Autoantibodies targeting LINE-1-encoded ORF1p are associated with systemic lupus erythematosus diagnosis but not with disease activity

• Type of Material: Article
• Authors: B. Antiochos, Johns Hopkins University; M. Paz, Johns Hopkins University; J. Li, Johns Hopkins University; D.W. Goldman, Johns Hopkins University; M. Petri, Johns Hopkins University; E. Darrah, Johns Hopkins University; K. Cashman, Emory University; I. Sanz, Emory University; K.H. Burns, Johns Hopkins University; D. Ardeljan, Johns Hopkins University; F. Andrade, Johns Hopkins University; A. Rosen, Johns Hopkins University
• Language: English
• Date: 2021-10-13
• Publisher: Rheumatology Society of Turkey
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Clinical and Experimental Rheumatology
• Final Published Version (URL): https://doi.org/10.55563/clinexprheumatol/bfz387
• Title of Journal or Parent Work: Clinical and Experimental Rheumatology
• Volume: 40
• Issue: 9
• Start Page: 1636
• End Page: 1641
• Grant/Funding Information: B. Antiochos is supported by the Rheumatology Research Foundation (RRF), Jerome L. Greene Foundation and grant National Institute of Health (NIH), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) K08AR077100. F. Andrade is supported by the National Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) grant R21 AI147598. M. Petri, J. Li, and D.W. Goldman are supported by the National Institute of Health (NIH), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant R01 AR069572. Confocal imaging was performed at the Johns Hopkins Microscope Facility, supported by NIH grant S10 OD016374 (Institutes: Office of the Director [OD], Office of Research Infrastructure Programs [ORIP]).
• Keywords: autoantigens; systemic lupus erythematosus; long interspersed nucleotide elements; autoantibodies
• Research Categories: Biology, Neuroscience; Health Sciences, Epidemiology

Abstract

Objective Long Interspersed Element 1 (LINE-1) is an endogenous retroelement that constitutes a significant portion of the human genome and has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The LINE-1 RNA chaperone protein ORF1p was recently identified as an SLE autoantigen. Here we analyse ORF1p for qualities underlying SLE autoantigen status, compared anti-ORF1p antibodies to markers of SLE disease activity, and performed screening for antibodies against LINE-1 reverse transcriptase ORF2p. Methods ORF1p was examined in epithelial cell lines treated with cytotoxic lymphocyte granules and UV irradiation. Anti-ORF1p and anti-ORF2p antibodies were assayed by ELISA and analysed in two SLE cohorts. Results We found that ORF1p localises to cytoplasmic RNA-containing blebs in apoptotic cells, and is a substrate of the cytotoxic protease granzyme B (GrB). Anti-ORF1p antibodies were present in 4.2% of healthy controls, compared to 15.8% (p=0.0157) and 15.5% (p=0.036) of subjects in the two SLE cohorts. Anti-ORF1p antibodies were not associated with SLE disease activity nor peripheral blood markers of interferon (IFN) activation. Anti-ORF1p titres demonstrated stability over serial time points. Anti-ORF1p antibodies were not associated with anti-DNA, anti-RNP, or other SLE autoantibodies. There was no difference in anti-ORF2p ELISA results in controls versus SLE patients. Conclusion LINE-1 ORF1p is a component of apoptotic blebs and a substrate for GrB. Anti-ORF1p antibodies are enriched in SLE subjects but are not associated with dynamic markers of disease activity. These data support a potential role for LINE-1 dysregulation in SLE pathogenesis.