Autism Research and Treatment by components of postindustrial culture that reduce expo- sure to sunlight (e.g., indoor work environments, sunscreen). The association of vitamin D deﬁciency with a spectrum of hyperimmune-associated diseases places this consequence of biology/culture mismatch alongside biome depletion as an underlying agent destabilizing immune system function in postindustrial populations. However, vitamin D deﬁciency is an ancient problem, as indicated by the ancient occurrence of rickets, whereas epidemics of hyperimmune-associated diseases are more recent in nature. Thus, it seems likely that vitamin D deﬁciency is a contributor to hyperimmune- associated disease, but not suﬃcient by itself to lead to disease. Further, the prevalence of vitamin D deﬁciency in postindustrial society is somewhat less than the prevalence of biome depletion: although the prevalence of vitamin D deﬁciency is substantial, with one study ﬁnding 24% of individuals deﬁcient (≤20 ng/mL) with an additional 34% having levels that were insuﬃcient (≤29 ng/mL) [59], the prevalence of biome depletion in postindustrial populations is essentially 100%. Thus, it is expected that the impact of vitamin D deﬁciency on immunity in postmodern culture may be a matter of exacerbating the problems associated with biome depletion more so than a signiﬁcant problem when considered in isolation. Some mechanisms by which vitamin D might stabilize the immune system have been elucidated. Vitamin D acts as a signaling molecule to enhance immune cell function in the presence of infection and is important for maintaining the normal interface between the microbiome and the immune system [60]. However, the mechanisms by which vitamin D interacts within the body are complex, with the molecule being intertwined either directly or indirectly in virtually all aspects of human biology. The active form of vitamin D binds and activates the Vitamin D receptor, altering the expression of a variety of genes involved in such diverse processes as cell growth and proliferation, bone remodeling, and calcium homeostasis [61]. It has been estimated that vitamin D binds human DNA in more than 2,500 places and changes the expression of more than 200 genes [62]. Thus, while it is known that vitamin D is required for normal immune function, it is likely that vitamin D deﬁciency could cause a general destabilization of the human biome independent of the immune system, particularly during early development. Fortunately, regardless of the extent to which vitamin D deﬁciency destabilizes the human biome, dietary supplements are readily available, and thus this consequence of culture/biology mismatch is easily avoided. 9. Mismatches between Normal Human Genetics and Postindustrial Culture Leading to Hyperimmune Epidemics: Other Factors The above discussion points out two factors, primarily biome depletion and secondarily vitamin D deﬁciency, which generally destabilize the human immune system. These factors can be identiﬁed by their association with a wide range of hyperimmune-associated diseases. Other 5 consequences of postindustrial culture can also be found which are associated with a wide range of disease, but limits in space prevent a complete discussion. For example, chronic uncontrollable psychosocial stress is yet another factor that is generally associated with a range of hyperimmune-associated diseases that include allergy, autoimmunity, and inﬂamma- tion [63–66]. Such stress derives from a complex range of biology/culture mismatches, including, for example, the loss of physical exercise [67–69] as a requirement for survival in postindustrial culture (Figure 1). As another example of con- sequences of biology/culture mismatches which destabilizes immune function, deprivation from mother’s milk during infancy (not included in Figure 1) is associated with a wide range of allergic and autoimmune conditions [70–74]. This genetic/culture mismatch, like other mismatches, involves an aspect of postindustrial society which should not be reversed (the survival of infants despite the unavailability of mother’s milk), and thus ﬁts into the “pretherapeutic zone” of Figure 1. The extent to which factors such as uncontrollable stress and lack of mother’s milk can contribute to disease in the presence of an otherwise normal biome remains to be elucidated, although, as outlined above, biome depletion appears to be the single most important factor contributing to the increased incidence of hyperimmune-associated dis- eases. 10. Metabolism and Transport of Toxins and Hyperimmune-Associated Disease The connection between metabolism and immunity is important in a consideration of hyperimmune-associated diseases. A variety of enzymes have been identiﬁed which are useful in the biotransformation of endogenous (produced by the body or the associated biome) as well as exogenous (pharmaceutical) substrates. This system of enzymes pro- vides the body with a means of processing a wide range of substances, some of which are toxins, and is profoundly aﬀected by the immune system [75]. The metabolic portion of this system is readily divided into two components: Phase I biotransformation includes the oxidative reactions of the microsomal cytochrome P450 monooxygenase system that is expressed in the liver and gastrointestinal tract, and to some extent in a variety of extrahepatic tissues. Phase II biotransformation includes conjugation reactions of substrates with endogenous cofactors such as glucuronate, sulphate, acetate, or glycine. In addition to Phase I and Phase II biotransformation, the transport of their substrates and byproducts is also an important component of this system. A variety of membrane spanning polypeptides have been identiﬁed in the liver, gastrointestinal tract, kidney as well as other tissues in the body, each responsible for the active traﬃcking of substrates across cell membranes. These transport proteins are in fact regulated by the same pathways that regulate the Phase I and II enzymes, and they can be thought of as being regulated in tandem [76–80]. Immune activation results in a downregulation of Phase I components [81, 82], transporters [83, 84] and potentially