The hygiene hypothesis in autoimmunity: the role of pathogens and commensals

Key Points The initial application of the hygiene hypothesis for autoimmune diseases proposed in the early 2000s has been confirmed and consolidated by a wealth of published data in both animal models and human autoimmune conditions. The hygiene hypothesis probably explains the uneven geographical distribution of autoimmune diseases in the world. Individuals migrating from countries with low incidence of autoimmune diseases to countries with high incidence develop the disease with the frequency of the host country, provided that migration occurred at a young age and under a threshold that varies according to the disease. Pathogenic bacteria, viruses and parasites are often endowed with strong protective effects on autoimmunity even when infection occurs late after birth. Gut commensal bacteria may also have a protective role in autoimmunity when administered early in life. Pathogens, parasites and commensals essentially act by stimulating immune regulatory pathways, implicating the innate and the adaptive immune system. Importantly, the effect is seen with both living organisms and their derivatives or purified extracts. Both pathogens and commensals stimulate pattern recognition receptors, including Toll-like receptors (TLRs) to protect against autoimmunity. This effect may be mimicked by TLR agonists acting through pharmacological stimulation or desensitization of the target receptor. The hygiene hypothesis postulates that an increased frequency of infections contributes to a decrease in autoimmune and allergic diseases. Here, Bach summarizes the epidemiological and experimental evidence supporting this hypothesis and discusses the importance of innate immune receptors in mediating the protective effect of pathogens and commensals on autoimmunity. The incidence of autoimmune diseases has been steadily rising. Concomitantly, the incidence of most infectious diseases has declined. This observation gave rise to the hygiene hypothesis, which postulates that a reduction in the frequency of infections contributes directly to the increase in the frequency of autoimmune and allergic diseases. This hypothesis is supported by robust epidemiological data, but the underlying mechanisms are unclear. Pathogens are known to be important, as autoimmune disease is prevented in various experimental models by infection with different bacteria, viruses and parasites. Gut commensal bacteria also play an important role: dysbiosis of the gut flora is observed in patients with