Seroconversion to Islet Autoantibodies After Enterovirus Infection in Early Pregnancy

Abstract

Gestational enterovirus (EV) infections have been associated with an increased risk for type 1 diabetes in the offspring. We therefore analyzed non-diabetic mothers for EV exposure in early pregnancy in relation to type 1 diabetes HLA-DQ risk genotypes and seroconversion to islet autoantibodies during pregnancy. Non-diabetic mothers who had islet autoantibodies (n = 365) against glutamic acid decarboxylase (GADA), islet antigen-2 autoantibodies (IA-2A), or insulin autoantibodies (IAA), in early pregnancy and at delivery were compared to islet autoantibody-negative mothers (n = 1457) matched for age and sampling date. Mothers were genotyped for HLA-DQ and analyzed for both EV-RNA and EV-IgM. EV-IgM, but not EV-RNA, was detected during early pregnancy in 12% of islet autoantibody-positive mothers compared to 11% of the controls. In early pregnancy, mothers with HLA-DQ 2/2 or 2/X genotypes showed an increased risk for islet autoantibodies at delivery (OR 1.85; p = 0.001). After adjusting for parity, maternal age, year of birth, and season of early pregnancy, early pregnancy EV-IgM combined with DQ2/2 or 2/X increased the risk for islet autoantibodies (OR 3.10; 95% CI 1; p = 0.008). EV-IgM in early pregnancy increased the risk for islet autoantibodies at delivery in non-diabetic mothers with HLA-DQ 2/2 or 2/X type 1 diabetes risk genotypes.

Environmental risk factors for type 1 diabetes

“…Recent findings consistent with a persistent enteroviral infection in patients at diagnosis of type 1 diabetes include: more frequent detection of enteroviral VP1 protein immunoreactivity in the β cells of children with type 1 diabetes than in age-matched controls; 23, 24 VP1 expression in β-cells that also produce elevated levels of PKR consistent with degradation of myeloid cell factor 1 (MCL1) and higher susceptibility of the cells to apoptosis; 25 and that double-stranded RNA (dsRNA) and elevated levels of MDA5 in the β cells of patients with type 1 diabetes. 26 An intriguing line of evidence suggests that enteroviral infections during pregnancy might result in persistent infection and islet autoimmunity in the mother 27 and off spring. 28, 29 A plausible mechanism for persistence of enteroviruses in the pancreatic islets has been proposed from studies of enteroviral myocarditis.…”

Maternal virus infections in pregnancy and type 1 diabetes in their offspring: Systematic review and meta‐analysis of observational studies

“…This suggests investigation and/or publication bias, which may overestimate the degree of association between EV and type 1 diabetes. Investigations of EV infections in myocarditis have yielded conceivable mechanisms of EV persistence during pregnancy, and islet autoimmunity in the mother . Despite this, there is a paucity of data examining the contribution of perinatal virus infections on the development of islet autoimmunity and type 1 diabetes.…”

Early prediction of autoimmune (type 1) diabetes

“…Enteroviruses and rubella virus are commonly studied, although the link between congenital rubella infections and type 1 diabetes is controversial [52]. Coxsackie infection during pregnancy may induce beta cell autoimmunity in the mother [53] and may increase the risk for type 1 diabetes in the offspring [54, 55]. Virus studies need to be related to the staging of type 1 diabetes.…”