[PDF][PDF] Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease

A Gall, P Treuting, KB Elkon, YM Loo, M Gale… - Immunity, 2012 - cell.com
A Gall, P Treuting, KB Elkon, YM Loo, M Gale, GN Barber, DB Stetson
Immunity, 2012cell.com
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 …
Summary
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.
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