A number of epidemiological studies support the hypothesis that viral infections play a causative role in type 1 diabetes. However, systematic review of control studies published between 1966 and 2002 has shown no convincing evidence for or against an association between type 1 diabetes and the prime candidate for infectious cause, Coxsackievirus B (CVB). In animal models for type 1 diabetes, solid evidence supporting an inductive role for viruses is faced with just as solid evidence supporting a protective effect of viral infections. For example, based on mouse studies alone, there is no doubt that association between viruses and type 1 diabetes is extremely complex: while belonging to the same enteroviral group, CVB3 and CVB4 have opposing effects on type 1 diabetes in the same mouse model. Thus, the reason for current failure to associate a particular virus with induction of autoimmune diabetes likely is that such an association might be impossible to make. Certain viruses might be capable of inducing diabetes and others of preventing diabetes, and type 1 diabetes inducers might be capable of preventing disease under certain conditions. This will depend of course on the nature of the considered virus, but also on the state of advancement of autoimmunity at the time of infection. A given viral infection could thus be an essential disease precipitator once required predisposing events have occurred, but could on the other hand disrupt accumulation of these events.
Most important is the indication from animal studies that modulation of autoimmunity during viral infection does not depend merely on inherent properties of the virus, but also significantly on intrinsic factors of the host. The close interplay between the two will dictate whether enhancement or abrogation of autoimmune diabetes occurs. While molecular mimicry might activate autoreactive T-cells, it could also segregate these cells away from the islets and/or induce the activation of protective Tregs. While inflammatory cytokines might promote bystander activation of APCs and autoreactive T-cells, infection could occur at a time where inflammation will induce the relocation or demise of these cells. Whereas β-cell lysis and presentation of islet antigen might promote activation of autoreactive T-cells, it could also suppress the function of these cells by promoting Treg activity. Whereas repeated/sustained infections might lead to the accumulation of autoreactive T-cells within the memory pool, they could also induce suppressor mechanisms that will hinder autoimmunity.