Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 5, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201138
Keywords
-
Categories
Funding
- National Institutes of Health [AR071703, AR070591, CA232666, AI100853, AR069515, GM136573]
- Lupus Research Alliance
- Colton Center for Autoimmunity
- German Research Foundation
Ask authors/readers for more resources
The majority of sporadic SLE patients with nephritis have reduced DNASE1L3 activity and neutralizing autoantibodies to DNASE1L3, leading to the accumulation of cfDNA in microparticles and increased disease severity. Autoantibody-mediated impairment of DNASE1L3 activity is a common non-genetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available