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Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease.
Title | Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Gall, A, Treuting, P, Elkon, KB, Loo, Y-M, Gale, M, Barber, GN, Stetson, DB |
Journal | Immunity |
Volume | 36 |
Issue | 1 |
Pagination | 120-31 |
Date Published | 2012 Jan 27 |
ISSN | 1097-4180 |
Keywords | Animals, Autoimmune Diseases, Autoimmune Diseases of the Nervous System, Autoimmunity, Exodeoxyribonucleases, Interferons, Lymphocytes, Mice, Mice, Knockout, Models, Biological, Nervous System Malformations, Phosphoproteins, Signal Transduction |
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 (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. |
DOI | 10.1016/j.immuni.2011.11.018 |
Alternate Journal | Immunity |
PubMed ID | 22284419 |