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Author Notes:

Boris Reizis, boris.reizis@nyulangone.org

Jill P. Buyon, jill.buyon@nyulangone.org

J. Hartl, L. Serpas, A. Rashidfarrokhi, Y. Wang, O.A. Perez, B. Sally, V. Sisirak, C. Soni, and G.J. Silverman performed experiments and analyzed and interpreted results. A. Khodadadi-Jamayran, A. Tsirigos, and M.Y. Kim analyzed results. A.S. Chida and I. Sanz developed and provided reagents. I. Caiello, C. Bracaglia, S. Volpi, G.M. Ghiggeri, H.M. Belmont, R.M. Clancy, P.M. Izmirly, and J.P. Buyon obtained and provided patient samples. J.P. Buyon and B. Reizis conceived and supervised the project. J. Hartl, L. Serpas, and B. Reizis wrote the original manuscript. All authors reviewed and edited the manuscript.

P. Izmirly reported personal fees from GlaxoSmithKline outside the submitted work. J.P. Buyon reported personal fees from Bristol-Myers Squibb LN advisory board, personal fees from GSK panel on LN, personal fees from Amgen, and personal fees from Ventus outside the submitted work. B. Reizis reported being an advisor at Related Sciences. No other disclosures were reported.

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Research Funding:

This work was supported by National Institutes of Health grants AR071703 (B. Reizis and J.P. Buyon), AR070591 (B. Reizis, G.J. Silverman, J.P. Buyon, and R.M. Clancy), CA232666 (O.A. Perez), AI100853 (O.A. Perez, L. Serpas, and A. Rashidfarrokhi), AR069515 (L. Serpas), and GM136573 (L. Serpas). This work was also supported by the Lupus Research Alliance (B. Reizis), the Colton Center for Autoimmunity (B. Reizis and J.P. Buyon), and the German Research Foundation (J. Hartl).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • CELL-FREE DNA
  • CLASSIFICATION CRITERIA
  • PLASMA DNA
  • SJOGRENS-SYNDROME
  • REVISED CRITERIA
  • AMERICAN-COLLEGE
  • DISEASE-ACTIVITY
  • IN-VITRO
  • ANTIBODIES
  • MICROPARTICLES

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

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Journal Title:

JOURNAL OF EXPERIMENTAL MEDICINE

Volume:

Volume 218, Number 5

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Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2021 Hartl et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License (https://creativecommons.org/licenses/by-nc-sa/4.0/rdf).
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