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Mechanisms of Disease: the hygiene hypothesis revisited


In industrialized countries the incidence of diseases caused by immune dysregulation has risen. Epidemiologic studies initially suggested this was connected to a reduction in the incidence of infectious diseases; however, an association with defects in immunoregulation is now being recognized. Effector TH1 and TH2 cells are controlled by specialized subsets of regulatory T cells. Some pathogens can induce regulatory cells to evade immune elimination, but regulatory pathways are homeostatic and mainly triggered by harmless microorganisms. Helminths, saprophytic mycobacteria, bifidobacteria and lactobacilli, which induce immunoregulatory mechanisms in the host, ameliorate aberrant immune responses in the setting of allergy and inflammatory bowel disease. These organisms cause little, if any, harm, and have been part of human microecology for millennia; however, they are now less frequent or even absent in the human environment of westernized societies. Deficient exposure to these 'old friends' might explain the increase in immunodysregulatory disorders. The use of probiotics, prebiotics, helminths or microbe-derived immunoregulatory vaccines might, therefore, become a valuable approach to disease prevention.

Key Points

  • The recent identification of regulatory T cells has prompted a paradigm shift in our understanding of immune regulation

  • Deficient activity of regulatory T cells has been demonstrated in individuals with immune-mediated diseases

  • Induction and regulation of mucosal immunity occurs primarily in gut-associated lymphoid tissues and the gut-draining mesenteric lymph nodes

  • Helminths, saprophytic mycobacteria and lactobacilli have all been shown to stimulate regulatory-T-cell responses

  • Reduced exposure to relatively harmless microorganisms in modern society could be associated with defects in the development of immunoregulatory pathways

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Figure 1: Schematic representation of two major adaptive immune mechanisms in the gut.
Figure 2: Decision-making in the adaptive immune system is modulated by innate costimulatory signals.
Figure 3: The 'old friends' hypothesis.


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Correspondence to Francisco Guarner.

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Competing interests

Raphaëlle Bourdet-Sicard is employed by Danone Vitapole (Palaiseau, France), a company that produces probiotic products.

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Guarner, F., Bourdet-Sicard, R., Brandtzaeg, P. et al. Mechanisms of Disease: the hygiene hypothesis revisited. Nat Rev Gastroenterol Hepatol 3, 275–284 (2006).

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