Sjogren’s syndrome (SS) is a chronic inflammatory disease characterized by salivary and lacrimal gland dysfunction although
extraglandular manifestations are also found. Suitable study models and in vitro cell culture designs are used to approach SS pathogenic
mechanisms. Cellular and molecular pathways involved in gland homeostasis loss and the autoimmune response are focused in the search
of novel drug targets and biomarkers. Vasoactive intestinal peptide (VIP) has trophic, pro-secretory and immunomodulatory effects in
several chronic and autoimmune disease models. Here we review evidence pointing to its role as an endogenous modulator of gland homeostasis
at early stages of the disease. Particularly, mechanisms involving VIP/VPAC system in the course of salivary function impairment
in the non obese diabetic (NOD) mouse model of Sjögren’s syndrome are described.