Congenital rubella syndrome as a model for Type 1 (insulin-dependent) diabetes mellitus: increased prevalence of islet cell surface antibodies

Abstract

An increased prevalence of Type 1 (insulin-dependent) diabetes has been reported in patients with congenital rubella. Rubella virus multiplies in the pancreas, and we have hypothesized that studies of children with congenital rubella would be of great importance in following the development of Type 1 diabetes in a defined, susceptible population. Two hundred and forty-one children with congenital rubella (mean age 17.4 +/- 0.3 years; 65% black and hispanic) have been evaluated, 30 of whom already have diabetes and 17 of whom have borderline glucose tolerance. In these latter two groups, HLA-DR3 is significantly increased and HLA-DR2 significantly decreased. Pancreatic islet cell cytotoxic surface antibodies are found in 20% of the total congenital rubella population, including in more than 50% in the time period before they develop diabetes and are not related to any specific HLA type. In addition, anti-microsomal and anti-thyroglobulin antibodies are found in 34% of this population. The data demonstrate that Type 1 diabetes developing in congenital rubella patients has the genetic and immunological features of classical Type 1 diabetes, namely the presence of HLA-DR3, the absence of HLA-DR2, islet cell surface antibodies before decompensation and an increased prevalence of anti-thyroid antibodies. Patients with non-diabetic congenital rubella represent an easily identifiable group in whom other immunological factors associated with Type 1 diabetes can be elucidated and possibly modified.

Viruses, cytokines, antigens, and autoimmunity.

“…Interestingly, several other endocrine diseases (25)(26)(27), thought to be autoimmune, can also develop following congenital rubella infection. Autoantibodies to tissue-specific antigens have been identified in the sera of patients with rubella-associated endocrine disease, suggesting their autoimmune pathogenesis (28,29).…”

Coxsackievirus B4 Infection of Human Fetal Thymus Cells

“…Recently, we reported that CVB4 JVB (a laboratory reference strain) and CVB4 E2 persistently infect human TEC in vitro, and we hypothesized that this persistence could interfere with thymus function and contribute to the development of autoimmunity (5). Congenital rubella syndrome provides an example of in utero acquired infection causing type 1 diabetes (14); therefore, it has been suggested that fetal viral infections may be causally related to type 1 diabetes (10). Otonkoski et al detected postnatally several types of diabetes-associated autoantibodies in an infant infected in utero by an enterovirus, which suggests that enterovirus infections in utero may induce ␤-cell autoimmunity (36).…”

Cross-reactive rubella virus and glutamic acid decarboxylase (65 and 67) protein determinants recognised by T cells of patients with Type I diabetes mellitus

“…Type I diabetes that is CRS-associated has been used as a model to study the viral influences in the pathogenesis of the disease [7,30]. The present study suggests that the positive frequencies responding to cross-reactive determinents beta-cell epitopes B4, GAD65(274±286) and B10, GAD67(212±226), and RV peptides V3, RVE1(157±176) of PBMC from patients of CRS-associated Type I diabetes seem to be higher than those of PBMC from patients of CRS without Type I diabetes.…”

“…The best-documented information linking a preceding viral infection in humans with the subsequent onset of diabetes has come from studies of children and young adults who were infected with RV during intra-uterine development and subsequently diagnosed as having congenital rubella syndrome (CRS) [1,4,5]. The incidence of insulin-dependent diabetes in CRS patients has been estimated to be 10±12 % whereas up to 40 % of CRS patients show impaired glucose tolerance [3,6,7]. Results of studies in mice and humans with Type I diabetes suggest that beta-cell destruction could occur directly as a result of viral replication or indirectly due to viral bystander damage or viral induction of autoimmune cell damage [1,4,8].…”

“…Patients with Type I diabetes associated with CRS show the same immunogenetic (DR3 or DR4 or both) associations as conventional Type I diabetic patients [29]. Thus, CRS-associated Type I diabetes serves as an excellent human model in which to study viral influences in the pathogenesis of diabetes [7]. There are, however, no reports of cross-reactions between T-cell epitopes of rubella virus and beta-cell proteins so far.…”