Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity.
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.
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Vanja
V
Sisirak
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.
Benjamin
B
Sally
Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA.
Vivette
V
D'Agati
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Wilnelly
W
Martinez-Ortiz
Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Ankara University, Ankara, 06100, Turkey.
Z Birsin
ZB
Özçakar
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Joseph
J
David
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Ali
A
Rashidfarrokhi
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ada
A
Yeste
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Casandra
C
Panea
Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Asiya Seema
AS
Chida
Department of Microbiology and Immunology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033, USA.
Milena
M
Bogunovic
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Ivaylo I
II
Ivanov
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Francisco J
FJ
Quintana
Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Inaki
I
Sanz
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Keith B
KB
Elkon
Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Mustafa
M
Tekin
Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Ankara University, Ankara, 06100, Turkey.
Fatoş
F
Yalçınkaya
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Timothy J
TJ
Cardozo
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Robert M
RM
Clancy
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Jill P
JP
Buyon
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: boris.reizis@nyumc.org.
Boris
B
Reizis
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D055252:Cell-Derived Microparticles / Q000737:chemistry* / Q000378:metabolism; D002843:Chromatin / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D004195:Disease Models, Animal; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D001323:Autoantibodies; D002843:Chromatin; D004247:DNA; C114484:Dnase1l3 protein, mouse; D004706:Endodeoxyribonucleases