In type 1 diabetes (T1D), the insulin-producing pancreatic beta cells are destroyed by misguided immune cells. The incidence of childhood T1D has increased annually by ∼3 %, worldwide, although regional differences exist [
1,
2]. Genetic as well as environmental factors affecting the immune system and possibly beta cells contribute to the development of the disease. More than 40 genetic loci associated with T1D have been identified including those of insulin, cytotoxic T lymphocyte antigen 4 (CTLA-4), interleukin 2 receptor a (IL2RA), tyrosine phosphatase PTPN22, and the viral double-stranded RNA (dsRNA) sensor IFIH1 [
3]. However, human leukocyte antigen (HLA) loci, and in particular selected HLA class II DR and DQ alleles, confer the strongest risk being associated with ∼40 % of T1D cases, clearly indicating that susceptibility for the disease is at least partially inherited [
4]. Furthermore, regional differences in the incidence of T1D can be attributed, at least in part, to the varying frequencies of HLA haplotypes among different populations [
5]. On the other hand, studies conducted in several countries have revealed that concordance for the disease among monozygotic twins does not exceed 50 %, as it would be expected if T1D were to be caused by genetic factors alone [
6,
7]. Additionally, migration studies have shown that children of immigrants, who moved from an area with a low incidence to an area of high incidence of T1D, increased their risk for developing the disease compared to children in the area of origin [
8,
9]. Taken together, these data point to the contribution of environmental factors toward the onset and/or progression of autoimmunity directed against beta cells.
Viruses as Agents for T1D
Several viruses, including cytomegalovirus [
10], Epstein-Barr virus [
11], mumps virus [
12,
13], rotavirus [
14], and rubella virus [
15] are among the environmental factors thought to foster the development of T1D. Above all, enteroviruses (EVs), and especially coxsackievirus B (CVB), have been linked to the disease.
Animal models for virus induction of diabetes exist since 1968, when it was first shown that infection of adult mice with encephalomyocarditis virus resulted in persistent hyperglycemia secondary to degranulation and focal necrosis of islet beta cells [
16]. Subsequent studies in the non-obese diabetic (NOD) mouse, which spontaneously develops insulitis and autoimmune diabetes, pointed to the ability of both CVB3 and CVB4, also picornaviruses, to accelerate the onset of T1D in old prediabetic animals with established insulitis [
17,
18]. On the other hand, infection of young NOD mice with different strains of CVB3 and CVB4 reduced the incidence of T1D onset [
19]. From these data, one can conclude that the timing of infection might play a major role. Nevertheless, also various other factors such as the viral dose, the viral strain, and/or the species infected by the virus might be of importance. Findings from animal models might not necessarily reflect the conditions in human and, therefore, extrapolation from one species to another should be evaluated carefully.
In 1969, Gamble and colleagues first reported the occurrence of higher titer of neutralizing antibodies against CVB4 in recently diagnosed T1D patients [
20]. These authors also noted a seasonal pattern of T1D onset with incidence increasing in late fall and early winter following outbreaks of CVB infection [
21]. A decade later, Yoon and colleagues isolated CVB4 from the pancreas of a child, who died from diabetic ketoacidosis immediately after the onset of the disease, and induced diabetes in mice infected with the isolated virus [
22]. This was followed by further serological studies showing a correlation between T1D and EV infection [
23,
24]. However, a meta-analysis including 26 serological case-control studies found no convincing evidence for a correlation between CVB serology and T1D [
25]. Yet, blood samples from recent-onset T1D patients were found positive for enteroviral RNA by PCR [
26,
27]. Moreover, enteroviral RNA and capsid protein VP1 were detected in islets of pancreatic autopsy specimens from patients with T1D [
28‐
30]. In addition, another meta-analysis of 24 retrospective and prospective studies found a significant association between T1D-related autoimmunity and EV infection, as detected by measuring enteroviral RNA or protein in stool, blood, or tissue [
31]. Conversely, next-generation sequencing of plasma samples from children with rapid-onset T1D did not provide evidence for correlation with enteroviral infection [
32]. More recently, Krogvold et al. reported the expression of VP1 in <2 % of islets and low levels of enteroviral RNA in pancreatic biopsies from seven T1D subjects and thus postulated that a low-grade infection of islet cells contributes to the development of the disease [
33••]. On the other hand, EV infection might be responsible for a fulminant form of T1D reported in Japan, which is characterized by massive beta cell destruction in the absence of autoantibodies against beta cell antigens [
34,
35].
As in mice, some CVB strains may protect from the development of T1D in humans. In Finnish children, the presence of neutralizing antibodies against CVB1 was recently shown to be associated with an increased risk of beta cell autoimmunity, while neutralizing antibodies to CVB3 and CVB6 correlated with a reduced risk for T1D [
36••]. Due to the close phylogenetic relatedness of these three CVB serotypes, the authors suggested that CVB3/CVB6-specific T cells may induce an immunological cross-protection against the diabetogenic effect of a later CVB1 infection. Similar findings were also reported in a second study, which found the frequency of antibodies against CVB1 to be higher in diabetic children compared to controls [
37•].
These discrepancies about the role of EVs in the development of T1D in humans could reflect the different effects of different strains in different populations and the limitations of many studies (size of cohorts, types, timing, and frequency of sampling). Most recently, a nationwide, population-based cohort study in Taiwan concluded that EV infection is associated with an increased risk of childhood T1D [
38]. Also, repeated infections rather than a single event as well as the concomitance of other predisposing environmental factors might be needed for the development of the disease, which would make more difficult to prove an association. Furthermore, laboratory protocols have not been standardized and thus thresholds for detection may vary considerably, while transient infections may escape detection. Hence, despite the progressive applications of more sensitive and accurate methodologies, a consensus about a link between viral infection and the onset of T1D has yet to be reached. In light of this uncertainty, the acquisition of knowledge about the biology of viruses in beta cells may be useful.