Dysregulated long non-coding RNA in Sjögren’s disease impacts both interferon and adaptive immune responses

Abstract

ObjectiveSjögren’s disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjDRo+) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised.MethodsWhole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjDRo−); n=27 Ro/SSA positive (SjDRo+) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log2fold change ≥2 or ≤0.5; padj<0.05) were used to predict lncRNA function.LINC01871was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targetedLINC01871deletion (LINC01871−/−) and in vitro stimulation assays.ResultsWhole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene,RSAD2, in SjDRo+(r≥0.65 or ≤−0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines.LINC01871was upregulated in all SjD cases. RNA-seq and pathway analyses ofLINC01871−/−cells implicated roles in cytotoxic function, differentiation and IFNγ induction.LINC01871was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells.ConclusionLINC01871influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. AlteredLINC01871expression may influence the dysregulated T cell inflammatory pathways implicated in SjD.