2 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 dis- orders, and functional changes in brain glial cells (microglia and astrocytes) [4–11]. Microglia are the primary immuno- competent cells of the brain and rapidly respond to any infection, injury or other perturbation of homeostasis via a dynamic process of activation [12]. Notably, increased microglial activation has been observed in several brain regions of autistic patients [13]. 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 [14]. 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. Autism Research and Treatment 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 [21]. Early in development, microglia are highly mobile and primarily amoeboid, consistent with their role in the phagocytosis of apoptotic cells [22]. The expression of many cytokines within the developing brain, including IL-1β and TGF-β, depends on the presence of amoeboid microglia [23]. 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 [27]. Astrocytes mediate synapse formation within the developing brain [28], 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 [31]. Notably, astrocyte maturation marks the end of the perinatal synaptogenic period when the brain is most plastic [32]. 5. Long-Term Consequences of Immune Activation during Early Development Developmental or “fetal programming” is a growing ﬁeld of science based on evidence that experiences during critical or sensitive periods of perinatal life may modulate or “program” the normal course of development, with the result that adult outcomes, including behavior, are signiﬁcantly and often permanently altered [33]. Given the many ways in which the immune system is important for normal brain development, the capacity for immune-inducing events to inﬂuence the long-term trajectory and function of these processes is likely profound, perhaps more so than at any other stage of life [34]. Notably, there is strong evidence that early-life infection can permanently alter stress reactivity, disease susceptibility, and notably, vulnerability to cognitive and neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and autism [35–38]. One of the most dra- matic and direct illustrations of this eﬀect is the induction of autism-like symptoms in mice by stimulation of the maternal immune system during pregnancy [39]. Neuroinﬂammatory-induced alterations in neurogene- sis, migration, axon growth, myelination, synaptogenesis, and dendritic spine density/function are all candidate mech- anisms by which long-term changes in behavior might result. Further, the long lifespan of microglia and their