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Proinsulin peptide promotes autoimmune diabetes in a novel HLA-DR3-DQ2-transgenic murine model of spontaneous disease – published online 14/10/2019

Fig from Verhagen paper

Johan Verhagen, Norkhairin Yusuf, Emma L. Smith, Emily M. Whettlock, Kerina Naran, Sefina Arif, Mark Peakman

The HLA-DR3-DQ2 haplotype represents a major risk factor for the development of type 1 diabetes. However, it is not fully established which antigen presented on these HLA molecules is important in disease development. In this issue, Verhagen and colleagues (https://doi.org/10.1007/s00125-019-04994-8) report a novel two-stage in vivo approach to identify these antigens. The authors first generated a new transgenic mouse model expressing HLA-DR3-DQ2 and found a high rate of spontaneous autoimmune diabetes. They then used adjuvanted priming with candidate antigens to demonstrate that only proinsulin is capable of further accelerating diabetes development. Moreover, this diabetogenicity maps to a 15-mer residue, with its core MHC-binding region in the N-terminal of C-peptide, which was not previously known to be disease relevant. The authors suggest that the identification of diabetogenic peptides in this way will provide new insights into the role of HLA in diabetes development, which could be relevant to human studies and therapies.

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