TY - JOUR
T1 - B-cell DNA damage response promotes islet inflammation in type 1 diabetes
AU - Horwitz, Elad
AU - Krogvold, Lars
AU - Zhitomirsky, Sophia
AU - Swisa, Avital
AU - Fischman, Maya
AU - Lax, Tsuria
AU - Dahan, Tehila
AU - Hurvitz, Noa
AU - Weinberg-Corem, Noa
AU - Klochendler, Agnes
AU - Powers, Alvin C.
AU - Brissova, Marcela
AU - Jörns, Anne
AU - Lenzen, Sigurd
AU - Glaser, Benjamin
AU - Dahl-Jørgensen, Knut
AU - Dor, Yuval
N1 - Publisher Copyright:
© 2018 by the American Diabetes Association.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85055181634
U2 - 10.2337/db17-1006
DO - 10.2337/db17-1006
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C2 - 30150306
AN - SCOPUS:85055181634
SN - 0012-1797
VL - 67
SP - 2305
EP - 2318
JO - Diabetes
JF - Diabetes
IS - 11
ER -
