Review series on helminths, immune modulation and the hygiene hypothesis: how might infection modulate the onset of type 1 diabetes?

Abstract

The development of type 1 diabetes is influenced by both genetic and environmental factors. The current rise in the incidence of diabetes is occurring more rapidly than can be accounted for by genetic change, highlighting the influence of environmental modifiers. Considerable effort has been expended to identify infectious agents that might be responsible for this rise in incidence, but no single infectious agent has been linked to this dramatic increase in type 1 diabetes. There has been increasing interest in the possibility that infections of historical importance that might have shaped our immune systems over evolutionary time may also have played a role in down-modulating some autoimmune and allergic disorders. In this review, some of the ways in which certain organisms might have influenced the onset of autoimmunity are discussed.

Figure 1

Infection can inhibit the development of type 1 diabetes through a range of mechanisms. The development of type 1 diabetes is influenced by several genes with MHC Class II playing a major role. Over time there has been an interplay between the genetics of the host and infectious agents leading to a mutual adaptation. Infections which induce immunoregulatory cytokines such as IL-10 and TGFβ are able to downmodulate inflammation and also reinforce regulatory T cell activity and induce iNKT cell activity. Alternatively activated macrophages and ‘tolerogenic’ dendritic cells have been shown to inhibit Th1 responses through a range of mechanisms including skewing of the response to Th2, inducing regulatory T cells and producing amino acid catabolising enzymes such as arginase or indoleamine 2,3-dioxygenase. The induction of such responses limits host tissue pathology and benefits both infectious agent and host. aamφ, alternatively activated macrophages; DC, dendritic cell; IL, interleukin; iNKT, invariant natural killer T cell; TGF, transforming growth factor; Treg, regulatory T cell; Th, T helper.