Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes

Natasha J. Hill; Aleksandr Stotland; Michelle Solomon; Patrick Secrest; Elizabeth Getzoff; Nora Sarvetnick

doi:10.1186/1745-6150-2-5

Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes

Natasha J. Hill, Aleksandr Stotland, Michelle Solomon, Patrick Secrest, Elizabeth Getzoff, Nora Sarvetnick^*

^*Corresponding author for this work

School of Biomedical Sciences

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

Abstract

AbstractAbstractType 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet β cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at theIdd9diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction. Susceptible islets exhibit hyper-responsiveness to inflammatory cytokines resulting in enhanced cell death and increased expression of the death receptor Fas. Fas upregulation in β cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD β cells is altered.TNFR2lies within the candidateIdd9interval and the diabetes-associated variant contains a mutation adjacent to the TRAF2 binding site. A component of diabetes susceptibility may therefore be determined by the target of the autoimmune response, and protective TNFR2 signaling in islets inhibit early cytokine-induced damage required for the development of destructive autoimmunity.ReviewersThis article was reviewed by Matthiasvon Herrath, HaraldVon Boehmer, and Ciriaco Piccirillo (nominated by Ethan Shevach).

Original language	English
Number of pages	0
Journal	Biology Direct
Volume	2
Issue number	1
Early online date	25 Jan 2007
DOIs	https://doi.org/10.1186/1745-6150-2-5
Publication status	Published - Dec 2007

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@article{3347a045a8364927aeeba48e39593552,

title = "Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes",

abstract = "AbstractAbstractType 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet β cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at theIdd9diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction. Susceptible islets exhibit hyper-responsiveness to inflammatory cytokines resulting in enhanced cell death and increased expression of the death receptor Fas. Fas upregulation in β cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD β cells is altered.TNFR2lies within the candidateIdd9interval and the diabetes-associated variant contains a mutation adjacent to the TRAF2 binding site. A component of diabetes susceptibility may therefore be determined by the target of the autoimmune response, and protective TNFR2 signaling in islets inhibit early cytokine-induced damage required for the development of destructive autoimmunity.ReviewersThis article was reviewed by Matthiasvon Herrath, HaraldVon Boehmer, and Ciriaco Piccirillo (nominated by Ethan Shevach).",

author = "Hill, {Natasha J.} and Aleksandr Stotland and Michelle Solomon and Patrick Secrest and Elizabeth Getzoff and Nora Sarvetnick",

year = "2007",

month = dec,

doi = "10.1186/1745-6150-2-5",

language = "English",

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journal = "Biology Direct",

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T1 - Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes

AU - Hill, Natasha J.

AU - Stotland, Aleksandr

AU - Solomon, Michelle

AU - Secrest, Patrick

AU - Getzoff, Elizabeth

AU - Sarvetnick, Nora

PY - 2007/12

Y1 - 2007/12

N2 - AbstractAbstractType 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet β cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at theIdd9diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction. Susceptible islets exhibit hyper-responsiveness to inflammatory cytokines resulting in enhanced cell death and increased expression of the death receptor Fas. Fas upregulation in β cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD β cells is altered.TNFR2lies within the candidateIdd9interval and the diabetes-associated variant contains a mutation adjacent to the TRAF2 binding site. A component of diabetes susceptibility may therefore be determined by the target of the autoimmune response, and protective TNFR2 signaling in islets inhibit early cytokine-induced damage required for the development of destructive autoimmunity.ReviewersThis article was reviewed by Matthiasvon Herrath, HaraldVon Boehmer, and Ciriaco Piccirillo (nominated by Ethan Shevach).

AB - AbstractAbstractType 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet β cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at theIdd9diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction. Susceptible islets exhibit hyper-responsiveness to inflammatory cytokines resulting in enhanced cell death and increased expression of the death receptor Fas. Fas upregulation in β cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD β cells is altered.TNFR2lies within the candidateIdd9interval and the diabetes-associated variant contains a mutation adjacent to the TRAF2 binding site. A component of diabetes susceptibility may therefore be determined by the target of the autoimmune response, and protective TNFR2 signaling in islets inhibit early cytokine-induced damage required for the development of destructive autoimmunity.ReviewersThis article was reviewed by Matthiasvon Herrath, HaraldVon Boehmer, and Ciriaco Piccirillo (nominated by Ethan Shevach).

U2 - 10.1186/1745-6150-2-5

DO - 10.1186/1745-6150-2-5

M3 - Article

SN - 1745-6150

VL - 2

JO - Biology Direct

JF - Biology Direct

IS - 1

ER -

Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes

Abstract

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