Primary Sjögren’s syndrome (pSS) is a common autoimmune systemic rheumatic disease with an unrevealed pathophysiology, affecting around 1-2% of the population. The main presenting symptoms are ocular and oral dryness. In addition to these sicca symptoms, systemic features with more serious complications affecting joints, skin, lungs, and peripheral nervous system are seen in 15% of pSS patients. Furthermore, about 5% of patients develop a B cel-lymphoma. Due to the lack of understanding of the underlying disease mechanism and the clinical and biological heterogeneity in patients, referred to as endotypes, the current treatment is based on symptom management, often with unsatisfactory results. This project aims to exploit the molecular basis of this heterogeneity. We will address the hypothesis that pSS, despite the diverse initial clinical features, undergoes in all patients a stepwise pathway from anti-SSA antibody positive asymptomatic individuals into a full blown disease. To better understand this transition, we will focus on conversion of glycosilation patterns of autoantibodies and on deep molecular profiling using high end flowcytometry and single-cell RNA sequencing approaches. The results from this project will permit us to better define the best window of opportunity for immune intervention in pSS.