Enterovirus infections are associated with the induction of β‐cell autoimmunity in a prospective birth cohort study

Abstract

Enterovirus infections have been associated with the manifestation of clinical type 1 diabetes in a number of reports, and recent prospective studies have suggested that enterovirus infections may initiate the autoimmune process, leading to the disease. In the present study, we analyzed the role of enterovirus infections in a Finnish birth cohort study, Diabetes Prediction and Prevention (DIPP), in which all newborn infants are screened for diabetes-associated HLA-DQB1 alleles, and those with an increased genetic risk are invited for prospective follow-up. Enterovirus infections were diagnosed by serology and reverse transcriptase-polymerase chain reaction (RT-PCR) from serum samples taken from birth every 3-6 months. Case children included 41 infants who became positive for diabetes-associated autoantibodies during the observation. Control children comprised altogether 196 infants who remained autoantibody negative and were matched for the time of birth, sex, and HLA-DQB1 alleles. Enterovirus infections were more frequent in case children than in control children (P = 0.004), and the average enterovirus antibody levels were also higher in the case children (P = 0.003). Enterovirus infections were particularly frequent during the 6-month period preceding the first detection of autoantibodies: 51% of the case children compared with 28% of the control children had an infection in that time interval (P = 0.003). There was no difference in the frequency of adenovirus infections between the groups (P = 0.9). The present results imply that enterovirus infections are associated with the appearance of beta-cell autoantibodies. A possible causal relationship is supported by the clustering of infections to the time when autoantibodies appeared.

Case report: type 1 diabetes in monozygotic quadruplets

“…In this respect, the lack of information concerning the quadruplets' autoantibody positivity before enteroviral infection precluded us to establish direct causative links between the enteroviral seropositivity, islet autoimmunity and the onset of diabetes. 42 Enteroviruses enter the body via ingestion and young children are their main target and reservoir. The incubation period lasts usually 3-6 days and symptoms of infection are usually subclinical, or very mild in the form of uncomplicated summer cold.…”

Baseline heterogeneity in glucose metabolism marks the risk for type 1 diabetes and complicates secondary prevention

“…Proposed environmental triggers are viral infections [3][4][5] infant diet [6,7], early infant growth [8] and insulin resistance [9], among others. A possibility that different environmental events may be associated with diverse patterns in beta cell autoimmunity have been raised [9], indicating that many factors may be involved in the initiation of the autoimmune process.…”

Relationship Between Ljungan Virus Antibodies, HLA-DQ8, and Insulin Autoantibodies in Newly Diagnosed Type 1 Diabetes Children

“…The HLA-DQ locus on chromosome 6p21 confers the strongest genetic risk for T1D (24). The majority of individuals with these genetic risk factors do not develop T1D and several environmental factors have been considered including infections (6,13,34,40), climate (35), diet (3,21), and stress (16). The possible influence of viral infections as a trigger of islet autoimmunity or clinical onset of T1D has been reported in numerous studies (5,19).…”

“…A fluctuating pattern of infectious diseases, including zoonoses (29), has been suggested to contribute to the appearance of either islet autoimmunity, T1D, or both (4,34). The Ljungan virus (LV), a parechovirus, possibly pathogenic to humans (8,23,28) has been proposed to contribute to T1D.…”