Abstract
Loss of function mutations of the intracellular enzyme 3’ repair exonuclease (TREX) 1 cause Aicardi-Goutieres syndrome (AGS). As AGS clinically overlaps with systemic lupus erythematosus (SLE) and, like SLE, features a spontaneous activation of the antiviral type I-interferon (IFN) system as well as production of antinuclear autoantibodies, this condition may be considered a monogenic variant of SLE. TREX1-deficient mice spontaneously develop multiorgan autoimmune disease that is fully dependent on a functional type I-IFN system. This phenotype suggested a new concept of systemic autoimmunity arising from intracellular accumulations of (so far enigmatic) nucleic acid substrates of TREX1, which trigger chronic antiviral IFN responses and thereby autoimmunity. Nonhematopoietic cells were proposed to be the cellular source of the pathogenic IFN. Uncontrolled activity of endogenous retroelements was suspected to induce the chronic antiviral response.
Highlights
Loss of function mutations of the intracellular enzyme 3’ repair exonuclease (TREX) 1 cause Aicardi-Goutières syndrome (AGS)
As AGS clinically overlaps with systemic lupus erythematosus (SLE) and, like SLE, features a spontaneous activation of the antiviral type I-interferon (IFN) system as well as production of antinuclear autoantibodies, this condition may be considered a monogenic variant of SLE
TREX1-deficient mice spontaneously develop multiorgan autoimmune disease that is fully dependent on a functional type I-IFN system
Summary
Loss of function mutations of the intracellular enzyme 3’ repair exonuclease (TREX) 1 cause Aicardi-Goutières syndrome (AGS). As AGS clinically overlaps with systemic lupus erythematosus (SLE) and, like SLE, features a spontaneous activation of the antiviral type I-interferon (IFN) system as well as production of antinuclear autoantibodies, this condition may be considered a monogenic variant of SLE. TREX1-deficient mice spontaneously develop multiorgan autoimmune disease that is fully dependent on a functional type I-IFN system. This phenotype suggested a new concept of systemic autoimmunity arising from intracellular accumulations of (so far enigmatic) nucleic acid substrates of TREX1, which trigger chronic antiviral IFN responses and thereby autoimmunity. Uncontrolled activity of endogenous retroelements was suspected to induce the chronic antiviral response
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