**Acknowledgements**

**Figure 4.** Information brought by in vitro studies regarding coxsackievirus B infection

protective regulatory T cells with TGF-β production [49].

14 in US and even more than 30 per 100,000 in Scandinavia [139].

**6. Conclusion**

54 Type 1 Diabetes

**5.3. Complex relationship between enteroviruses and type 1 diabetes**

As mentioned above, the role of enteroviruses in T1D disease is strongly suspected. In con‐ trast, a protective role of enteroviruses is suggested as well. Experimental data in favour of a protective role of these viruses have been reported. Indeed, some studies have shown that, rather than triggering an autoimmune process, CVB infections can provide significant pro‐ tection against the development of T1D [155, 48]. Coxsackievirus B4, the human enterovirus most associated with an etiologic role in human T1D, has been reported to increase the rate of diabetes onset in older NOD mice but not in younger mice [134]. This result has been con‐ firmed by other groups who provided evidence that disease induction required a pre-exist‐ ing accumulation of β-cell specific autoreactive T cells within the pancreas, a phenomenon observed in older NOD mice, but not in younger mice [74, 156]. This protective effect may involve the virus strain, its virulence and replication rate, as well as the stage of autoim‐ mune development, and the mechanism relies in long-term tolerance due to an increase in

These findings support the concept that virus infections occurring early in childhood had a protective effect against T1D and are in agreement with the hygiene hypothesis [7, 157]. In‐ deed, it should be emphasized that there are significantly more enterovirus infections annu‐ ally than new cases of T1D in population. The decreased enterovirus exposure rates following the increased hygiene levels might explain the high risk of developing the disease, since it has been revealed in epidemiological studies that T1D incidence is higher in devel‐ oped countries than in developing ones, from less than 1 per 100,000 inhabitants in Asia to

Type 1 diabetes is a complex multifactorial disease. The involvement of enteroviruses as a major non-genetic etiological factor is a topic of reflexion for several research teams world‐ wide. Studies from these teams have shown that enteroviral infections, especially coxsackie‐ virus B infections, are closely linked with T1D. Findings from experimental in vitro and in vivo studies have lightened the potent role that can play enteroviruses in inducing and/or worsening the disease. However, in certain particular conditions, enteroviruses can induce a The authors thank Delphine Caloone for technical assistance and all their collaborators. The studies performed by the authors or in progress have been or are supported by EU FP5 VIR‐ DIAB Project (Contract QLK 2-CT-2001-01910), EU FP6 Integrated Project EURO-THY‐ MAIDE, (Contract LSHB-CT-2003-503410), EU FP7 PEVNET Project (FP7-HEALTH-2010 single-stage N° 261441), grants from Nord-Pas-de-Calais Région (ArCir convention 2004/018; BBS 2006), CHRU Lille, the ministère de l'Education nationale de la recherche et de la technologie, Université de Lille 2, France, and the comité mixte de coopération univer‐ sitaire franco-tunisien (CMCU 2004 N◦ 04/G0810 and CMCU 2008N808/G0808). Didier Hob‐ er was Fondation pour la Recherche Médicale 2008 prize winner. Didier Hober is a member of the VIrus in Diabetes International Study group (VIDIS group).
