Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus.
Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus.
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DOI：
10.1084/jem.20201138
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发表时间：
2021-05-03
期刊：
影响因子：
--
通讯作者：
Reizis B
中科院分区：
文献类型：
--
作者：
Hartl J;Serpas L;Wang Y;Rashidfarrokhi A;Perez OA;Sally B;Sisirak V;Soni C;Khodadadi-Jamayran A;Tsirigos A;Caiello I;Bracaglia C;Volpi S;Ghiggeri GM;Chida AS;Sanz I;Kim MY;Belmont HM;Silverman GJ;Clancy RM;Izmirly PM;Buyon JP;Reizis B
分泌型核酸酶DNASE1L3的突变导致单基因系统性红斑狼疮（SLE）。这项研究表明，许多患有肾炎的散发性SLE患者表现出降低的DNASE1L3活性，这与阻断针对该酶的自身抗体有关。双链DNA（dsDNA）抗体在系统性红斑狼疮（SLE）中普遍存在，特别是在狼疮性肾炎患者中，但对抗原性无细胞DNA（cfDNA）的性质和调节知之甚少。分泌型DNA酶DNASE1L3的突变导致具有抗dsDNA自身反应性的人类单基因SLE。我们报道了>50%的散发性SLE肾炎患者表现出循环中DNASE1L3活性降低，这与DNASE1L3的中和性自身抗体有关。这些患者具有正常的总血浆cfDNA水平，但显示cfDNA在循环微粒中的积累。微粒相关的cfDNA含有较高分数的较长多核小体cfDNA片段，其以比单核小体片段更高的亲和力结合自身抗体。针对微粒上的DNASE1L3敏感抗原的自身抗体在SLE肾炎患者中普遍存在，并且与微粒中cfDNA的积累和疾病严重程度相关。DNASE1L3敏感性抗原包括DNA相关蛋白，如HMGB1。我们的研究结果揭示了自身抗体介导的DNASE1L3活性受损是一种常见的非遗传机制，可促进严重散发性SLE患者的抗dsDNA自身反应性。
Null mutations in secreted nuclease DNASE1L3 cause monogenic systemic lupus erythematosus (SLE). This study shows that many patients with sporadic SLE with nephritis manifest reduced DNASE1L3 activity, which is associated with blocking autoantibodies to the enzyme. Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.
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影响因子：
2.6
作者：
Carbonella, A.;Mancano, G.;Ferraccioli, G.
通讯作者：
Ferraccioli, G.
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
影响因子：
3.6
作者：
ALI, R;DERSIMONIAN, H;STOLLAR, BD
通讯作者：
STOLLAR, BD
DOI：
10.1016/s0735-1097(98)00161-2
发表时间：
1998-06-01
影响因子：
24
作者：
Buyon, JP;Hiebert, R;Skovron, ML
通讯作者：
Skovron, ML
DOI：
10.1111/j.1365-2362.2010.02435.x
发表时间：
2011-06-01
影响因子：
5.5
作者：
Atamaniuk, Johanna;Hsiao, Yu-Yang;Stuhlmeier, Karl M.
通讯作者：
Stuhlmeier, Karl M.