Background/Purpose: Primary Sjögren’s syndrome (PSS) is a chronic inflammatory disease affecting exocrine glands with an important systemic autoimmune reaction against some nuclear and membrane bound proteins. A glandular epithelial deregulation is thought to be the critical at early stages of PSS development. However, the nature of the initial damage and the cellular mechanisms behind the initiation of autoimmunity are still unknown. We sought to evaluate the epithelial changes induced by secretory stress in submandibular salivary glands (SMG) of mice developing PSS.

Methods: Secretory stress was induced in wild type BALB/c and Ncf1** mutant mice daily for 3 weeks. Salivary glands, saliva and sera were collected at the end of the secretory stress and 8 weeks later. Sera were tested for autoantibodies against SSA1, SSB and M3R. One half of SMG was prepared for next generation sequencing and the second half was fixed in formalin and embedded in paraffin for further histological analyses including image mass cytometry (IMC). Saliva volume and rheological features were determined.

Results: Secretory stress mice caused the enlargement of lumen areas of granular convoluted tubules (GCT) and an absolute loss of tubular epithelial cells. Serology of mice recovered from tubular cell injury showed elevated titers of autoantibodies against SSA1, SSB and M3R. Reactive oxygen species deficient mice (Ncf1**) were protected from tubular epithelial damage and autoimmunity. The analysis of the rheological properties of saliva revealed an increased viscosity associated with the oxidative state of saliva components. Tubular epithelial cell damage mediated by NETs was confirmed by Tunel staining and neutrophil elastase immunostaining. Sjögren´s syndrome relevant autoantigens were found translocated from the tubular into the acinar compartment. IMC based spatial analyses revealed an increased abundance of neutrophils in the acinar areas next to acutely damaged GCT and accumulation of neutrophil extracellular traps (NETs) markers in the tubular compartment. Mice with tubular injury upregulated genes of the set response to topologically incorrect protein. SMG regenerated after 8 weeks revealing a pronounced fibroblast proliferation and accumulation of T and B cells around the newly grown tubular compartment. Impaired oxidative capacity of myeloid cells prevented the development of an endogenous autoimmune response that was associated with the downregulation of G protein-coupled receptor signalling pathway.

Conclusion: We have digitally dissected SMG of wild type mice during the course of acute sialadenitis revealing neutrophils infiltrating glandular compartments adjacent to the actually damaged tubular cells. NETs were found in GCT of mice with increased viscosity of the saliva and in close relationship with translocated Sjögren´s autoantigens. The oxidative damage of GCT cells initiates a profound tissue reorganization of SMG that drives an autoimmune response resembling other Sjögren’s Syndrome murine models.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/salivary-granular-convoluted-tubules-contribute-to-maintain-tissue-specific-tolerance-implications-for-the-development-of-murine-sjogrens-syndrome/