Viral infections and molecular mimicry in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a disease characterized by inflammation of pancreatic islets associated with autoimmunity against insulin-producing beta cells, leading to their progressive destruction. The condition constitutes a significant and worldwide problem to human health, particularly because of its rapid, but thus far unexplained, increase in incidence. Environmental factors such as viral infections are thought to account for this trend. While there is no lack of reports associating viral infections toT1D, it has proven difficult to establish which immunological processes link viral infections to disease onset or progression. One of the commonly discussed pathways is molecular mimicry, a mechanism that encompasses cross-reactive immunity against epitopes shared between viruses and beta cells. In this review, we will take a closer look at mechanistic evidence for a potential role of viruses in T1D, with a special focus on molecular mimicry.

Fig. 1

A model for the development of T1D. (1) An unknown environmental agent, possibly a virus, triggers uptake and drainage of islet antigens. The virus may or may not infect beta cells directly as depicted, establish a local inflammatory milieu, or may act by directly activating T cells via molecular mimicry. (2) In susceptible individuals, autoreactive T cells recognize these antigens and become activated, resulting in (3) T cell release into the circulation and (4) B cell activation. (5) T cell effectors subsequently extravasate in the pancreas and M (6) recognize their targets, the beta cells, leading to ‘antigen spreading’ and (7) influx of new autoreactive T cell species. T cells attract innate cells such as macrophages during this progressed stage, which produce cytokines such as TNF-α and IL-1β. (8) Ultimately, most beta cells are destroyed and hyperglycemia develops.

Fig. 2

Possible timing of infectious events during the natural course of T1D. (1) The linear model proposed by Eisenbarth assumed the involvement of an environmental trigger, followed by a linear decline in beta cell mass. (2) An alternative scenario would imply the presence of low-grade, subclinical inflammation that is rapidly enhanced by an infectious agent around the time of onset. Beta cell decay is consequentially aggravated and enters an exponential decline. (3) Multiple infectious stages may act in concert in a hit-and-run fashion, ultimately driving most beta cells into apoptosis. Note that none of the pathways described here are mutually exclusive.