B-cell DNA damage response promotes islet inflammation in type 1 diabetes

Elad Horwitz, Lars Krogvold, Sophia Zhitomirsky, Avital Swisa, Maya Fischman, Tsuria Lax, Tehila Dahan, Noa Hurvitz, Noa Weinberg-Corem, Agnes Klochendler, Alvin C. Powers, Marcela Brissova, Anne Jörns, Sigurd Lenzen, Benjamin Glaser, Knut Dahl-Jørgensen*, Yuval Dor

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Type 1 diabetes (T1D) is an autoimmune disease where pancreatic b-cells are destroyed by islet-infiltrating T cells. Although a role for b-cell defects has been suspected, b-cell abnormalities are difficult to demonstrate. We show a b-cell DNA damage response (DDR), presented by activation of the 53BP1 protein and accumulation of p53, in biopsy and autopsy material from patients with recently diagnosed T1D as well as a rat model of human T1D. The b-cell DDR is more frequent in islets infiltrated by CD45+ immune cells, suggesting a link to islet inflammation. The b-cell toxin streptozotocin (STZ) elicits DDR in islets, both in vivo and ex vivo, and causes elevation of the proinflammatory molecules IL-1b and Cxcl10. b-Cell-specific inactivation of the master DNA repair gene ataxia telangiectasia mutated (ATM) in STZ-treated mice decreases the expression of proinflammatory cytokines in islets and attenuates the development of hyperglycemia. Together, these data suggest that b-cell DDR is an early event in T1D, possibly contributing to autoimmunity.

Original languageAmerican English
Pages (from-to)2305-2318
Number of pages14
JournalDiabetes
Volume67
Issue number11
DOIs
StatePublished - 1 Nov 2018

Bibliographical note

Publisher Copyright:
© 2018 by the American Diabetes Association.

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