Antibody response to serpin B13 induces adaptive changes in mouse pancreatic islets and slows down the decline in the residual beta cell function in children with recent onset of type 1 diabetes mellitus

Yury Kryvalap, Chi Wen Lo, Ekaterina Manuylova, Raman Baldzizhar, Nicholas Jospe, Jan Czyzyk

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1 Scopus citations

Abstract

Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology.Werecently identified a novel antibody to clade B serpin that reduces isletassociated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation ofβ80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans.

Original languageEnglish (US)
Pages (from-to)266-278
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number1
DOIs
StatePublished - Jan 1 2016

Bibliographical note

Funding Information:
This work was supported by the Juvenile Diabetes Research Foundation Grant 17-2013-428 (to J. C.). The authors declare that they have no conflicts of interest with the contents of this article. We thank Sarah Muller and the Type 1 Diabetes TrialNet for help in providing human serum samples and supporting data. We also thank Dr. Jerry Palmer for coordinating review of our manuscript by the TrialNet Publications and Presentations Subcommittee prior to its submission for publication.

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