Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity

Vanja Sisirak, Benjamin Sally, Vivette D'Agati, Wilnelly Martinez-Ortiz, Z.  Birsin Özçakar, Joseph David, Ali Rashidfarrokhi, Ada Yeste, Casandra Panea, Asiya Seema S. Chida, Milena Bogunovic, Ivaylo I I. Ivanov, Francisco J J. Quintana, Inaki Sanz, Keith B B. Elkon, Mustafa Tekin, Fatoş Yalçınkaya, Timothy J J. Cardozo, Robert M M. Clancy, Jill P P. BuyonBoris Reizis

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)88-101
Number of pages14
JournalCell
Volume166
Issue number1
DOIs
StatePublished - Jun 30 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sisirak, V., Sally, B., D'Agati, V., Martinez-Ortiz, W., Özçakar, Z. B., David, J., Rashidfarrokhi, A., Yeste, A., Panea, C., Chida, AS. S., Bogunovic, M., Ivanov, II. I., Quintana, FJ. J., Sanz, I., Elkon, KB. B., Tekin, M., Yalçınkaya, F., Cardozo, TJ. J., Clancy, RM. M., ... Reizis, B. (2016). Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity. Cell, 166(1), 88-101. https://doi.org/10.1016/j.cell.2016.05.034