Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity
2016
Summary Antibodies to DNA and
chromatindrive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted
deoxyribonucleaseDNASE1L3 are linked to familial and sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and
chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting
chromatinin
microparticlesreleased from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating
microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive
chromatinon the surface of
microparticles. Thus, extracellular
microparticle-associated
chromatinis a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism can contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.
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