Cytokine storm and autoimmunity. Sjögren’s syndrome (SS) is a systemic autoimmune disorder affecting multiple organ systems. The targeting of exocrine salivary and lacrimal glands by a dysregulated immune response often leads to reduced fluid secretion, translating into the classic dry mouth and dry eye symptoms of the disorder. Genetic susceptibility plays a critical role in SS development, and genome-wide association studies have established that SS is a multi-genic disorder. The presence of viral nucleic acids and retroviral Line-1 elements in salivary gland cells, and an elevated type I IFN responsive gene signature, suggest that innate immune activation might be involved in SS’s etiology.

Nevertheless, how a systemic or/and localized innate immune response transitions into an adaptive autoimmune response targeting the exocrine glands remains unclear. This issue becomes even more critical in the context of the ongoing COVID-19 pandemic. The systemic cytokine storm elicited by the SARS-Cov-2 infection and the discovery of salivary gland tropism of this virus raises a strong possibility that a significant proportion of the population might develop SS. Thus, identifying pathways and mechanisms responsible for transitioning innate immunity activation into salivary gland disease and SS is a critical need of time.

In this project, using a unique genetic animal model resource, we are investigating how cytokine storms generated by excessive activation of innate immunity will lead to the development of SS and other autoimmune disorders.

Schematic representation of the hypothesis. In a genetically susceptible individual, salivary gland response to innate immune stimuli are of higher magnitude and initiate inflammatory cell infiltration within the gland. This progresses to the development of SS if the individual is also predisposed for autoimmunity.