Sj?gren’s syndrome(SS) is a systemic autoimmune disease that affects primarily the lacrimal and salivary glands. In addition to a systemic autoimmune response directed against ubiquitous antigens(such as Ro and La antigens),patients with SS mount a localized response that affects the epithelial component of exocrine glands leading to the establishment of a destructive inflammatory infiltrate comprised of activated T and B cells. Local chemokine and cytokine production drive the recruitment and local activation of immune cells that cause injury to acinar cells. CD4 T cells with different functional differentiation programs including Th1(IFN-γ),Th2(IL-13,IL-4) and Th17(IL-17,IL-21,IL-22) as well as diverse cytokine signaling pathways,are involved at the initiation,perpetuation,and progression of the disease. Which factors initiate this response and allow it to become chronic are unknown. Proposed mechanisms include viral infections and acinar cell apoptosis. Moreover risk-conferring genetic variants,probably through the facilitation of innate and adaptive immune activation,most certainly contribute to the creation of an underlying environment that fosters tolerance loss and facilitates perpetuation of the autoimmune response. In this review,we describe the mechanisms through which the immune response causes SS and emphasize the pathways that are amenable of being targeted with therapeutic purposes. In addition to a systemic autoimmune response directed against ubiquitous antigens (such as Ro and La antigens), patients with SS mount a localized response that affects the epithelial component of exocrine glands leading to the establishment of a destructive inflammatory infiltrate comprised of activated T and B cells. Local chemokine and cytokine production drive the recruitment and local activation of immune cells that cause injury to acinar cells. CD4 T cells with different functional differentiation programs including Th1 (IFN-γ), Th2 (IL-13, IL-4) and Th17 (IL-17, IL- 21, IL- 22) as well as diverse cytokine signaling pathways, are involved at the initiation, perpetuation , and progression of the disease. Which pathogens include viral infections and acinar cell apoptosis etic variants, probably through the facilitation of innate and adaptive immune activation, most certainly contribute to the creation of an underlying environment that fosters tolerance loss and facilitates perpetuation of the autoimmune response. in this review, we describe the mechanisms through which the immune response causes SS and emphasize the pathways that are amenable of being targeted with therapeutic purposes.