Author:
Moadab Fatemeh,Sohrabi Sepideh,Wang Xiaoxing,Najjar Rayan,Wolters Justina C.,Jiang Hua,Miao Wenyan,Romero Donna,Zaller Dennis M.,Tran Megan,Bays Alison,Taylor Martin S.,Kapeller Rosana,LaCava John,Mustelin Tomas
Abstract
Abstract
Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p.
Results
Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis.
Conclusions
These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease.
Funder
Rockefeller University Cooperative Centers on Human Immunology (NIAID) Infrastructure and Opportunity Fund
Center for Scientific Review
Publisher
Springer Science and Business Media LLC