Janice Dietert

Potential for Early-Life Immune Insult Including Developmental Immunotoxicity in Autism and Autism Spectrum Disorders: Focus on Critical Windows of Immune Vulnerability

Early-life immune insults (ELII) including xenobiotic-induced developmental immunotoxicity (DIT) are important factors in childhood and adult chronic diseases. However, prenatal and perinatal environmentally induced immune alterations have yet to be considered in depth in the context of autism and autism spectrum disorders (ASDs). Numerous factors produce early-life-induced immune dysfunction in offspring, including exposure to xenobiotics, maternal infections, and other prenatal–neonatal stressors. Early life sensitivity to ELII, including DIT, results from the heightened vulnerability of the developing immune system to disruption and the serious nature of the adverse outcomes arising after disruption of one-time immune maturational events. The resulting health risks extend beyond infectious diseases, cancer, allergy, and autoimmunity to include pathologies of the neurological, reproductive, and endocrine systems. Because these changes may include misregulation of resident inflammatory myelomonocytic cells in tissues such as the brain, they are a potential concern in cases of prenatal–neonatal brain pathologies and neurobehavioral deficits. Autism and ASDs are chronic developmental neurobehavioral disorders that are on the rise in the United States with prenatal and perinatal environmental factors suspected as contributors to this increase. Evidence for an association between environmentally associated childhood immune dysfunction and ASDs suggests that ELII and DIT may contribute to these conditions. However, it is not known if this linkage is directly associated with the brain pathologies or represents a separate (or secondary) outcome. This review considers the known features of ELII and DIT and how they may provide important clues to prenatal brain inflammation and the risk of autism and ASDs.

Environmental risk factors for autism

Autism is a devastating childhood condition that has emerged as an increasing social concern just as it has increased in prevalence in recent decades. Autism and the broader category of autism spectrum disorders are among the increasingly seen examples in which there is a fetal basis for later disease or disorder. Environmental, genetic, and epigenetic factors all play a role in determining the risk of autism and some of these effects appear to be transgenerational. Identification of the most critical windows of developmental vulnerability is paramount to understanding when and under what circumstances a child is at elevated risk for autism. No single environmental factor explains the increased prevalence of autism. While a handful of environmental risk factors have been suggested based on data from human studies and animal research, it is clear that many more, and perhaps the most significant risk factors, remain to be identified. The most promising risk factors identified to date fall within the categories of drugs, environmental chemicals, infectious agents, dietary factors, and other physical/psychological stressors. However, the rate at which environmental risk factors for autism have been identified via research and safety testing has not kept pace with the emerging health threat posed by this condition. For the way forward, it seems clear that additional focused research is needed. But more importantly, successful risk reduction strategies for autism will require more extensive and relevant developmental safety testing of drugs and chemicals.

Possible role for early-life immune insult including developmental immunotoxicity in chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME)

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME) in some countries, is a debilitating disease with a constellation of multi-system dysfunctions primarily involving the neurological, endocrine and immune systems. While substantial information is available concerning the complex dysfunction-associated symptoms of CFS, environmental origins of the disease have yet to be determined. Part of the dilemma in identifying the cause(s) has been the focus on biomarkers (hormones, neurotransmitters, cytokines, infectious agents) that are contemporary with later-life CFS episodes. Yet, recent investigations on the origins of environmental diseases of the neurological, endocrine, reproductive, respiratory and immune systems suggest that early life toxicologic and other insults are pivotal in producing later-life onset of symptoms. As with autism and childhood asthma, CFS can also occur in children where the causes are certainly early-life events. Immune dysfunction is recognized as part of the CFS phenotype but has received comparatively less attention than aberrant neurological or endocrine function. However, recent research results suggest that early life immune insults (ELII) including developmental immunotoxicity (DIT), which is induced by xenobiotics, may offer an important clue to the origin(s) of CFS. The developing immune system is a sensitive and novel target for environmental insult (xenobiotic, infectious agents, stress) with major ramifications for postnatal health risks. Additionally, many prenatal and early postnatal neurological lesions associated with postnatal neurobehavioral diseases are now recognized as linked to prenatal immune insult and inflammatory dysregulation. This review considers the potential role of ELII including DIT as an early-life component of later-life CFS.

The Completed Self: An Immunological View of the Human- Microbiome Superorganism and Risk of Chronic Diseases

In this review, we discuss an immunological-driven sign termed the Completed Self, which is related to a holistic determination of health vs. disease. This sign (human plus commensal microbiota) forms the human superorganism. The worldwide emergence of an epidemic of chronic diseases has caused increased healthcare costs, increased premature mortality and reduced quality of life for a majority of the worlds population. In addition, it has raised questions concerning the interactions between humans and their environment and potential imbalances. Misregulated inflammation, a host defense- homeostasis disorder, appears to be a key biomarker connecting a majority of chronic diseases. We consider the apparent contributors to this disorder that promote a web of interlinked comorbid conditions. Three key events are suggested to play a role: (1) altered epigenetic programming (AEP) that may span multiple generations, (2) developmental immunotoxicity (DIT), and (3) failure to adequately incorporate commensal microbes as a newborn (i.e., the incomplete self). We discuss how these three events can combine to determine whether the human superorganism is able to adequately and completely form during early childhood. We also discuss how corruption of this event can affect the risk of later-life diseases.

Early-life immune insult and developmental immunotoxicity (DIT)-associated diseases: potential of herbal- and fungal-derived medicinals.

Developmental immunotoxicity (DIT) is increasingly recognized as a significant risk factor contributing to later life immune dysfunction as well chronic disease. In fact, recent increases in the incidence of asthma, allergic disease, autoimmunity and childhood infections maybe linked to problematic early life environmental exposures. The immune system of the non-adult is particularly susceptible to environmental influences whether from prenatal exposure to environmental toxins, maternally-administered drugs, infections or from postnatal exposure to toxicants, infectious agents and allergens. Additionally, adult-exposure models of immunotoxicity have been largely ineffective in predicting DIT risk. DIT-induced immune dysfunction can take many forms depending upon the environmental factor(s) involved and the precise developmental timing of exposure. If one examines the spectrum of published studies, a predominant phenotype has emerged that includes: Th balance skewing toward Th2, suppression of Th1 function, regulatory T cell function alteration, T cell repertoire abnormalities, problematic regulation of inflammatory cell function leading to hyperinflammatory responses and perturbation of cytokine networks. Early-life immune insult can also result in damage to the neurological and cardiovascular systems as well as endocrine and reproductive organs. Most therapeutic approaches to date have addressed the disease outcomes of DIT (e.g. asthma, allergy, autoimmunity, infections, and cancer) rather than focusing on the underlying immune dysfunction that creates the increased disease risk. While identification and prevention of problematic early life exposures is the best protection against DIT, this is not always possible. Therefore, identification of potential therapeutic approaches to reverse the immune dysfunction in the juvenile or adult is needed. In this review, we consider potential phytotherapeutic candidates among herbal- and fungal-derived medicinals for possible postnatal correction of the most predominant DIT-induced immune problems.

The Microbiome and Sustainable Healthcare

Increasing prevalences, morbidity, premature mortality and medical needs associated with non-communicable diseases and conditions (NCDs) have reached epidemic proportions and placed a major drain on healthcare systems and global economies. Added to this are the challenges presented by overuse of antibiotics and increased antibiotic resistance. Solutions are needed that can address the challenges of NCDs and increasing antibiotic resistance, maximize preventative measures, and balance healthcare needs with available services and economic realities. Microbiome management including microbiota seeding, feeding, and rebiosis appears likely to be a core component of a path toward sustainable healthcare. Recent findings indicate that: (1) humans are mostly microbial (in terms of numbers of cells and genes); (2) immune dysfunction and misregulated inflammation are pivotal in the majority of NCDs; (3) microbiome status affects early immune education and risk of NCDs, and (4) microbiome status affects the risk of certain infections. Management of the microbiome to reduce later-life health risk and/or to treat emerging NCDs, to spare antibiotic use and to reduce the risk of recurrent infections may provide a more effective healthcare strategy across the life course particularly when a personalized medicine approach is considered. This review will examine the potential for microbiome management to contribute to sustainable healthcare.

Strategies for Protecting Your Child's Immune System: Tools for Parents and Parents-To-Be

The text provides expecting and existing parents, their families and physicians with science-based information to protect and proactively manage their childs immune system. Environmental exposures (pollutants, allergens, drugs, diet, physical factors) in the home, school and community can damage the developing immune system and increase the risk of lifelong chronic diseases such as allergies, asthma, type 1 diabetes, celiac disease and neurological problems. This book imparts specific tools to parents and their physicians to help keep the early-life immune system out of harms way and minimize environmental health risk

Risk of Autoimmune Disease: Challenges for Immunotoxicity Testing

Autoimmunity represents a potentially diverse and complex category among the range of adverse outcomes for detection with immunotoxicity testing. For this reason, the risk of autoimmune disease is discussed in this overview chapter with additional mention among the later specific protocol chapters. Improvements in clinical diagnostic capabilities and disease recognition have led to a more accurate picture of the extent of autoimmune diseases across different human populations. While the risk of any single autoimmune disease remains modest when compared with that of lung or heart disease, the cumulative prevalence of autoimmune diseases is both significant and increasing. Autoimmune diseases are usually viewed in the context of the damaged tissue or organ (e.g., as a thyroid, gastrointestinal, cardiovascular or neurological disease). But improved recognition that underlying immune dysfunction can connect the risks for these as well as other diseases is critical for optimizing risk assessment. Since autoimmune diseases are chronic in nature with many first appearing in children or in young adults, these diseases exert a serious impact on both health care costs and quality of life. This chapter provides a discussion of the issues that should be considered with immunotoxicity testing for risk of autoimmunity.

Immunotoxicology and Foods

Foods play important roles in determining both the risk of immunotoxicity and the potential for adverse health outcomes linked to immunotoxicity-based immune dysfunction. Foods (1) can be a source of immunotoxicity-inducing contaminants and endogenous chemicals, (2) can protect against some immunotoxicants, and (3) can correct or repair some forms of immune damage. In this chapter, we discuss each of the aspects that connect foods with immunotoxicology.