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

doi:10.2337/db17-1006

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

Department of Developmental Biology and Cancer Research

The Hebrew University of Jerusalem

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	2305-2318
Number of pages	14
Journal	Diabetes
Volume	67
Issue number	11
DOIs	https://doi.org/10.2337/db17-1006
State	Published - 1 Nov 2018

All Science Journal Classification (ASJC) codes

Internal Medicine
Endocrinology, Diabetes and Metabolism

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/db17-1006

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Horwitz, E., Krogvold, L., Zhitomirsky, S., Swisa, A., Fischman, M., Lax, T., Dahan, T., Hurvitz, N., Weinberg-Corem, N., Klochendler, A., Powers, A. C., Brissova, M., Jörns, A., Lenzen, S., Glaser, B., Dahl-Jørgensen, K., & Dor, Y. (2018). B-cell DNA damage response promotes islet inflammation in type 1 diabetes. Diabetes, 67(11), 2305-2318. https://doi.org/10.2337/db17-1006

@article{4ec805f29d8e418da070dba10e311f0b,

title = "B-cell DNA damage response promotes islet inflammation in type 1 diabetes",

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.",

author = "Elad Horwitz and Lars Krogvold and Sophia Zhitomirsky and Avital Swisa and Maya Fischman and Tsuria Lax and Tehila Dahan and Noa Hurvitz and Noa Weinberg-Corem and Agnes Klochendler and Powers, \{Alvin C.\} and Marcela Brissova and Anne J{\"o}rns and Sigurd Lenzen and Benjamin Glaser and Knut Dahl-J{\o}rgensen and Yuval Dor",

note = "Publisher Copyright: {\textcopyright} 2018 by the American Diabetes Association.",

year = "2018",

month = nov,

day = "1",

doi = "10.2337/db17-1006",

language = "الإنجليزيّة",

volume = "67",

pages = "2305--2318",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "11",

}

Horwitz, E, Krogvold, L, Zhitomirsky, S, Swisa, A, Fischman, M, Lax, T, Dahan, T, Hurvitz, N, Weinberg-Corem, N, Klochendler, A, Powers, AC, Brissova, M, Jörns, A, Lenzen, S, Glaser, B, Dahl-Jørgensen, K & Dor, Y 2018, 'B-cell DNA damage response promotes islet inflammation in type 1 diabetes', Diabetes, vol. 67, no. 11, pp. 2305-2318. https://doi.org/10.2337/db17-1006

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

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.

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U2 - 10.2337/db17-1006

DO - 10.2337/db17-1006

M3 - مقالة

C2 - 30150306

SN - 0012-1797

VL - 67

SP - 2305

EP - 2318

JO - Diabetes

JF - Diabetes

IS - 11

ER -

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

Abstract

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