Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus

Johannes Hartl, Lee Serpas, Yueyang Wang, Ali Rashidfarrokhi, Oriana A. Perez, Benjamin Sally, Vanja Sisirak, Chetna Soni, Alireza hodadadi-Jamayran, Aristotelis Tsirigos, Ivan Caiello, Claudia Bracaglia, Stefano Volpi, Gian Marco Ghiggeri, Asiya Seema Chida, Ignacio Sanz, Mimi Y. Kim, H. Michael Belmont, Gregg J. Silverman, Robert M. ClancyPeter M. Izmirly, Jill P. Buyon, Boris Reizis

Research output: Contribution to journalArticlepeer-review

Abstract

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 antidsDNA autoreactivity in patients with severe sporadic SLE.

Original languageEnglish (US)
Article numbere20201138
JournalJournal of Experimental Medicine
Volume218
Issue number5
DOIs
StatePublished - May 3 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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