Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity.
Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity.
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DOI：
10.1016/j.cell.2016.05.034
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发表时间：
2016-06-30
期刊：
影响因子：
64.5
通讯作者：
Reizis B
中科院分区：
文献类型：
--
作者：
Sisirak V;Sally B;D'Agati V;Martinez-Ortiz W;Özçakar ZB;David J;Rashidfarrokhi A;Yeste A;Panea C;Chida AS;Bogunovic M;Ivanov II;Quintana FJ;Sanz I;Elkon KB;Tekin M;Yalçınkaya F;Cardozo TJ;Clancy RM;Buyon JP;Reizis B
DNA和染色质抗体驱动系统性红斑狼疮（SLE）的自身免疫。分泌型脱氧核糖核酸酶DNASE1L3的突变和亚纯型变体分别与家族性和散发性SLE相关。我们报告说，DNASE1L3缺陷小鼠迅速发展自身抗体的DNA和染色质，随后SLE样疾病。循环DNASE1L3由树突状细胞和巨噬细胞产生，其水平与抗DNA抗体应答呈负相关。DNASE1L3独特地能够消化从凋亡细胞释放的微粒中的染色质。因此，DNASE1L3缺陷小鼠和人类患者在血浆中，特别是在循环微粒中具有升高的DNA水平。鼠和人自身抗体克隆和来自人SLE患者的血清抗体结合到微粒表面上的DNASE1L3敏感的染色质。因此，细胞外微粒相关染色质是一种潜在的自身抗原，通常被循环DNASE1L3消化。这种耐受机制的丧失可能导致SLE，其恢复可能代表疾病的治疗机会。
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 micro-particle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanismcan contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.
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影响因子：
12.8
作者：
Ghodke-Puranik Y;Niewold TB
通讯作者：
Niewold TB
影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
DOI：
10.1084/jem.20151876
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
通讯作者：
Pascual V
DOI：
10.1038/nri3477
发表时间：
2013-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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影响因子：
4.1
作者：
Napirei, M;Wulf, S;Kloeckl, T
通讯作者：
Kloeckl, T