Abstract
To assess the types of salivary gland (SG) T cells contributing to Sjögren’s syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4+ memory T cell transcriptomes of subjects with either primary SS (pSS) or non-SS sicca (nSS). SG biopsies were evaluated for proportions and absolute numbers of CD4+ and CD8+ T cells. SG memory CD4+ T cells were evaluated for gene expression by microarray. Differentially-expressed genes were identified, and gene set enrichment and pathways analyses were performed. CD4+CD45RA− T cells were increased in pSS compared to nSS subjects (33.2% vs. 22.2%, p < 0.0001), while CD8+CD45RA− T cells were decreased (38.5% vs. 46.0%, p = 0.0014). SG fibrosis positively correlated with numbers of memory T cells. Proportions of SG CD4+CD45RA− T cells correlated with focus score (r = 0.43, p < 0.0001), corneal damage (r = 0.43, p < 0.0001), and serum Ro antibodies (r = 0.40, p < 0.0001). Differentially-expressed genes in CD4+CD45RA− cells indicated a T follicular helper (Tfh) profile, increased homing and increased cellular interactions. Predicted upstream drivers of the Tfh signature included TCR, TNF, TGF-β1, IL-4, and IL-21. In conclusion, the proportions and numbers of SG memory CD4+ T cells associate with key SS features, consistent with a central role in disease pathogenesis.
Highlights
Sjögren’s syndrome (SS) is a systemic autoimmune disease featuring focal lymphocytic infiltration of salivary and lacrimal glands, antibodies to Ro/SS-A and La/SS-B antigens, and chronic dry eyes and mouth [1]
salivary gland (SG) of primary SS (pSS) subjects contained a higher proportion of memory CD4+ T cells compared to non-SS sicca (nSS) controls (33.2% ± 2.0 vs. 22.2% ± 1.2; p < 0.0001, Figure 1A)
Proportions of memory SG CD8+ T cells were reduced in pSS cases compared to nSS controls (38.5% ± 1.7 vs. 46.0% ± 1.5; p = 0.0014, Figure 1B)
Summary
Sjögren’s syndrome (SS) is a systemic autoimmune disease featuring focal lymphocytic infiltration of salivary and lacrimal glands, antibodies to Ro/SS-A and La/SS-B antigens, and chronic dry eyes and mouth [1]. Another study provided immunohistochemical evidence showing co-expression of CD3 and Bcl-6, suggesting the presence of Tfh cells in SG infiltrates, but only one example was presented [13]. Maehara et al failed to observe association of Treg gene expression with either the severity of infiltration or with GC-like structures [17]. Though laser capture microdissection is a powerful approach that can identify SS-associated gene expression patterns in lymphocytic infiltrates [23], assignment of transcripts to CD4+ T cells, CD8+ T cells, or other lymphocytic lineage cells remains challenging. Flow cytometry and microarray analyses of highly purified SG memory CD4+ T cells from well-characterized primary SS (pSS) cases and matched sicca controls (nSS) were used to assess disease associations and effector cell phenotypes. Our results strengthen the argument that SG memory CD4+ T cells play a prominent role in SS disease pathogenesis
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