Case report: type 1 diabetes in monozygotic quadruplets

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the lack of insulin due to an autoimmune destruction of pancreatic beta cells. Here, we report a unique case of a family with naturally conceived quadruplets in which T1D was diagnosed in two quadruplets simultaneously. At the same time, the third quadruplet was diagnosed with the pre-diabetic stage. Remarkably, all four quadruplets were positive for anti-islet cell antibodies, GAD65 and IA-A2. Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms. Serological examination confirmed that all quadruplets and their father suffered from a recent enteroviral infection of EV68-71 serotype. To assess the nature of the molecular pathological processes contributing to the development of diabetes, immunocompetent cells isolated from all family members were characterized by gene expression arrays, immune-cell enumerations and cytokine-production assays. The microarray data provided evidence that viral infection, and IL-27 and IL-9 cytokine signalling contributed to the onset of T1D in two of the quadruplets. The propensity of stimulated immunocompetent cells from non-diabetic members of the family to secrete high level of IFN-a further corroborates this conclusion. The number of T regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was found diminished in all family members. Thus, this unique family is a prime example for the support of the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity is 'fertilized' and precipitated by a viral infection leading to a fully blown T1D.

The Effect of Diabetes-Associated Autoantigens on Cell Processes in Human PBMCs and Their Relevance to Autoimmune Diabetes Development

“…However, we believe that approximately ten subjects per group are sufficient to reveal genes with statistically significant alterations in their gene expression levels when high-density microarray chips are used. In this context and in many other aspects, the results of this study parallel our previous work [35] and the studies of other research teams in which microarray analyses obtained from a limited number of subjects provided highly relevant and statistically significant data [16, 36–38]. Moreover, while our control group was not ideally age-matched to our other study groups, this variable produces negligible effects on our statistical analyses (data not shown) according to our comprehensive statistical analysis described elsewhere [35].…”

Serum IL-9, IL-17, and TGF-β levels in subjects with diabetic kidney disease (CURES-134)

“…Beriou et al first reported an increased frequency of IL-9 + IL-17 + memory CD4 + T cells in subjects with type 1 diabetes mellitus (T1DM) [13]. In a subsequent study, gene expression analysis carried out on T1DM monozygotic quadruplets reconfirmed the involvement of IL-9 signaling in the pathogenesis of pancreatic β cell destruction [14]. However, whether the same holds good for type 2 diabetes mellitus (T2DM) is largely unknown.…”

Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

“…It is also known that IL-17F is expressed earlier than IL-17A during Th17 cell development (38). A recent study showed that IL-9 signaling was associated with type 1 diabetes in two of monozygotic quadruplets (39). Increased numbers of TGF-b1-induced IL-9-secreting Th17 cells have been reported in type 1 diabetes, too (16).…”