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. Buyon; Boris Reizis

doi:10.1016/j.cell.2016.05.034

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 journal › Article › peer-review

356 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 language	English (US)
Pages (from-to)	88-101
Number of pages	14
Journal	Cell
Volume	166
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2016.05.034
State	Published - Jun 30 2016

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

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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

@article{c9e1f24c71064503a37161e0b1122fd1,

title = "Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity",

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.",

author = "Vanja Sisirak and Benjamin Sally and Vivette D'Agati and Wilnelly Martinez-Ortiz and {\"O}z{\c c}akar, {Z. Birsin} and Joseph David and Ali Rashidfarrokhi and Ada Yeste and Casandra Panea and Chida, {Asiya Seema S.} and Milena Bogunovic and Ivanov, {Ivaylo I I.} and Quintana, {Francisco J J.} and Inaki Sanz and Elkon, {Keith B B.} and Mustafa Tekin and Fato{\c s} Yal{\c c}ınkaya and Cardozo, {Timothy J J.} and Clancy, {Robert M M.} and Buyon, {Jill P P.} and Boris Reizis",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = jun,

day = "30",

doi = "10.1016/j.cell.2016.05.034",

language = "English (US)",

volume = "166",

pages = "88--101",

journal = "Cell",

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Sisirak, V, Sally, B, D'Agati, V, Martinez-Ortiz, W, Özçakar, ZB, David, J, Rashidfarrokhi, A, Yeste, A, Panea, C, Chida, ASS, Bogunovic, M, Ivanov, III, Quintana, FJJ, Sanz, I, Elkon, KBB, Tekin, M, Yalçınkaya, F, Cardozo, TJJ, Clancy, RMM, Buyon, JPP & Reizis, B 2016, 'Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity', Cell, vol. 166, no. 1, pp. 88-101. https://doi.org/10.1016/j.cell.2016.05.034

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

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.

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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 -

Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity

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