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Invited Reviews

Rotavirus Infections and Development of Type 1 Diabetes: An Evasive Conundrum

Ballotti, Serena; de Martino, Maurizio

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Journal of Pediatric Gastroenterology and Nutrition: August 2007 - Volume 45 - Issue 2 - p 147–156
doi: 10.1097/MPG.0b013e31805fc256
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Type 1 diabetes (T1D) is the second most common form of diabetes mellitus worldwide, accounting for as many as 10% of diabetic patients (1). According to the most recent classification of diabetes by the American Diabetes Association Expert Committee and the World Health Organization Consultation, T1D can be subdivided into 2 subtypes: immune-mediated (type 1A) and idiopathic (type 1B) diabetes (2). Type 1A diabetes is a multifactorial disease that results from autoimmune destruction of insulin-producing β cells in genetically predisposed individuals (2). Type 1B diabetes is a heterogeneous insulin-deficient subtype of diabetes with a remarkably rapid onset. In type 1B diabetes the destruction of insulin-producing β cells is not associated with immunological evidence of β cell autoimmunity (3,4).

The presence of autoantibodies at the onset of T1D strongly suggests the autoimmune nature of this subtype of diabetes (1,5). Autoantibodies against β cell antigens can be present early in life and may predict the development of T1D, acting also as valuable markers of disease activity (6,7). Generally, insulin autoantibodies (IAA) are the first to appear, followed by antibodies to multiple β cell antigens, such as autoantibodies to the 65-kDa isoform of glutamic acid decarboxylase (GADA), tyrosine phosphatase-related IA-2 molecule (IA-2A), and to islet cells (ICA) (8). In diabetic patients IAA disappear more often than other autoantibodies, whereas ICA are more likely to persist (8,9). The presence of IA-2A seems to be associated with a more rapid evolution of T1D and represents an important predictor of progression to disease in siblings of patients with T1D (10). The presence of a single autoantibody may be transient and is usually associated with nonprogressive or regressive β cell autoimmunity. By contrast, the presence of at least 2 diabetes-associated autoantibodies represents a kind of point of no return because seroreversion is rarely observed (8,9).


Genes play a relevant role in the development of T1D. The human leukocyte antigens (HLA) account for 50% of the inherited risk for T1D (11). However, a T1D concordance rate of 30% to 50% (and consequently, a 50%–70% discordance) in monozygotic twins suggests that both genetic and environmental agents are involved in disease development (11–13). A Danish study indicated an equal prevalence of ICA in dizygotic and monozygotic twins of T1D patients, stressing the importance of external factors in the development of β cell autoimmunity (14). These findings have been discussed by Redondo et al (15), who observed evidence that monozygotic and dizygotic twins of T1D patients display differences in progression to diabetes and in ICA production. In particular, autoantibody prevalence is similar between dizygotic twin and nontwin siblings of patients with T1D, whereas it is higher in monozygotic twins (15). This finding suggests the role of inherited factors in islet autoimmunity (15,16).

The incidence of T1D is rising in almost all populations, particularly in younger age groups (0–4 years), with a consequent decrease in the average age of onset (17–19). An earlier age at onset is usually associated with a higher proportion of HLA high-risk haplotypes, whereas the contribution of additional factors seems to be less (20). However, the rise in recent decades in the incidence of T1D has been too fast to be explained only by a major transmission of susceptible haplotypes (21). It is likely that an increased pressure exerted by environmental factors must be considered. Gillespie et al (20) compared the frequency of HLA susceptible haplotypes in 2 different cohorts of patients with previous or recent diagnoses, demonstrating that high-risk susceptibility haplotypes were increased in the earlier cohort (P = 0.003), especially in those who received diagnoses before the age of 5 years. In patients with new diagnoses, an increase of lower risk haplotypes has been revealed (21). These results are consistent with a major involvement of environmental factors in T1D development, with particular attention to external events occurring during the early part of life.


Infectious agents are the most studied environmental factors potentially involved in autoimmunity induction, because they represent a potent stimulus for the immune system and may contribute to the selection and triggering of autoreactive lymphocytes in susceptible individuals. Furthermore, the seasonal differences in T1D incidence and the frequent report of local “epidemics” of T1D suggest a key role for infectious agents (22–24). Infections may contribute to β cell destruction and/or initiate an autoimmune disease, operating at various levels and through several mechanisms (13,25,26).

An acute viral infection of the pancreas may cause massive β cell destruction with a non–immune-mediated mechanism and consequent development of insulin deficiency and T1D. Several studies have shown the presence of viruses in the pancreas at the onset of the disease, and the ability of many viruses to replicate in the pancreas is known (27,28). However, acute fulminant infections are not consistent with the commonly observed history of T1D, characterized by the presence of a long autoantibody-positive interval that suggests that the disease has an autoimmune nature.

A viral pancreatic infection has been hypothesized to explain the pathogenesis of type 1B diabetes. The high frequency of flulike symptoms and the common absence of insulitis before the rapid onset of type 1B diabetes suggest an infective pathogenesis (3,4). However, the recognition of GAD-reactive or insulin-reactive Th1 cells in patients with type 1B diabetes indicates that the mechanism of β cell destruction may be heterogeneous and partially immune mediated (29).

An early direct infection of the fetal pancreas, resulting in β cell dysgenesis, has been hypothesized in T1D associated with congenital rubella syndrome (CRS) (13,30). The rubella virus can infect human β cells in vitro and induce hyperglycemia and hypoinsulinemia in animal models (30,31). However, rubella virus infection of human β cells in tissue culture is associated with hypoinsulinemia but not with an evident cytopathic effect (32). Thus, it seems unlikely that a similar mechanism is operating in T1D development. In CRS patients with T1D, T cell clones that cross-react with rubella virus epitopes and GAD have been reported, suggesting an immune-mediated mechanism (33). However, the data about the presence of β cell autoimmunity in T1D associated with CRS are controversial. Diabetes-associated autoantibodies have been reported in 20% to 25% of patients with CRS (34,35). By contrast, Viskari et al (36) did not demonstrate the presence of β cell autoimmunity in CRS patients. (36) Finally, a recent report described a reduced prevalence of T1D associated with CRS in Japanese patients, all of whom had autoantibodies against pancreatic β cells (37). At present, rubella virus is the only pathogen for which a significant casual association with T1D has been established. Indeed, rubella virus satisfies all 9 of the criteria proposed to establish the causality of a disease: temporal relationship, statistical strength, dose–response relationship, consistency, plausibility, rejection of other alternative explanations, the possibility to replicate experimental results, specificity, and coherence (13,25). Despite this the exact mechanism underlying rubella-mediated pathogenesis is still unknown.

Pancreatic viral infections may also act indirectly, providing a “fertile field” for an interruption in peripheral tolerance and the induction of autoimmunity. Specific mechanisms, such as bystander activation or epitope spreading, may contribute to this scenario (38–41). Viruses may activate antigen presenting cells (APC) at the site of infection. Activated APC could elicit a response by local anergic cells or stimulate the proliferation of local autoreactive cells, which may initiate autoimmune disease (bystander activation of autoreactive T cells) (26,40). Alternatively, the cytolysis of infected cells realized by virus-specific T cells leads to the release of cytokines such as tumor necrosis factor-β and nitric oxide, which can induce the bystander killing of the uninfected neighboring cells (26,38,39). Moreover, the exposition of hidden autoantigens consequent to cell damage offers new targets for autoimmune responses, according to a mechanism of epitope spreading (42). The specific immune response is initially limited to an antigen region of high reactivity, but subsequently other epitopes within the same protein (intramolecular epitope spreading) (42,43) or other peptides within the same antigenic complex (intermolecular epitope spreading) can be involved (43,44).

Virus persistence increases the risk of an autoimmune phenomenon because of the constant presence of viral antigens activating the immune response. In turn, an aberrant immune response can lead to a delay in virus clearance and favor autoimmunity induction (38). Children with T1D display a generally impaired type 1 immune response against virus in vitro (45–48). Flodström et al (49) demonstrated that coxsackievirus B3 can cause T1D in mice lacking adequate interferon (IFN) antiviral responses. Moreover, a recent study conducted in murine models identified genetic variants in the Idd4 locus, which is involved in the regulation of the threshold for triggering the IFN pathway in macrophages (50). An impaired secretion of IFN-γ by macrophages or APC may alter type 1 responses and enable virus persistence.

IFN-γ is also crucial to mediate the killing of β cells, either by a direct effect or by enhancing of β cell sensitivity to tumor necrosis factor (51). Thus, an upregulation of this cytokine may increase β cell loss and favor the progression of diabetes (52). In summary, the multiple role of IFN-γ (mediator of antiviral responses and effector of immune-mediated cell death) is difficult to evaluate because it likely changes according to the features of the environment and the nature of the viral infection.

Viruses may encode for proteins with superantigenic activity. Indeed, a skewing of T cell receptor Vβ chain selection in lymphocytes infiltrating pancreatic islets at the onset of T1D has been described (53,54). A possible explanation is a T cell activation driven by a viral superantigen, which may lead also to the activation and expansion of autoreactive T cells (55).

Several studies highlight the critical role of regulatory T cells in T1D. Regulatory T cells are involved in the maintenance of peripheral tolerance (56). Several subpopulations of regulatory T cells exist in human and murine models. CD4+CD25+ T cells are naturally occurring regulatory T cells that develop in the thymus and exert a suppression function in the periphery (56,57). The mechanism underlying regulatory T cell suppression is not completely defined. Cell-to-cell contact between effector cells and regulatory T cells, secretion of cytokines, and interaction with APC have been proposed, and they may act in a not–mutually exclusive way (58,59). In murine models the adoptive transfer of CD4+CD25+ T cells prevents T1D (60,61), whereas individuals with T1D demonstrate a decrease in regulatory function of this T cell subpopulation in comparison with healthy individuals (62–65). The microenvironment in the periphery may highly influence the capacity of regulatory T cells to exert their functions. Thus, viral infections may interrupt the balance between regulatory T cells and effector cells, enabling autoreactive T cells to expand. Alternatively, viruses may contribute to the inactivation or destruction of regulatory T cells. An increase in CD4+CD25+ T cell apoptosis has been recently described in patients with recent-onset T1D and in individuals at high risk for the development of T1D (66).

One intriguing process that may explain the relationship between autoimmunity and viral infections is molecular mimicry. This mechanism implies a cross-reactivity between viral and self-determinants (67). Molecular mimicry may become effective through random assembly of antibody variable, diversity, and joining gene segments and development of a wide repertoire of T cell receptors able to recognize both foreign antigens and autoantigens (68). Furthermore, many individual T cell receptors may degenerate, with a consequent change in specificity (69). It is possible, then, that T or B lymphocytes, activated during an immune response to infectious agents, may recognize self-determinants and initiate an autoimmune process (68,69). Moreover, cumulative infections, with viruses that share antigenic determinants with autoantigens, may lead to the generation of a pool of autoreactive T cells (70). Thus, it may be that a single further viral infection, also unrelated to previous infectious events, triggers the final cascade determining β cell damage and T1D (40).

Despite the intriguing data available, the evidence of functional molecular mimicry in human T1D is still missing, and several points remain unresolved. First, the presence of a homology between viral peptides and self antigens does not necessarily induce activation of immune responses, but it can also determine anergy or abrogate effector functions (71). Another critical point in autoimmunity induction by molecular mimicry is represented by the avidity of mimic epitope; a low-affinity epitope may be not sufficient to induce the cross-reactive T cell activation and necessitate an additional environmental factor (68). Finally, the presence of β cell antigen–reactive T cells both in T1D patients and in healthy individuals has been repeatedly described (72,73). This suggests that the presence of a certain degree of “benign” autoimmunity, generally transient, may have a protective effect, for example, contributing to the homeostasis of peripheral regulatory T cells (74,75). This hypothesis is supported by the recent finding of an equal frequency of β cell autoimmunity among schoolchildren in Russian Karelia and in Finland, although the incidence of T1D is 6 times higher in Finland. By contrast, IA-2A was more frequent in Finland. Inasmuch as IA-2A is commonly the latest autoantibody to appear in the preclinical phase, this suggests that in Russian Karelia, progressive β cell autoimmunity is rarer, whereas a “benign” autoimmunity may be prevalent (76).


Rotaviruses (RV) are a major cause of severe pediatric gastroenteritis worldwide (77). RV infections have been long considered to be restricted to the small intestine, where the virus replicates in the mature villous epithelial cells. RV infection is actually systemic, with an acute active viremia and extraintestinal replication, as the authors have previously reported (78,79). These findings highlight the plausibility of RV involvement as an etiological factor in nongastrointestinal diseases (80).

Accumulating evidence points to a role of RV as possible triggers of the immune-mediated destruction of pancreatic β cells leading to T1D. Several aspects of this potential correlation have been evaluated (Fig. 1).

FIG. 1
FIG. 1:
Potential mechanisms involved in RV-mediated β cell destruction. An involvement of the pancreas by RV infections is possible, with a direct cytotoxic effect on β cells. Alternatively, β cell damage may be immune mediated, with several potential mechanisms including molecular mimicry and epitope spreading, generally together with bystander processes.

Epidemiological Data

Epidemiological data support the coherence of a correlation between RV infections and T1D. The incidence of RV infections typically increases after the age of 6 months with the decline of maternal antibody levels (81,82). The highest frequency of RV infections is registered in early infancy, especially in children under the age of 4 years. This is the same age group in whom T1D incidence rapidly increased in recent decades (77).

Honeyman et al (83) monitored from birth a cohort of children at risk for T1D and reported a significant association between RV infections and the increase of IA-2A and GADA levels. Strikingly, a RV infection seemed temporally associated with the first appearance of IAA, GADA, and IA-2A in children with a first-degree T1D. ICA levels, instead, increased on repeated RV infections. However, a Finnish study later failed to confirm a similar correlation. In fact, children at risk for T1D in whom diabetes-related autoantibodies developed did not experience more RV infections than those in the control group (84).

Several differences exist between the Finnish and the Australian studies. Different RV serotypes with different epidemiological distributions were taken into account (13). The Australian authors considered for the diagnosis of RV infection both RV-specific immunoglobulin G (IgG) and IgA levels. The Finnish authors used IgG titers only because of the booster effect on IgA levels caused by prolonged shedding of RV associated with an acute infection. However, the use of only RV-specific IgG may increase the probability of false-negative results because some infections early in life are detectable only by RV-specific IgA (85). Furthermore, the Australian authors interpreted consecutive increases in antibody levels as separate RV infections. The Finnish authors considered, instead, repeated infections as rare events. (84). To clarify this point, Mäkela et al (86) analyzed the correlation between the RV-specific lymphoproliferative responses and the antibody titers in young children who were prospectively followed up. T cell responses are weak in infancy but increase in adults and seem to be tightly related to increases in antibody titers. Consecutive increases in antibody levels seem to reflect, consequently, the occurrence of several reinfections with a progressive maturation of T cell responses.

Molecular Mimicry

A body of evidence has established an analogy between the tyrosine phosphatase IA-2, 1 of the major β cell antigens in T1D, and the protein VP7 of RV serotype G3 and, with a lesser affinity, G1 and G2. Indeed, the immunodominant T cell epitope of IA-2 shows 56% identity with, and 100% similarity to, a sequence in RV structural protein VP7 (87). Both viral protein and self antigen are restricted for the susceptible HLA-DR4 (*0401) haplotype, suggesting an identical presentation to T cells (87,88). Furthermore, the VP7 amino-terminal region of all RV serotypes displays a high degree of similarity with a sequence in GAD65 that represents a T cell epitope both in mice and in predisposed humans (87).

VP7 GAD- and IA-2-related regions contain sequences acting as immunogenic epitopes, able to bind HLA class II molecules and elicit an anti-RV cytotoxic immune response (89). Thus, these VP7 regions, normally involved in antiviral immune responses, present a potential for molecular mimicry. RV infection may activate T cells, which can cross-react with 2 prominent β cell antigens, initiating or enhancing insulitis.

Epitope Spreading

RV infection may induce inflammation of the pancreas, causing tissue damage and the exposition of new autoantigens, targets of the autoimmune response. The specific immune response, initially limited to a region of strong reactivity, can extend or change to include other epitopes (42,43). Schlosser et al (90) recently established that T1D progression from the preclinical stage to overt disease is accompanied in genetically predisposed individuals by a process of intramolecular epitope spreading for GADA, which can consequently be useful for monitoring T1D activity. Bystander mechanisms, such as cytokine secretion, may also actively contribute to an interruption in peripheral tolerance, activating anergic or low-affinity autoreactive T cells.

Cellular Immunity

RV infection induces RV-specific T cells and cytokine production in children (86). CD4+ T cells are essential for the development of RV-specific IgA in murine models (91,92). CD8+ T cells exert a direct antiviral effect, being involved in the resolution of a primary RV infection and in the prevention of reinfections (93,94). T cell responses in children are weak and decrease rapidly after an acute infection (95). Moreover, children with RV diarrhea have very low levels of CD4+ and CD8+ T cells producing IFN-γ (96). This suggests a potential delay in virus removal, with an enhanced risk of extraintestinal spread and infection of pancreatic β cells. A similar mechanism has been recently suggested for coxsackievirus B4 (97). In healthy adults, by contrast, T cell proliferative responses and cytokine production are increased and persistent (96). This indicates the need for several RV infections to reach a consistent and persistent T cellular responsiveness.

A recent study compared the responsiveness of peripheral blood T cells to RV antigens between children with newly diagnosed T1D, healthy children with T1D-associated autoantibodies, and control children (98). If T1D or T1D-associated autoantibodies depend on molecular mimicry between RV and β cell antigens, an increase of T cell responsiveness to RV antigens may be expected. Alternatively, the presence of an impaired immune response to RV may favor a chronic viral infection. However, the authors did not find any differences in T cell responses against RV between children with T1D, T1D-associated autoantibodies, and control children (98).

Caution is needed in considering these results because several aspects have yet to be clarified. Previous studies that analyzed T cell responsiveness to viral homologous antigens gave conflicting results (99–103). Besides RV-specific T cell responsiveness, Mäkela et al (98) also investigated T cell responses to a coxsackievirus B lysate antigen, and no differences were found between children with T1D-associated autoantibodies and control children. By contrast, in previous reports the same authors demonstrated an increased T cell responsiveness to coxsackievirus B in children positive for T1D autoantibodies and in those with non–newly diagnosed T1D (100,101). Also, Jones et al (99) observed a strong T cell response to a CBV4 lysate antigen in individuals with newly diagnosed T1D. However, other authors failed to obtain the same results (102,103).

Technical differences may have a role in determining these divergent results (104,105). Moreover, the study of Mäkela et al (98) did not report the time intervals between eventual RV infections and sample collection in the children studied. A sample collected after a short time from a patient with RV infection may overestimate T cell responsiveness, above all in younger children, whose T cell responses are weak and decline quickly. A prospective study may allow a better definition of correlations between antibody level variations and T cell responsiveness.

Finally, RV-specific memory CD4+ T cells that proliferate in response to RV infections express high levels of α4β7 (intestinal homing receptor). CD4+ T cells expressing high levels of α4β7 interact with the mucosal vascular addressin cell adhesion molecule-1 (MadCAM 1) present on the vascular endothelium of the postcapillary venules in the gut. This binding mediates CD4+ T cell homing to intestinal Peyer's patches and lamina propria and CD4+ T cell recirculation through intestinal tissues (106). Thus, it is likely that a part of RV-specific memory CD4+ T cells expressing high levels of α4β7 is localized to the intestine and is not present for detection in the circulation.

Alterations in Intestinal Permeability

Recent reports suggest that alterations in gut permeability may play an important role in the pathogenesis of autoimmune diseases. VP7 and VP4 are RV structural proteins and represent important virulence factors for the virus, allowing receptor binding and cell penetration. These events are mediated by the proteolytic cleavage of VP4 by pancreatic trypsin into VP5 and VP8 subunits (107). The latter seem to be able to alter tight junction fence function, increasing epithelial permeability in a reversible, time-dependent, and dose-dependent way (108). One suggested hypothesis is that alterations in intestinal permeability, induced by RV together with a local modified cytokine microenvironment, contribute to autoimmune phenomenon (108). Moreover, IFN-γ and tumor necrosis factor-α produced during RV infection alter the function of tight junctions and exert a direct toxic effect on epithelial cells, eventually enabling the transit of potentially pathological factors that may favor autoimmune events (109).

The upregulation of zonulin in a subgroup of T1D patients was recently described. Zonulin increases intestinal permeability, and its augmented expression seems to precede the onset of T1D (110). This may confirm the intriguing correlation between the loss of intestinal barrier function, the increased exposure to several antigens, and the development of autoimmune diseases in predisposed individuals.

A recent study showed evidence of a relation between enteral viral infections, high concentrations of insulin-binding antibodies, and the appearance of β cell autoimmunity in children fed with cow's milk formula (111). Interestingly, higher levels of insulin-binding antibodies were present in children who experienced enteral infections (by adenoviruses, enteroviruses, or RV) before 6 months of age, compared with those who were unaffected. These data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin present in cow's milk. An increased antibody response to dietary insulin preceded the development of β cell autoimmunity and T1D (111). Mechanisms potentially involved may be an increase of the intestinal absorption of dietary macromolecules (eg, bovine insulin molecules), the enhancement of local inflammation and immune responses to food antigens, and consequent upregulation of Toll-like receptors, with a possible interruption in peripheral tolerance (112).

Similar mechanisms have been hypothesized for celiac disease. Stene et al (113) suggested that an augmented frequency of RV infections may be associated with an increased risk of development of serum tissue transglutaminase (tTG) autoantibodies, a typical serological marker in patients with active disease. RV infections and the consequent inflammation may be responsible for the initial secretion of intracellular tTG and the increase in intestinal permeability. This may lead to augmented intact gliadin molecule absorption and facilitated gliadin deamidation in nonself T cell epitopes recognized in celiac disease (113). Moreover, a recent study identified in active celiac disease a subset of tTG antibodies recognizing the viral protein VP-7, suggesting a possible mechanism for the involvement of RV infections in the pathogenesis of the disease. These antibodies recognize self antigens and seem to be able to augment intestinal absorption and induce monocyte activation, through the engagement of Toll-like receptor 4 (114). If definite associations between infections, increased intestinal permeability, and autoimmunity could be achieved, then several new therapeutic and prevention measures, such as dietary changes or vaccinations, may be evaluated as preventive measures not only for infectious diseases but also for T1D and celiac disease.

Direct Involvement of the Pancreas

A potential mechanism to explain the relation between RV infections and T1D is through direct involvement of the pancreas, as in the rubella model. Some reports have documented pancreatitis during RV diseases in children (115,116). RV dissemination and replication has been demonstrated in several organs, including the pancreas, in a neonatal rat model inoculated intragastrically with human RV (80). Interestingly, RV extraintestinal dissemination also occurs in the presence of maternal antibody or active immunity and in the absence of diarrheal disease (80). In experimental models Rhesus RV induced hepatitis in 21% of normal mice and 84% of neonatal immunodeficient mice, whereas reovirus, another member of the Reoviridae family, has been associated with T1D-like syndromes and pancreatitis in mice (117). Reovirus infections of human endocrine pancreas were associated with an increase in major histocompatibility complex class I molecule levels and β cell apoptosis (118).

RV-specific memory CD4+ T cells show high levels of the intestinal homing receptor α4β7. The selected expression of specialized homing receptors on RV-specific memory CD4+ T cells leads to a compartmentalization of immune response that results in their being localized mainly to the gut (106). However, adhesion molecules interacting with α4β7 were found to be constitutively expressed also in pancreatic islets. Thus, RV-specific memory CD4+ T cells showing high levels of α4β7 can infiltrate pancreatic islets and induce cellular damage (119). This may contribute to the susceptibility of islets to T cell–mediated attack (119).

Finally, it is interesting to note that RV requires cleavage by the pancreatic trypsin to acquire its virulence, confirming the existence of a close relation. Coulson et al (120) demonstrated the susceptibility of pancreatic islets in nonobese diabetic mice to a certain degree of Rhesus RV growth, whereas human RV are able to replicate in monkey islets. These findings suggest the possibility of a direct infection of the pancreas as a pathogenic process. This mechanism may operate not exclusively but synergistically with molecular mimicry or bystander activation to induce or favor an autoimmune phenomenon leading to overt disease (120).


Although several significant results have been obtained, the exact pathogenic relationship between enteral infections and T1D is not yet well defined. This is also due to difficulties in investigating complex phenomena such as multifactorial diseases.

RV infections satisfy many but not all 9 criteria to verify the causality of a disease, as suggested by Honeyman (13). A temporal relation between RV infections and T1D development was evidenced by an Australian study but was not confirmed by a Finnish study (83,84). The statistical strength of the association between RV infection and the appearance of islet autoantibodies has been demonstrated (13,83).

The dose–response relationship has been demonstrated by the association between repeated infections and the appearance or increase of islet autoantibody titers. This association is specific because only islet antibodies rose, whereas no other autoantibody movements have been observed (13).

The plausibility is supported by the structural identity between viral epitopes and islet cell antigens, with the potential for molecular mimicry (87–89). Moreover, pancreatic trypsin is fundamental for RV virulence, and RV may infect the human pancreas, as demonstrated in vitro by several experiments (80,120). Recent reports, furthermore, hypothesize a potential correlation between RV infections, increase in intestinal permeability, and autoimmunity development, not only for T1D but also for other autoimmune disease such as celiac disease (108,110–112).

The coexistence of other infections explaining the increase in autoantibody titers has not been demonstrated (13,83). Finally, the coherence of this association is supported by the increase of TD1 incidence in children from birth to 4 years of age, who represent the population principally affected by RV infections (17–19). Consistency is missing because of the different results between the Australian and Finnish studies (83,84). Also, the results of reports on cellular immunity seem inconsistent (98,99).

The implications of a potential relationship between RV infections and T1D are relevant, above all in terms of prevention. In fact, if a similar hypothesis were to be confirmed, vaccination against RV, like that against EV, may be taken into account as a valid attempt to prevent T1D.


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Bystander activation; Cellular immunity; Molecular mimicry; Rotavirus; Type 1 diabetes

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