Figure 2

Human physiology was shaped by the hunter-gatherer way of life, which is regarded as the human "environment of evolutionary adaptedness," although there have been further adaptations during the approximately 10,000 years (≈500 generations) since the introduction of farming and livestock. Most human evolution has been cultural and technological rather than genetic, and a gene-environment misfit may be occurring. Harmless organisms that were abundant in food and water (such as environmental actinomycetes) and helminths that had to be tolerated developed a role in the induction of immunoregulatory circuits. Without these, there may be a failure to terminate inappropriate inflammatory responses, leading to an increased susceptibility to chronic inflammatory disorders, the precise nature of which depends on the genetics and history of the individual. DCreg = dendritic regulatory cells; Th = T helper; Treg = regulatory T cells.