Coxsackievirus and type 1 diabetes: diabetogenic mechanisms and implications for prevention.

The evidence for an association between Coxsackievirus B (CVB) infection, pancreatic islet autoimmunity and clinical type 1 diabetes is increasing. Results from prospective cohorts and pancreas histopathology studies have provided a compelling case. However, the demonstration of a causal relationship is missing, and is likely to remain elusive until tested in humans by avoiding exposure to this candidate viral trigger. To this end, CVB vaccines have been developed and are entering clinical trials. However, the progress made in understanding the biology of the virus and in providing tools to address the long-standing question of causality contrasts with the scarcity of information about the anti-viral immune responses triggered by infection. Beta-cell death may be primarily induced by CVB itself, possibly in the context of poor immune protection, or secondarily provoked by T-cell responses against CVB-infected beta cells. The possible involvment of epitope mimicry mechanisms skewing the physiological anti-viral response toward autoimmunity has also been suggested. We here review the available evidence for each of these three non-mutually exclusive scenarios. Understanding which ones are at play is critical to maximize the odds of success of CVB vaccination, and to develop suitable tools to monitor the efficacy of immunization and its intermingling with autoimmune onset or prevention.