TY - JOUR
T1 - Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity
AU - Sisirak, Vanja
AU - Sally, Benjamin
AU - D'Agati, Vivette
AU - Martinez-Ortiz, Wilnelly
AU - Özçakar, Z. Birsin
AU - David, Joseph
AU - Rashidfarrokhi, Ali
AU - Yeste, Ada
AU - Panea, Casandra
AU - Chida, Asiya Seema S.
AU - Bogunovic, Milena
AU - Ivanov, Ivaylo I I.
AU - Quintana, Francisco J J.
AU - Sanz, Inaki
AU - Elkon, Keith B B.
AU - Tekin, Mustafa
AU - Yalçınkaya, Fatoş
AU - Cardozo, Timothy J J.
AU - Clancy, Robert M M.
AU - Buyon, Jill P P.
AU - Reizis, Boris
N1 - Funding Information:
We thank G. Silverman for help and discussions, M. Shlomchik and A. Davidson for reagents, and S. Rasmussen for technical assistance. This work was supported by NIH grants (AR064460 and AI072571 to B.R.; DK098378 to I.I.I.), the Lupus Research Institute (to B.R.), the Judith and Stewart Colton Center for Autoimmunity (to B.R. and J.P.B.), and the Irvington Institute Fellowship of the Cancer Research Institute (to V.S.). K.B.E. is a co-founder and consultant of Resolve Therapeutics, which develops soluble nucleases for therapeutic purposes.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6/30
Y1 - 2016/6/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84976583862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84976583862&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2016.05.034
DO - 10.1016/j.cell.2016.05.034
M3 - Article
C2 - 27293190
AN - SCOPUS:84976583862
SN - 0092-8674
VL - 166
SP - 88
EP - 101
JO - Cell
JF - Cell
IS - 1
ER -