There is substantial epidemiological and in vivo evidence that human enteroviruses (EV) contribute to the development of type 1 diabetes. Many human EV genotypes demonstrate β-cell tropism; their specificity for β-cells is evidenced by detection of the Coxsackie adenovirus receptor, a major EV receptor, in the islets but not the exocrine pancreas. In a recent meta-analysis, we reported that EV infections were significantly associated with onset of type 1 diabetes (odds ratio ~10) and islet autoimmunity (odds ratio ~3) (1). However, viral infections can also protect from diabetes, possibly by an immunoregulatory or ‘bystander suppression’ effect.

Innate immunity and inflammatory mediators have a broad and important role in the pathogenesis of type 1 diabetes. Viral infection of β-cells initiates a complex molecular response, with increased expression of receptors critical for host antiviral response, such as Toll-like receptors and Melanoma Differentiation-Associated protein 5; activation of transcription factors such as NFκB and Interferon regulatory factor 3, which leads to production of cytokines and chemokines, resulting in β-cell apoptosis (2). Cytokines and chemokines are upregulated in pre-diabetes and therefore may provide additional surrogate markers of disease. However, there are limited data examining the interplay between EV infection and cytokines in the development of type 1 diabetes. We recently reported that children with islet autoimmunity demonstrate a marked and primarily pro-inflammatory cytokine profile, along with some immunoregulatory and anti-inflammatory effects. Apart from differences in IL-10 and IL-21, EV infection was not associated with a specific cytokine profile (3). However, circulating cytokine levels may not reflect local cytokine production by β-cells, particularly following acute infection. Furthermore, the contributory role, if any, of many cytokines in the disease pathway remains to be defined.