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

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 (Ro52 alpha and a potentially novel isoform termed Ro52 gamma) upregulated in SLE neutrophils. Further analysis of Ro52 gamma revealed a subset of autoantibodies against a unique C-terminal domain (Ro52 gamma CT) generated from a frameshift due to the lack of exon 6 in Ro52 gamma. Antibodies to Ro52Ex4 and Ro52 gamma CT 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 Ro52 gamma CT as core targets of anti-Ro52 antibodies focus interest on Ro52 gamma as the potential isoform toward which immunological tolerance is initially lost in SLE.