2. Academic Validation
  3. Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity

Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity

  • Cell. 2016 Jun 30;166(1):88-101. doi: 10.1016/j.cell.2016.05.034.
Vanja Sisirak 1,  Benjamin Sally 2,  Vivette D'Agati 3,  Wilnelly Martinez-Ortiz 4,  Z Birsin Özçakar 5,  Joseph David 1,  Ali Rashidfarrokhi 1,  Ada Yeste 6,  Casandra Panea 7,  Asiya Seema Chida 8,  Milena Bogunovic 9,  Ivaylo I Ivanov 7,  Francisco J Quintana 6,  Inaki Sanz 8,  Keith B Elkon 10,  Mustafa Tekin 11,  Fatoş Yalçınkaya 5,  Timothy J Cardozo 4,  Robert M Clancy 12,  Jill P Buyon 12,  Boris Reizis 13
Affiliations

Affiliations

  • 1 Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
  • 2 Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
  • 3 Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA.
  • 4 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
  • 5 Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Ankara University, Ankara, 06100, Turkey.
  • 6 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
  • 8 Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 9 Department of Microbiology and Immunology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033, USA.
  • 10 Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • 11 Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
  • 12 Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
  • 13 Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. Electronic address: [email protected].
PMID: 27293190 DOI: 10.1016/j.cell.2016.05.034
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.

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