Abstract
The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense but is also associated with specific autoimmune diseases. Mutations in the human 3' repair exonuclease 1 (Trex 1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an invivo reporter of IFN activity in Trex 1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove Tcell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of Tcell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders.
| Original language | English |
|---|---|
| Pages (from-to) | 120-131 |
| Number of pages | 12 |
| Journal | Immunity |
| Volume | 36 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 27 2012 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Infectious Diseases
- Immunology
Cite this
Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease. / Gall, Alevtina; Treuting, Piper; Elkon, Keith B.; Loo, Yueh Ming; Gale, Michael; Barber, Glen N; Stetson, Daniel B.
In: Immunity, Vol. 36, No. 1, 27.01.2012, p. 120-131.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease
AU - Gall, Alevtina
AU - Treuting, Piper
AU - Elkon, Keith B.
AU - Loo, Yueh Ming
AU - Gale, Michael
AU - Barber, Glen N
AU - Stetson, Daniel B.
PY - 2012/1/27
Y1 - 2012/1/27
N2 - The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense but is also associated with specific autoimmune diseases. Mutations in the human 3' repair exonuclease 1 (Trex 1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an invivo reporter of IFN activity in Trex 1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove Tcell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of Tcell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders.
AB - The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense but is also associated with specific autoimmune diseases. Mutations in the human 3' repair exonuclease 1 (Trex 1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an invivo reporter of IFN activity in Trex 1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove Tcell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of Tcell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders.
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U2 - 10.1016/j.immuni.2011.11.018
DO - 10.1016/j.immuni.2011.11.018
M3 - Article
C2 - 22284419
AN - SCOPUS:84856301080
VL - 36
SP - 120
EP - 131
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 1
ER -