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-α 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.
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Acknowledgements
Gene expression study was exclusively supported by project NPVII 2B06019 from the Czech Ministry of Education. Studies on Tregs and DCs were supported by the project VZ MSM 0021620812 from the Ministry of Education, Youth and Sports of the Czech Republic, and by the project MZOFNM2005 from the Ministry of Health and by the project GACR P302/10/1679. AN and DF as well as the cytokine analysis were supported by the project NPVII 2B08066 from the Czech Ministry of Education, Youth and Sports. This work was also partially supported by Grant AVOZ50520514 from the Academy of Sciences of the Czech Republic.
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Stechova, K., Halbhuber, Z., Hubackova, M. et al. Case report: type 1 diabetes in monozygotic quadruplets. Eur J Hum Genet 20, 457–462 (2012). https://doi.org/10.1038/ejhg.2011.212
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DOI: https://doi.org/10.1038/ejhg.2011.212
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