public health importance, including TB, malaria and HIV/AIDS. Understanding such interactions could assist in the design of vaccines against these diseases.

A questão ambiental na promoção da saúde: uma oportunidade de ação multiprofissional sobre doenças emergentes / Environmental issues on health promotion: a multi-professional action on emerging diseases

A discussão sobre a emergência de agravos à saúde coloca todos os profissionais de saúde em alerta. Através de uma revisão sobre os conceitos de doença emergente, relacionando-a com uma situação concreta, a emergência da hantavirose em Santa Catarina, Brasil, constatou-se a necessidade de um enfoque sobre as condições ambientais em tais situações. O melhor conhecimento sobre os fatores ambientais envolvidos e contextualizados torna possível um melhor posicionamento para a elaboração das políticas de controle e prevenção a serem adotadas. Tal posicionamento possibilita a ação multiprofissional, sob a forma de orientação às comunidades, como necessidade de um modelo assistencial diferenciado.

The discussion on the emergence of health injuries preoccupies all health workers. In a review on the concepts of emerging disease, related to a concrete situation, the emergence of the Hantaviruses in the State of Santa Catarina, Brazil, the author highlights the need for focusing on environmental conditions in such situations. The best knowledge on environmental factors makes it possible to elaborate controlling and preventive policies. This enables the multi-professional action in providing community information, as the need for a differentiated assistance model.