Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease

Alevtina Gall, Piper Treuting, Keith B. Elkon, Yueh Ming Loo, Michael Gale, Glen N Barber, Daniel B. Stetson

Research output: Contribution to journalArticle

264 Citations (Scopus)

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 languageEnglish
Pages (from-to)120-131
Number of pages12
JournalImmunity
Volume36
Issue number1
DOIs
StatePublished - Jan 27 2012

Fingerprint

spleen exonuclease
Aicardi Syndrome
Autoimmunity
Interferons
Autoimmune Diseases
Interferon Type I
Lymphocytes
Antiviral Agents
Autoantigens
Human Activities
Autoantibodies
Nucleic Acids
B-Lymphocytes
Inflammation
Mutation
Mortality
Genes
exodeoxyribonuclease I

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 journalArticle

Gall, Alevtina ; Treuting, Piper ; Elkon, Keith B. ; Loo, Yueh Ming ; Gale, Michael ; Barber, Glen N ; Stetson, Daniel B. / Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease. In: Immunity. 2012 ; Vol. 36, No. 1. pp. 120-131.
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