The Hygiene Hypothesis or Old Friends Hypothesis

The mechanism by which these organisms prime immunoregulation and mediate protection from allergies, autoimmunity and IBD is explained by the fact that, rather than provoking aggressive immune responses, these organisms cause a pattern of maturation of dendritic cells (DC) that drives Treg rather than T helper cell 1 (Th1) or Th2 effector cells. See Figure 1 below.

This in turn leads to two mechanisms that help to control inappropriate inflammation. First, the constitutive presence of the ‘old friends’ causes continuous background activation of the regulatory DC (DCreg) and of Treg specific for the old friends themselves, resulting in constant background bystander suppression of inflammatory responses.

Thus, strikingly raised levels of IL-10 and TGF-b can be seen in individuals with parasite infections, and suppression of allergic manifestations in these individuals is attributed to the IL-10. Second, these DCreg inevitably sample self, gut contents and allergens, and so induce Treg specific for the illicit target antigens of the three groups of chronic inflammatory disorder. These inhibitory mechanisms are aborted when there are legitimate ‘danger’ signals.

The validity of this hypothetical model is supported by clinical trials and experimental models in which exposure to microorganisms that were ubiquitous during mammalian evolutionary history, but are currently ‘missing’ from the environment in rich countries, will treat allergy, autoimmunity or intestinal inflammation.

We do not understand all of the ways in which DCreg and Treg block or terminate inflammatory responses. However, the release of the anti-inflammatory cytokines IL-10 and TGF-b is often involved. In the next sections, we summarize the evidence that chronic inflammation is able

Hygiene hypothesis mechanism, how benign infectious organisms prime immunoregulatory circuits that control inflammation and anaphylaxis

Figure 1. Environmental organisms, that are part of human evolutionary history (‘old friends’), are recognized as harmless by pattern recognition receptors on DC. The DC mature into regulatory DC (DCreg) that drive regulatory T cell responses to the antigens of these organisms (Treg). The continuing presence of these antigens (left), either because they are inhaled into the lungs, present in the gut flora, ingested with food or water or resident as parasites that must be tolerated (such as microfilariae), leads to high continuous background release of regulatory cytokines, exerting bystander suppression of inflammatory responses and counteracting activation of the innate immune system. Meanwhile, the increased numbers of DCreg lead to increased processing by such DC of self antigens, gut content antigens and allergens (right). Therefore, the numbers of Treg specific for these antigens are also increased, downregulating autoimmunity, IBD and allergies, respectively.