Autism Res Treat. 2012; 2012: 910946.
Is Autism a Member of a Family of Diseases Resulting from Genetic/Cultural Mismatches? Implications for Treatment and Prevention
Several lines of evidence support the view that autism is a typical member of a large family of immune-related, noninfectious, chronic diseases associated with postindustrial society. This family of diseases includes a wide range of inflammatory, allergic, and autoimmune diseases and results from consequences of genetic/culture mismatches which profoundly destabilize the immune system. Principle among these consequences is depletion of important components, particularly helminths, from the ecosystem of the human body, the human biome. Autism shares a wide range of features in common with this family of diseases, including the contribution of genetics/epigenetics, the identification of disease-inducing triggers, the apparent role of immunity in pathogenesis, high prevalence, complex etiologies and manifestations, and potentially some aspects of epidemiology. Fortunately, using available resources and technology, modern medicine has the potential to effectively reconstitute the human biome, thus treating or even avoiding altogether the consequences of genetic/cultural mismatches which underpin this entire family of disease. Thus, if indeed autism is an epidemic of postindustrial society associated with immune hypersensitivity, we can expect that the disease is readily preventable.
1. Introduction: Autism as a Member of a Large Family of Postindustrial Epidemics Involving a Hyperimmune Response
In this paper, we outline a paradigm that points toward autism as one disease among many other well-known diseases which all share a common origin and, most likely, a common prevention strategy . These emerging, noninfectious diseases are all epidemics of postindustrial culture, which are absent in antiquity in any culture, and absent in present day developing cultures. Members of this family of disease are invariably associated with a hyperimmune response and can have a very high prevalence in postindustrial populations, with prevalence often greater than 0.1% and sometimes greater than 1.0%. These hyperimmune-associated diseases include a wide range of allergic, autoimmune, and inflammatory diseases such as lupus, multiple sclerosis, hay fever, appendicitis, chronic fatigue syndrome, inflammatory bowel disease, asthma, celiac disease, type 1 diabetes, Graves’ disease, some types of eczema, and a wide range of food allergies. Here, based on a variety of evidence, we argue that autism is yet another member of this family of diseases, despite the slowness of the medical community to recognize it as such. Since the pathogenesis of at least one form of autism has been directly linked to autoantibody production , and since seven out of every eight cases of severe autism are associated with antineuronal antibodies in the serum , this idea has already been demonstrated, at least in part. Further, as described below, autism is associated with a wide range of immune abnormalities. Even though some children with autism appear to have “normal” immune systems, it is argued that adverse immune events early in development might lead to an autistic phenotype.
A primary consideration in this view of autism as a hyperimmune-associated disease is the connection between immunity and brain development in general, and between hyperimmune responses and autism in particular. Although these connections have little bearing on the overall model describing induction of disease by immune hypersensitivity in postindustrial society, the connections provide reason to expect that the developing brain is sensitive to the same postindustrial changes in the immune system which are known to affect virtually all other organs of the human body (e.g., kidneys, pancreas, epidermis, adult nervous tissues, large and small bowel, cardiovascular system, thyroid, lungs, and others). The next four sections will summarize much of what is currently known regarding those very extensive connections.
2. Pervasive Immune System Abnormalities in Autism
Immune system abnormalities exist throughout the body and brain of autistic children. These include evidence of brain specific auto-antibodies, altered T, B, and NK cell responses to antigen, altered cytokine production, an increased incidence of allergies and other autoimmune disorders, and functional changes in brain glial cells (microglia and astrocytes) [4–11]. Microglia are the primary immunocompetent cells of the brain and rapidly respond to any infection, injury or other perturbation of homeostasis via a dynamic process of activation . Notably, increased microglial activation has been observed in several brain regions of autistic patients . Once activated, glia produce a wide number of immune signaling molecules, including cytokines (e.g., interleukin [IL]-1β, tumor necrosis factor [TNF]-α), chemokines (e.g., monocyte chemoattractant protein [MCP]-1), and other inducible factors (e.g., nitric oxide), which may profoundly influence neural function .
3. Immune System-Central Nervous System Communication
Beyond its traditional role in host defense and tissue repair, the immune system is now considered a diffuse sensory organ that works in concert with the endocrine, metabolic, and nervous systems to achieve and maintain homeostasis throughout the body [15, 16]. In essence, the immune system serves as an interface between the human body and the environment, coordinating the response of the body to the environment. Immunocompetent cells are located throughout every organ of the body, including the brain, and regular communication occurs between the central nervous system and immune tissues during both health and disease processes. Many excellent reviews have been written on these topics [17–20]. Importantly, bidirectional communication between the brain and immune system has significant consequences for plasticity mechanisms within the brain, including cognition and emotion, which are markedly altered in autism.
4. Glial Cells Direct Normal Brain Development
Microglia are the resident macrophages of the central nervous system, are associated with the pathogenesis of many inflammatory diseases of the brain, and derive from primitive yolk sac macrophage precursors, which are of mesodermal origin and enter the neuroectoderm during embryogenesis . Early in development, microglia are highly mobile and primarily amoeboid, consistent with their role in the phagocytosis of apoptotic cells . The expression of many cytokines within the developing brain, including IL-1β and TGF-β, depends on the presence of amoeboid microglia . Microglia transform into a highly branched, ramified morphology by adulthood in most brain regions. This morphological transition occurs in parallel with neural cell genesis and migration, synaptogenesis, and synaptic pruning, suggesting functions for microglia in each of these processes, though these are just beginning to be explored [24–26]. Oligodendrocytes myelinate axons primarily during the postnatal period, and disruption of their function can be profoundly debilitating as in the case of periventricular leukomalacia leading to cerebral palsy . Astrocytes mediate synapse formation within the developing brain , in part via the secretion of extracellular matrix proteins called thrombospondins (TSPs) [29, 30]. Alterations in spine density via a putative TSP mechanism are implicated in neurodevelopmental disorders such as Down’s and Rett Syndrome . Notably, astrocyte maturation marks the end of the perinatal synaptogenic period when the brain is most plastic .