In response to the comment by Vecchio et al. (1) regarding our work recently published in Diabetes (2), we wish to emphasize that the purpose of our short report was simply to assess whether the extensive RNA sequencing (RNA-seq) data collected to date by the Human Pancreas Analysis Program (HPAP) provide evidence supporting persistent enteroviral B infection as a driver of type 1 diabetes pathogenesis. It was not the scope of this study to embark on a pathway seeking to elucidate a potential relationship between enteroviral infection and islet autoimmunity. The title of our article clearly states its primary finding: we found no evidence of enteroviral B infection when our pancreatic islet RNA-seq data were subject to such investigation. Indeed, the article notes multiple times that this finding does not rule out the possibility of a very-low-grade persistent enteroviral infection; we only stated that the HPAP RNA-seq data to date do not support the notion of a chronic pancreatic viral infection.
RNA-seq is considered a highly sensitive method, but, as we also wrote, our conclusions are limited to this particular method. The relevance of our work involves placing a concrete boundary on the viral hypothesis for type 1 diabetes pathogenesis. If this disease has a persistent pancreatic enteroviral infection, it is not detectable using RNA-seq. This observation agrees with the subsequent work of Laiho et al. (3), cited by Vecchio et al. (1), which also indicates that RNA-seq did not detect enteroviral RNA in pancreatic samples. The question of enteroviral infection by way of islet autoimmunity remains an open matter for debate, and we agree with Vecchio et al. that fully elucidating this concept will necessitate a comprehensive research strategy moving forward. Finally, our study has no bearing on the notion of viral molecular mimicry, i.e., the spreading of T- and B-cell reactivity directed at viral antigens encountered in intestinal infections in early childhood to islets proteins of similar sequence that, months or years following the infection, leads to autoimmunity. We eagerly await convincing findings using other methods that either support or refute the viral hypothesis for type 1 diabetes pathogenesis that has, unfortunately, existed for decades.
All authors are affiliated with the Human Pancreas Analysis Program (https://hpap.pmacs.upenn.edu/).
Article Information
Funding. Related work in the Kaestner laboratory was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants UC4-DK-112217 and U01-DK-123594.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
