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. 2021 Sep 14;12:706737. doi: 10.3389/fimmu.2021.706737

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Copyright © 2021 Pontarini, Sciacca, Grigoriadou, Rivellese, Lucchesi, Fossati-Jimack, Coleby, Chowdhury, Calcaterra, Tappuni, Lewis, Fabris, Quartuccio, Bella, Bowman, Pitzalis, Mavilio, De Vita and Bombardieri

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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NCR3 gene is upregulated in pSS salivary glands with higher inflammatory infiltration. (A) Heatmap showing Z-score of NK, B-, and T-cell related genes from RNA sequencing analysis of labial salivary gland biopsies of Sicca (n = 17) and pSS (n = 24) patients. Color sets on top of the heatmap identify the presence (pos) or absence (neg) of circulating anti-nuclear (ANA), anti-Ro (aRo), and anti-La (aLa) antibodies, ectopic lymphoid structures (ELS) in the glands, and circulating immunoglobulin (Ig) levels (IgG, IgA, and IgM). Each square is a sample/patient. (B) Expression on natural cytotoxicity receptor (NCR) genes: NCR1 (NKp46), NCR2 (NKp44), and NCR3 (NKp30) between NSCS (sicca) and pSS salivary glands. Mann–Whitney U t-test statistics. (C) NCR3 (NKp30) gene expression level in SS patients segregated by the presence (pos) or absence (neg) of circulating auto-antibodies, such as rheumatoid factor (RF), anti-SSA/Ro (aRo), and anti-SSB/La (aLa). Mann–Whitney U t-test statistics. (D) Correlation matrix between NCR1 (NKp46), NCR2 (NKp44), NCR3 (NKp30), NCR3LG1 (B7/H6) gene expression level, circulating level of immunoglobulins (IgG, IgA, IgM), complement (C3, C4), EULAR Sjögren’s syndrome (SS) disease activity index (ESSDAI), and histological semi-quantitative score for CD3, CD20, and CD138. Graph shows NSCS and pSS patients. Spearman correlation coefficient, R (color denotes the strength of the correlation) and p-value, FDR correction for multiple comparison. *p < 0.05, **p < 0.01, ***p < 0.001. (E) NCR3 (NKp30) gene expression level in NSCS (sicca) and pSS salivary glands, segregated by the presence (ELS pos) or absence (ELS neg) of ectopic lymphoid structures within SG. Statistical analysis by Kruskal–Wallis test with Dunn’s multiple comparison correction. (F) Spearman correlation analysis between NCR3 with GZMB, PRF1, and IFNG in pSS patients segregated for the presence of ELS. Spearman correlation coefficient, R and p-value, *p < 0.05, **p < 0.01, ***p < 0.001. NSCS, non-specific chronic sialadenitis; SS, Sjogren’s syndrome; ELS, ectopic lymphoid structures; ns, not significant.