The Old Friends Hypothesis. Organisms such as helminths and environmental saprophytes, that are part of mammalian evolutionary history (‘Old Friends’) and must be tolerated, are detected by pattern recognition receptors such as Toll-like receptor 2 (TLR2) and CARD15 on dendritic cells (DC). The DC mature into regulatory DC that drive regulatory T cell (Treg) responses to the antigens of these organisms. The continuing presence of these antigens in the gut flora, in food, or resident as parasites such as microfilariae, leads to continuous background release of regulatory cytokines from these Treg, exerting bystander suppression of other responses, as shown in the upper arm of the figure. Meanwhile the increased numbers of regulatory DC lead to increased processing by such DC of self antigens, gut content antigens and allergens, as shown in the lower arm of the figure. Therefore the numbers of Treg specifically triggered by these antigens is also increased, downregulating autoimmunity, inflammatory bowel disease and allergies respectively. In addition to this ability to prime regulatory pathways, microorganisms also provide adjuvants (such as inhaled endotoxin) that might enhance development and polarization of responses to some allergens and tumour antigens (see main text). CTLA-4, cytotoxic T-lymphocyte antigen 4; IL-10, interleukin-10; TGF-β, transforming growth factor-β.

Pathologies that are increasing, and that might be partly attributable to defective immunoregulation. Human evolution and physiology was shaped by the hunter–gatherer way of life, which is regarded as the human ‘Environment of Evolutionary Adaptedness’ (EEA). Despite increasing human genetic diversity, most human adaptation to novel environments has been cultural and technological rather than genetic, so a gene–environment misfit may be occurring, particularly in the immune system which is not linked to a conscious sensory modality that can warn us of problems. Harmless organisms that were abundant in food and water, 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. These disorders may be mediated by T helper type 1 (Th1), Th17 or Th2 lymphocytes, or be mixed, as in ulcerative colitis and Alzheimer's disease, or in individuals with no obvious inflammatory pathology, who have persistently raised circulating cytokines that are associated with depression.