Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2012-01, Vol.36 (1), p.120-131

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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 (Trex1) 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 in vivo reporter of IFN activity in Trex1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove T cell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of T cell-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. [Display omitted] ► Trex1 is an essential negative regulator of the STING-dependent antiviral response ► Nonhematopoietic cells initiate IFN-dependent autoimmunity in Trex1-deficient mice ► T cells are necessary and sufficient for autoimmune inflammation in Trex1−/− mice ► B cells contribute to mortality in Trex1−/− mice independently of inflammation