The ‘target tissues’ as orchestrators of autoimmune responses: the paradigm of Sjögren’s syndrome

Systemic autoimmune diseases have been traditionally studied with a special focus on the immune system and less attention was paid to the roles of target tissues that are being exposed to the immune assault. For many common autoimmune diseases accumulating data unravel and highlight the potential role of the target tissues as orchestrators of the autoimmune responses. In this selective review, using Sjögren's disease (SjD) as a paradigm, we discuss the role of salivary gland epithelial cells (SGEC) not as innocent bystander targets of autoimmune responses, but rather as initiators and amplifiers of the inflammatory reactions. In fact, SGEC patients with Sjögren's disease are characterized by a unique phenotype which is capable of initiating and perpetuating both innate and adaptive immune responses in the glandular microenvironment. Aberrant expression and function of TLRs and IFN pathways, lymphocyte activating proteins as well as rewired cellular metabolism and antigen-presenting features, shape this distinct auto-antigenic phenotype of SGEC. These discoveries and ideas regarding the regulatory potential of the target SGEC in Sjögren's disease add a new dimension to our concept of regulatory circuits in autoimmunity.