Sjögren Syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of lacrimal and salivary glands with consequent irreversible loss of secretory function. SS is characterized by heterogeneous clinical, histological and laboratory features and this heterogeneity mirrors different underlying pathogenic mechanisms. The activation of the local salivary gland epithelial cells during inflammation plays a major role in SS pathogenesis. Indeed, during disease course, salivary gland epithelial cells become ¿activated¿ and express several molecules including chemokines, cytokines, costimulatory molecules and innate immune receptors, able to drive and maintain the local inflammation.
Currently, there is no effective therapy for SS and the primary reason for failure in clinical trials is represented by the lack of criteria to diversify and select patients. The hypothesis that is pivotal to this study is that different clinical phenotypes of SS arise from different grades/types of inflammation in exocrine glands, with epithelial cells playing a central pathogenic role. According to this hypothesis, the aim of this study is to determine the different molecular mechanisms driving the development of heterogeneous subsets of patients with SS.
Results will provide new information regarding the exact mechanisms driving salivary gland dysfunction, lymphocytic recruitment and development of autoimmunity in individual SS patients, and will instruct tailored therapeutic approaches.
This study is designed to evaluate for the first time the pattern of activation of salivary gland epithelium in different subsets of patients with SS. Previous studies on SS pathogenesis demonstrated an activation of this cell type in patient's salivary gland; the novelty of this project resides in the purpose to analyse epithelial cell activation according to specific SS subtypes with the aim to disclose differences in pathogenic molecular pathways. Deciphering the variability in epithelial cells activation would not only provide an explanation to the different clinical patterns observed in SS, but would also reveal novel molecular target.
SS therapy is one of the principal unmet need in the immunology and rheumatology field. Current therapies are not able to ameliorate the major patient's clinical complaint represented by sicca symptoms. The pressing need for new therapies is documented by several clinical trials performed in the past years in patients with SS. Of note, several biologic therapies were investigated (anti-CD20, anti-BAFF or BAFFR, cytokines or co-stimulatory molecules inhibitors) with inconclusive results.
The principal obstacle to an efficient and rational use of these and others targeted therapies is the absence of precise molecular taxonomic criteria to guide patient stratification. Even in clinical trials, patient selection is based on elementary clinical and serological criteria: for example, B cells depleting therapies were tested in SS patients with autoantibodies. In clinical practice, the heterogeneity of SS poses critical challenges to the choice of drugs, and regarding B cell depleting therapies there is no clear rationale on their use in seronegative patients.
Characterizing the exact mechanisms regulating salivary gland dysfunction, lymphocytic recruitment and autoantigen exposure in different subset of patients with SS (seronegative vs seropositive; highly infiltrated vs slightly infiltrated) is critical to develop a tailored therapeutic approach.
In conclusion, this study aim at determining which current therapeutic strategy is most suitable for different subtypes of patients with SS, while also revealing novel therapeutic targets for specific patient subtypes focusing on the role of salivary gland epithelium in the pathogenesis of SS.