**1. Introduction**

Type 1 diabetes (T1D) is one of the most common chronic diseases in developed countries and represents about 10% of all cases of diabetes. It is caused by a selective destruction of insulin-producing β cells in the pancreas. The disease has two subtypes: 1A, which includes the common, immune-mediated forms of the disease; and 1B, which includes nonimmune forms. In this review, we focus on subtype 1A, which for simplicity will be referred to as type 1 diabetes. [81, 34]. An increasing incidence rate of T1D has been observed for the last few decades especially in young individuals (less than five years old) [163]. The cause of T1D is still unknown. Several factors interact and lead to the development of the disease. An inflammatory islet infiltrate (insulitis) can be observed at the symptomatic onset of T1D, and reflects the immune response to β-cells [45]. T1D is an autoimmune disease, which implies a role of immune response effectors in the pathogenic processes and a failure of tolerance to‐ wards β-cell antigens.The susceptibility to T1D is influenced by genetic factors. More than 20 loci in addition to those located in the human leukocyte antigen (HLA) class II locus (es‐ pecially DQ and DR) on chromosome 6 are involved. Another contribution to the pathogen‐ esis of the disease could rely on epigenetic modifications (such as DNA methylation) and parent-of-origin effects [11]. Genetic modifications in the population cannot explain the rap‐ idly increased incidence of T1D in most populations. Altogether, the incidence variation from one season to another, the relationship between immigration and disease develop‐ ment, and the differences in incidence in different parts of the world in neighboring popula‐ tions with similar genetic profiles, suggest that the disease is a result of interaction of genetic and environmental factors [94].

© 2013 Hober et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Interplay between immune response, genetic and environmental factors such as nutriments, drugs, toxin and viruses play a role in the pathogenesis of the disease. Several teams paid attention to the relationship between viruses and type 1 diabetes, and their role in the patho‐ genesis of the disease. A novel subtype of type 1 diabetes called fulminant type 1 diabetes, without evidence of autoimmunity has been observed [61]. In that disease the role of viruses is strongly suspected as well, but is out of the scope of this chapter.

The serum levels of antibodies against measles, mumps, and rubella (MMR) and autoanti‐ bodies against pancreas islet cells (ICA), islet cell surface, glutamic acid decarboxylase auto‐ antibodies (GADA), and insulin were determined in 386 school children between 11 and 13 years of age, before and 3 months after vaccination with combined MMR vaccine. It has been shown that children with rubella antibodies before vaccination had higher levels of ICA than seronegative children [98]. However, a study conducted in 2003 showed inconsis‐ tent results: in fact, no signs of β-cells autoimmunity (ie detection of ICA, insulin autoanti‐ bodies (IAA), antibodies to the tyrosine phosphatase related IA-2 molecule (IA-2 A) and glutamic acid decarboxylase (GADA)) were detected in 37 subjects with congenital rubella syndrome or exposed to rubella virus during fetal life [165]. The role of rubella in the trig‐ gering of T1D has been determined in hamsters. This study revealed that an autoimmune process and diabetes developed after rubella virus infection in neonatal hamsters [121]. Some authors suggested the molecular mimicry as a mechanism for rubella virus causing T1D, on the basis of co-recognition of β-cell protein determinants, such as GAD, and various rubella peptides by T-cells [118]. Recently, a clinical study has confirmed a significant asso‐

Viruses and Type 1 Diabetes: Focus on the Enteroviruses

http://dx.doi.org/10.5772/52087

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ciation between type 1 diabetes incidence and rubella in children in Italia [120].

Rotavirus (RV), the most common cause of childhood gastroenteritis, has been suspected to trigger or exacerbate T1D in a few studies. Honeyman *et al.* showed a specific and highly significant association between RV seroconversion and increases in autoantibodies. Serum of 360 children with a parent or sibling with type 1 diabetes had been assayed for IAA, GA‐ DA, and IA-2A every 6 months from birth. In all children, 24 children had been classified as high-risk children because they developed diabetes or had at least 2 islet antibodies or 1 islet antibody detected on at least 2 occasions within the study period. In high-risk children, 86% developed antibodies to IA-2, 62% developed insulin autoantibodies, and 50% developed antibodies to GAD in association with first appearance or increase in RV IgG or IgA [70]. In 2002, Coulson et al demonstrated that rotavirus could infect pancreas *in vivo* [35]. In this study, nonobese diabetic (NOD) mice were shown to be susceptible to rhesus rotavirus in‐ fection. Pancreatic islets from NOD mice, nonobese diabetes-resistant mice, fetal pigs, and macaque monkeys supported various degrees of rotavirus growth. Human rotaviruses that were propagated in African green monkey kidney epithelial (MA104) cells in the presence of trypsin as previously described [128] replicated in monkey islets only [35]. In another study, the effect of RV infection on diabetes development, once diabetes was established, was de‐ termined on NOD and NOD8.3 TCR (transgenic for a T-cell receptor (TCR)) mice. The de‐ gree of diabetes acceleration was related to the serum antibody titer to RV. Thus, rotavirus infection aggravated insulitis and exacerbated diabetes, after β-cell autoimmunity was es‐ tablished [60]. Furthermore, rotavirus was also suspected to contain peptide sequences, in VP7 (viral protein 7), highly similar to T-cell epitopes in the islet autoantigens GAD and ty‐ rosine phosphatase IA-2, suggesting that T-cells directed against RV could induce or ampli‐ fy islet autoimmunity by molecular mimicry, in children with genetic susceptibility. Honeyman *et al.* also demonstrated that peptides in RV-VP7, similar to T-cell epitopes in IA-2 and GAD65, bound strongly to HLA-DRB1\*04. The proliferative responses of T-cells to

*2.1.2. Rotavirus*

The relationship between type 1 diabetes in human beings and animals and various viruses belonging to different families has been investigated. Enteroviruses are among the viruses most able to be involved in the pathogenesis of autoimmune type 1diabetes.

After a presentation of the role of various viruses in the disease we will focus on enteroviruses, and then the clinical studies that were conducted to assess the relationship between enterovi‐ ruses and autoimmune T1D will be detailled. Thereafter the results of experimental investiga‐ tions aimed to elucidate the link between these viruses and the disease will be analyzed.
