Joachims ML, Khatri B, Li C, Tessneer KL, Ice JA, Stolarczyk AM, Means N, Grundahl KM, Glenn SB, Kelly JA, Lewis DM, Radfar L, Stone DU, Guthridge JM, James JA, Scofield RH, Wiley GB, Wren JD, Gaffney PM, Montgomery CG, Sivils KL, Rasmussen A, Farris AD, Adrianto I, and Lessard CJ. Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses. RMD Open 2022; 8(2).
OBJECTIVE: Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjD(Ro+)) 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.
METHODS: Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjD(Ro-)); n=27 Ro/SSA positive (SjD(Ro+)) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log(2) fold change ≥2 or ≤0.5; p(adj)<0.05) were used to predict lncRNA function. LINC01871 was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targeted LINC01871 deletion (LINC01871(-/) (-)) and in vitro stimulation assays.
RESULTS: Whole 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 SjD(Ro+) (r≥0.65 or ≤-0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines. LINC01871 was upregulated in all SjD cases. RNA-seq and pathway analyses of LINC01871(-/) (-) cells implicated roles in cytotoxic function, differentiation and IFNγ induction. LINC01871 was 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.
CONCLUSION: LINC01871 influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. Altered LINC01871 expression may influence the dysregulated T cell inflammatory pathways implicated in SjD.
Medical Subject Headings
Humans; Interferons; RNA, Long Noncoding; Calcineurin; Antiviral Agents; Sjogren's Syndrome; Autoimmune Diseases; Autoantibodies; Immunity; Receptors, Antigen, T-Cell