Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity

• Published in: Cell Vol. 166; no. 1; pp. 88 - 101
• Main Authors: Sisirak, Vanja, Sally, Benjamin, D’Agati, Vivette, Martinez-Ortiz, Wilnelly, Özçakar, Z. Birsin, David, Joseph, Rashidfarrokhi, Ali, Yeste, Ada, Panea, Casandra, Chida, Asiya Seema, Bogunovic, Milena, Ivanov, Ivaylo I., Quintana, Francisco J., Sanz, Inaki, Elkon, Keith B., Tekin, Mustafa, Yalçınkaya, Fatoş, Cardozo, Timothy J., Clancy, Robert M., Buyon, Jill P., Reizis, Boris
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-06-2016; Elsevier
• Subjects: Adaptive immunology; Animals; Autoantibodies - immunology; Cell-Derived Microparticles - chemistry; Cell-Derived Microparticles - metabolism; Chromatin - immunology; Disease Models, Animal; DNA - immunology; Endodeoxyribonucleases - deficiency; Endodeoxyribonucleases - genetics; Endodeoxyribonucleases - metabolism; Humans; Immunology; Innate immunity; Jurkat Cells; Life Sciences; Lupus Erythematosus, Systemic - enzymology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.05.034

Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 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 chromatin in microparticles released 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 chromatin on the surface of microparticles. Thus, extracellular microparticle-associated chromatin is 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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•Rapid anti-DNA antibody response, followed by SLE in Dnase1l3-deficient mice•Autoreactivity is repressed by circulating DNASE1L3 and is independent of STING•DNASE1L3 digests genomic DNA in microparticles released from apoptotic cells•DNASE1L3 prevents autoantibody binding to chromatin on microparticle surface
Extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism in mice and humans contributes to lupus, and the restoration of this mechanism may represent a therapeutic opportunity in the disease.