Alternative exon usage in TRIM21 determines the antigenicity of Ro52/TRIM21 in systemic lupus erythematosus

Eduardo Gomez-Bañuelos, M. Javad Wahadat, Jessica Li, Merlin Paz, Brendan Antiochos, Alessandra Ida Celia, Victoria Andrade, Dylan P. Ferris, Daniel W. Goldman, Erika Darrah, Michelle Petri, Felipe Andrade*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Downloads (Pure)

Abstract

The origin and mechanisms of autoantigen generation in systemic lupus erythematosus (SLE) are poorly understood. Here, we identified SLE neutrophils activated in vivo by IFN as a prominent source of Ro52, also known as tripartite motif-containing protein 21 (TRIM21), a critical autoantigen historically thought to be primarily generated by keratinocytes in SLE. Different from mononuclear cells and keratinocytes, SLE neutrophils are enriched in several unique Ro52 species containing a core sequence encoded by exon 4 (Ro52Ex4) in TRIM21. Ro52Ex4 is the main target of anti-Ro52 antibodies and is found in 2 Ro52 variants (Ro52α and a potentially novel isoform termed Ro52γ) upregulated in SLE neutrophils. Further analysis of Ro52γ revealed a subset of autoantibodies against a unique C-terminal domain (Ro52γCT) generated from a frameshift due to the lack of exon 6 in Ro52γ. Antibodies to Ro52Ex4 and Ro52γCT distinguish SLE patient subsets characterized by distinct clinical, laboratory, treatment, and transcriptional profiles that are not discerned by the "classical" anti-Ro52 antibodies. These studies uncover IFN-activated neutrophils as a key source of unique immunogenic forms of Ro52 in SLE. Moreover, the finding of Ro52Ex4 and Ro52γCT as core targets of anti-Ro52 antibodies focus interest on Ro52γ as the potential isoform toward which immunological tolerance is initially lost in SLE.

Original languageEnglish
Article numbere163795
JournalJCI insight
Volume7
Issue number19
DOIs
Publication statusPublished - 10 Oct 2022

Bibliographical note

Funding Information:
Supported by the Rheumatology Research Foundation, the Ira T. Fine Discovery Fund, the Jerome L. Greene Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant nos. R01 AR069569 and R01 AR069572, and the National Institute of Allergy and Infectious Diseases (NIAID) grant no. R21AI147598. The content of this paper is solely the responsibility of the authors and does not represent the official views of the NIAMS, NIAID, or the NIH.

Publisher Copyright:
© 2022, Gomez-Bañuelos et al.

Fingerprint

Dive into the research topics of 'Alternative exon usage in TRIM21 determines the antigenicity of Ro52/TRIM21 in systemic lupus erythematosus'. Together they form a unique fingerprint.

Cite this