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.

Abstract

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 autoimmune diseases, although the causal relationship with the occurrence of autoimmune diseases has not been established. Both pathogens and commensals act by stimulating immunoregulatory pathways. Here, I discuss the importance of innate immune receptors, in particular Toll-like receptors, in mediating the protective effect of pathogens and commensals on autoimmunity.

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Figure 1: The geographical distribution of autoimmune disease, infectious disease and wealth.
Figure 2: Stimulation of immune regulation by pathogens and commensals: the role of TLRs.

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Acknowledgements

The laboratory of the author was supported by an advanced grant from the European Research Council (ERC, Hygiene N°: 250290).

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PowerPoint slides

Glossary

Atopy

A genetic predisposition to the cumulative development of common allergies, for example, atopic dermatitis and allergic asthma. Atopy involves phenomena of cutaneous or general hypersensitivity to allergens.

Hygiene hypothesis

A hypothesis that postulates that an increased frequency of infections contributes to a decrease in autoimmune and allergic diseases.

Non-obese diabetic (NOD) mice

An inbred mouse line that spontaneously develops an autoimmune syndrome including insulin-dependent diabetes mellitus (IDDM or type 1 diabetes).

Traveller's diarrhoea

A digestive tract disorder provoked by eating contaminated food or drinking contaminated water. In the context of our discussion, it is a self-limited pathology that illustrates the presence of a basic health environment.

Anti-islet β-cell autoantibodies

Autoantibodies to various β-cell-specific autoantigens that are markers of the destruction of insulin-producing β-cells, which is the hallmark of insulin-dependent diabetes mellitus (IDDM or type 1 diabetes).

Dysbiosis

An imbalance of the microbial flora that most frequently affects the digestive tract. Dysbiosis can also be detected in other 'barrier' organs such as the skin, the lungs or the vagina.

Metabolome

The metabolome consists of all signalling molecules (for example, metabolites and hormones) detected in a biological sample. The metabolome thus defines a given physiological or pathological state and is therefore dynamic.

Germ-free mice

Mice born by hysterectomy under sterile conditions and raised in isolators to guarantee an environment totally devoid of pathogenic and commensal germs.

Experimental autoimmune encephalomyelitis

(EAE). A demyelinating allergic encephalomyelitis produced by the injection of brain tissue or purified proteins of the nervous system or their derived peptides in the presence of an adjuvant.

Gnotobiotic mice

Germ-free mice whose intestinal microflora is reconstituted by a single commensal bacterium (monocolonized mice).

Probiotics

Gut commensal bacteria available as single or combined species delivered orally and putatively endowed with a health benefit.

Antigenic competition

The competition for recognition of the cognate antigen for soluble factors (cytokines) driving the proliferation and differentiation of antigen-specific lymphocytes.

Syngeneic islet grafts

Islet transplants between syngeneic (genetically identical) donor and recipient individuals, which therefore does not give rise to allograft rejection. These grafts performed in diabetic non-obese diabetic mice provide a robust model to test for recurrence of the autoimmune disease.

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Bach, J. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol 18, 105–120 (2018). https://doi.org/10.1038/nri.2017.111

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