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.

Long Non-Coding RNAs in Sjögren’s Disease

“…Linc01871, a lncRNA expressed in mature CD4+ and CD8+ T cells, class-switched memory B cells, plasma cells, natural killer cells, and hematopoietic progenitor cells was upregulated in SjD Ro + and SjD Ro − subgroups, with the highest expression found in the SjD Ro − patients. Linc1871 was induced by interferon (IFN)-γ in Kasumi 3 (early myeloid) cells and regulated by calcineurin and TCR signaling in primary human T cells [61]. The expression of OAS123-AS1, MX1-AS1, GBP5-AS1, and NRIR was increased in SjD Ro + patients but not in the SjD Ro − subgroup [61], in line with the established higher IFN signatures in SjD Ro + patients [62].…”

“…At least some of the differences observed might be based on altered immune cell composition, which was addressed by the authors using a deconvolution analysis. Most cell types were similarly distributed among the two SjD subgroups and healthy controls, with the exception of M2 macrophages, which were increased in both SjD subgroups; monocytes were increased and CD4+ T cells were decreased in the SjD Ro + group [61]. Linc01871, a lncRNA expressed in mature CD4+ and CD8+ T cells, class-switched memory B cells, plasma cells, natural killer cells, and hematopoietic progenitor cells was upregulated in SjD Ro + and SjD Ro − subgroups, with the highest expression found in the SjD Ro − patients.…”

“…RNA-seq of whole blood samples derived from patients with SjD compared to samples from healthy individuals detected 1812 differentially expressed lncRNAs, with the majority being downregulated in SjD. A subanalysis of samples derived from patients that were either positive (SjD Ro + ) or negative (SjD Ro − ) for anti-Ro/SSA auto-antibodies identified 97 lncRNAs that were specific to SjD Ro + when compared to healthy controls and 1114 lncR-NAs that were unique in the SjD Ro + subgroup [61]. At least some of the differences observed might be based on altered immune cell composition, which was addressed by the authors using a deconvolution analysis.…”

Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson Syndrome and Toxic epidermal necrolysis.

“…Indeed, although KLRC1 and KLRD1 form the inhibitory NKG2A/CD94 receptor, their expression on otherwise activated T-cells is shown only to limit excessive activation to sustain immune response 18 . Further, expanded clonotypes are expressed (i) under influence of LINC01871 , associated with TCR-dependent cytotoxicity in Sjogren’s disease 19 , (ii) on a subset of T-cells expressing two TCRαβ, associated with auto-and allo-cross-reactivities 14 , and (iii) in the same pathogenic cluster as diverse polyclonal T-cells, with a more limited but nonetheless cytolytic signature consistent with antigen-induced activation 15 . These data support a ‘selective-signaling’ model of TCR-triggered activation whereby different clonotypes support proliferation and/or cytolytic secretion.…”

Current Views on Pathophysiology and Potential Therapeutic Targets in Sjögren’s Syndrome: A Review from the Perspective of Viral Infections, Toll-like Receptors, and Long-Noncoding RNAs

“…However, no association between serological markers of SS and expression levels of MALAT1 were found, which was thought to be due to the small sample size [ 57 ]. Joachims et al reported the overexpression of lncRNA LINC01871 in patients with SS, suggesting that LINC01871 dysregulates T cell-mediated inflammatory pathways in SS [ 58 ]. Considering the knowledge introduced in this section, it was presumed that various lncRNAs differentially expressed in blood samples from patients with SS participated the pathophysiology of SS, the mechanism of which were in part in association with IFN-α.…”