Correlated Expression of Notch2 and ADAM17 in Primary Sjögren’s Syndrome Salivary Glands

Background/Objectives: The Notch-ADAM17 pathway is a fundamental signaling mechanism where ADAM17, a disintegrin and metalloprotease, cleaves the Notch re-ceptor after the Notch receptor binds to a ligand. Crosstalk between Notch and AD-AM17 is often altered in pathological situations. Alterations in Notch2 expression, in particular, appear to be correlated with the onset of various autoimmune diseases. In primary Sjögren's disease (pSjD), an autoimmune disorder characterized by chronic inflammation, the role of ADAM17 has been extensively explored, but a correlation with Notch2 has not yet been evaluated. Methods: To analyze the gene and protein expression of Notch2 in pSjD and a possible correlation with ADAM17 expression and with the patient’s inflammatory grade, we employed an integrated co-detection pro-tocol to analyze salivary gland tissue sections by combining in situ hybridization (ISH) with immunohistochemistry (IHC). Results: combined ISH/IHC allows us to demon-strate an increased expression of Notch2 mRNA and protein in pSjD salivary glands (SGs) biopsies, that appears correlated with an increased expression of ADAM17, both in acinar and duct cells and in infiltrating lymphocytes. Notch2/ADAM17 expression is higher in biopsies of pSjD SGs characterized by a high degree of inflammation. Con-clusion: this work demonstrates the correlated expression in pSjD SGs of ADAM17, which plays multiple roles in the pathogenesis of SjD, and Notch2, widely considered a key player in various inflammatory mechanisms, offering a starting point for future therapeutic interventions to investigate.