Table 1.

miRNAs involved in Sjögren’s syndrome

Group	Biological sources	Differentially expressed miRNAs	Expression in SjS or association	Note	References
pSjS (n = 16), HC (n = 8) +validation cohorts	MSG	miR-768-3p	Positive correlation with MSG focus score	Distinct miRNA expression patterns associated with SG inflammation and dysfunction in SjS miRNA microarray	Alevizos et al. (2011) [15]
		miR-574	Negative correlation with MSG focus score
SjS (n = 14), Non-SjS sicca (n=13)	MSG	miR-181a	Upregulated in SjS	Upregulated miR-181a, miR-200b, and miR-223 miRNAs in SS implying a negative feedback loop for the elevated Ro/SSA and La/SSB, and/or their inability to regulate those targets qRT-PCR	Kapsogeorgou et al. (2011) [16]
	SGEC	miR-200b	Upregulated in SjS
		let-7b	Downregulated in SjS patients positive for anti-Ro and/or La
	PBMC	miR-223	Upregulated in SjS
SjS (n=29), Non-SjS sicca (n=24)	MSG	miR-16	Upregulated in SjS	miR-16, miR200b-3p, miR223 and miR483-5p dysregulation in SjS qRT-PCR Significantly lower miR200b-5p levels expressed in SjS patients with MALT compared to SjS without lymphoma	Gourzi et al. (2015) [20]
		let-7b, miR-181a, miR-16, miR-223, miR-483-5p	Correlated positively with Ro52/TRIM21 mRNA
	SGEC	miR-200b-3p	Upregulated in SjS
		miR-181a	Correlated negatively with Ro52/TRIM21
		miR-200b-3p	Correlated negatively with Ro60/TROVE2 mRNAs
		Let-7b, miR-200b-5p, miR-223	Associated with La/SSB mRNA
	PBMC	miR-223, miR483-5p	Upregulated in SjS
		let-7b, miR-181a, miR-16, miR-483-5p	Correlated with Ro52/TRIM21
		let-7b, miR-181a, miR-16	Associated with La/SSB-mRNA
SjS (n = 6), HC (n = 3)	MSG	hsa-miR-4524b-3p, hsa-miR-4524b-5p, hsa-miR-5571-3p, hsamiR-5571-5p, hsa-miR-5100, hsa-miR-5572	Pooled RNA for sequencing were used as biological replicates for validation by RT-PCR	Previously unidentified six miRNAs in SjS patients newly discovered NGS	Tandon et al. (2012) [21]
SjS	SGEC, B cells	EBV-specific miRNA (ebv-miR-BART13-3p)	Present in both B cells and SG	ebv-miR-BART13-3p transferred from B cells to SGEC through exosomes involved in calcium signaling in a model system	Gallo et al. (2016) [22]
pSjS (n=40), HC (n=20)	MSG	miR-126, miR-335-5p	Significantly increased inversely with salivary flow rate	Decreased cystatin S proposed as a promising SjS biomarker Cystatin S strongly correlated with hyposalivation and miR-126 and miR-335-5P upregulation qRT-PCR and western blot analysis	Martini et al. (2017) [23]
	Cystatin S	Cystatin S transcript	No significant change in pSjS
		Salivary cystatin S	Decreased in pSjS, especially those with hyposalivation Positive correlation with unstimulated flow rate Reduced in patient with gland ultrasound score greater ≥2
SjS (n=25), HC (n=10)	PBMC	miR-146a, miR-155	Significantly increased in SjS	miR-146a increases phagocytic activity and suppresses inflammatory cytokines (TNF-α, IL-1β, MIP-1α and IL-6). Abnormal expression/regulation of miRNAs in innate immunity may contribute to, or be indicative of, the initiation and early stage of SjS. qRT-PCR	Pauley et al. (2011) [19]
SjS-prone mouse B6DC Wild type B6	SMX	miR-146a	Upregulated in B6DC at both 8and 20weeks of age
	PBMC	miR-146a	Upregulated in B6DC at 20 weeks
pSjS (n=8) SLE (n=8), HC (n=7)	PBMC	25 miRNAs such as miR-146a, miR-16, miR-21	Overexpressed in both pSjS and SLE	Expression levels of miR-223-5p, miR-150-5p, miR-155-5p and miR-342-3p potentially linked to B cell functions NGS	Chen et al. (2017) [10]
		miR-150-5p	Down-regulation in pSjS
		miR-148a-3p, miR-152, miR-155, miR-223, miR-224, miR-326, miR-342	No change in pSjS but over-expressed in SLE
pSjS (n=4), HC (n=3), +validation cohorts	PBMC	miRNA-181a, miRNA-146a, miRNA-155	Most highly regulated miRNAs among the upregulated 202 miRNAs	miR-181a was the most profoundly differentially expressed in pSjS, which may compromise B cell maturation. Many virus-derived miRNA were unexpectedly upregulated in the SjS. miRNA microarray	Peng et al. (2014) [24]
pSjS (n=12), RA (n=8), SLE (n=9), HC (n=9) +validation cohorts	Monocyte	miR-34b-3p, miR-609, miR-4701-5p, miR-300, miR-3162-3p, and miR-877-3p	Overexpressed in 43% of pSjS patients compared to 5.8% and 5.6% for SLE and RA, respectively	MiRNA-target pathway predictions identified SjS-miRNAs preferentially target the canonical TGFβ signaling pathway as opposed to IL-12 and TLR/NFkB pathways. miRNA microarray	Williams et al. (2016) [18]
pSjS (n=17), HC (n=15) +validation cohorts	CD4+T cells	hsa-let-7d-3p, hsa-miR-155 5p, hsa-miR-222 3p, hsa-miR-30c-5p, hsa-miR-146a-5p, hsa-miR-378a-3p, hsa-miR-28 5p	Upregulated in pSjS	Major miRNA dysregulation in T and B cells from patients with pSjS The loss of hsa-miR30b-5p can contribute to the increased expression of BAFF in patients with pSjS miRNA microarray	Wang-Renault et al. (2018) [25]
	CD19+B cells	hsa-miR-378a-3p, hsa-miR-222 3p, hsa-miR-26a-5p, hsa-miR-30b-5p, hsa-miR-19b-3p,	Significantly differentially expressed in pSjS
		hsa-miR-30b-5p	Inversely correlated with expression of BAFF mRNA

miRNAs, microRNAs; SjS, Sjögren’s syndrome; HC, healthy control; MSG, minor salivary gland; SG, salivary gland; SGEC, salivary gland epithelial cells; qRT-PCR, real-time quantitative reverse transcription-PCR; TRIM21, tripartite motif-containing protein 21; TROVE2, TROVE domain family, member 2; MALT, mucosa-associated lymphoid tissue lymphoma; PBMC, peripheral blood mononuclear cell; RT-PCR, reverse transcription-PCR; NGS, next generation sequencing; EBV, Epstein Barr virus; pSjS, primary Sjögren’s syndrome; RA, rheumatoid arthritis; B6, C57BL/6J; B6DC, C57BL/6.NOD-Aec1Aec2; SMX, submandibular glands; TNF-α, tumor necrosis factor α; IL, interleukin; MIP-1α, macrophage inflammatory protein 1α; SLE, systemic lupus erythematosus TGFβ, transforming growth factor β; TLR, Toll-like receptor; NF-κB, nuclear factor κB; BAFF, B-cell activating factor.