Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications

Abstract

Background: The Hygiene Hypothesis (HH) attributes the dramatic increase in autoimmune and allergic diseases observed in recent decades in Western countries to the reduced exposure to diverse immunoregulatory infectious agents. This theory has since largely been supported by strong epidemiological and experimental evidence.

Discussion: The analysis of these data along with the evolution of the Western world's microbiome enable us to obtain greater insight into microorganisms involved in the HH, as well as their regulatory mechanisms on the immune system. Helminthes and their derivatives were shown to have a protective role. Helminthes' broad immunomodulatory properties have already begun to be exploited in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes.

Summary: In this review, we will dissect the microbial actors thought to be involved in the HH as well as their immunomodulatory mechanisms as emphasized by experimental studies, with a particular attention on parasites. Thereafter, we will review the early clinical trials using helminthes' derivatives focusing on autoimmune diseases.

Figure 1

Immunoregulatory effects of helminthes on the immune system. Helminthes exert their immunoregulatory actions by modulating cells of both the innate and adaptive immune system. Regarding T-cells, helminthes may promote a Th2-type response and down-regulate Th1/Th17 differentiation, leading to increased Th2-type cytokine (IL-4, IL-5, IL-9, IL-10, IL-13) and decreased Th1/Th17-type cytokine (TNF-α, IFN-γ, IL-6, IL-12, IL-17) secretion. Furthermore, worms’ products enhance Treg cell proliferation, the latter hampering Th1/Th2/Th17 polarization mainly through the secretion of IL-10 and TGF-β. Helminthes also promote a regulatory phenotype of B-cells, DCs, and macrophages. Both tolerogenic DCs and regulatory M2-macrophages contribute to switching from a Th1/Th17 to a Th2/Treg profile. Finally, these parasites may hamper the proliferation of ILC2, a subset of innate immune cells responsible for allergic responses. Thus, helminthes create a tolerant environment ensuring their own survival but also protecting the host from immune-mediated conditions by limiting excessive inflammatory and autoimmune phenomena. We declare that this figure is original. Breg, B-regulatory cell; DC, Dendritic cell; IFN, Interferon; IL, Interleukin; ILC2, Type-2 Innate lymphoid cell; TGF, Transforming growth factor; Th, T-helper cell; TNF, Tumor necrosis factor; Treg, T-regulatory cell.