PO:24:062 | Transcriptomic profile of salivary glands in patients with primary Sjögren’s syndrome and interstitial lung disease: implications for pathogenesis and risk stratification

Elisa Pignatti¹, Monia Maccaferri¹, Alessandra Bisagni², Alberto Cavazza², Marco Sebastiani^3|4, Luca Keller², Luca Magnani⁵, Claudio Galluzzo², Tommaso Fasano⁶, Lucia Nota⁶, Giulia Canu⁶, Andreina Manfredi^1|2, Carlo Salvarani^1|2 | ¹Dipartimento Chimomo, Università di Modena e Reggio Emilia Modena; ²Struttura Complessa di Reumatologia, Azienda Unità Sanitaria Locale di Reggio Emilia-IRCCS; ³Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma; ⁴Divisione di Reumatologia, AUSL di Piacenza; ⁵UOC Medicina Interna ind. reumatologico, AUSL di Bologna, Ospedale Maggiore, Bologna; ⁶Dipartimento Interaziendale ad Attività Integrata Medicina di Laboratorio ed Anatomia Patologica AUSL di Modena, Italy

Background. Primary Sjögren’s syndrome (pSS) is a chronic autoimmune inflammatory disease that typically develops in the absence of another systemic autoimmune disorder. Interstitial lung disease (ILD) represents the most frequent pulmonary manifestation of pSS and is associated with impaired lung function and potentially severe complications. Stratifying patients according to their risk of developing pSS-associated ILD (pSS-ILD) and identifying those at increased risk at an early stage may enable timely therapeutic intervention. Therefore, transcriptomic studies aimed at identifying differentially expressed genes across the three study groups may prove useful for the characterization of predictive disease factors.

Materials and Methods. Transcriptomic analyses of inflammatory and immune-related gene panels were performed on patients with ILD, pSS, and pSS-ILD using the NanoString nCounter platform. RNA was extracted from FFPE-embedded minor salivary gland samples obtained from eight patients in each group. Only RNA samples with the highest DV200 values, as assessed by Bioanalyzer, were used for further analysis. Data were processed using the nSolver software, and genes showing significant up- or down-regulation with p < 0.05 were considered differentially expressed.

Results. Gene expression analysis in patients with ILD revealed significant differences in immune and inflammatory responses compared to patients with isolated pSS. The up-regulation of TSLP, IL1RN, MAP2K6, JUN, IL1RL1, TNFRSF14, CXCL10, and IL7, along with the down-regulation of PIGR and ITGA6, signifies modified immunologic activity that may aid in clarifying the pathophysiology associated with ILD. Moreover, substantial gene expression variations were observed between pSS-ILD and isolated ILD. Elevated expression of HIF1A, NFATC3, FLT1, APP, and CD14, alongside diminished expression of transcription factors like MYC and FOS, indicates significant modifications in intracellular signaling pathways that may be involved in the pathogenesis of ILD. In addition, upregulation of HDAC4, C4A, and C7 in pSS-ILD patients compared to those with isolated pSS highlights further dysregulation of immune and inflammatory processes, suggesting the emergence of a profibrotic microenvironment capable of exacerbating lung injury. Conversely, down-regulation of CCL21 implies possible disturbances in lymphocyte trafficking and immune surveillance, further complicating disease pathogenesis.

Conclusions. It is noteworthy that not all patients with pSS develop ILD, suggesting the possible contribution of genetic or environmental factors to disease manifestation and progression. In summary, the transcriptomic landscape distinguishing ILD, pSS, and their comorbidity provides crucial insights into disease pathogenesis. The differential expression of genes—particularly HDAC4, C4A, C7, and CCL21—offers valuable clues for future research focused on targeted therapies and precision medicine approaches for these complex clinical phenotypes.