JAK‐1 Inhibition Suppresses Interferon‐Induced BAFF Production in Human Salivary Gland

Objective To examine whether a JAK inhibitor regulates functional responses of human salivary gland epithelial cells ( SGEC s) and disease parameters in an animal model of Sjögren's syndrome ( SS ). Methods Common differentially expressed genes ( DEG s) were analyzed among peripheral blood mononuclear cells from patients with primary SS and other data sets, using blood and SG tissue. Validation of expression in SG s was analyzed by focus score. Inhibition of messenger RNA expression of DEG s and BAFF by filgotinib was analyzed using reverse transcription–polymerase chain reaction in primary SGEC s. SG organoid cultures were used to determine the association between DEG s and BAFF via knockdown using small interfering RNA s or to determine regulation of BAFF by JAK inhibitor. Filgotinib (1.5 mg/kg) was intraperitoneally injected into 8‐week‐old NOD /ShiLtJ mice 3 times per week to analyze manifestations of disease. Finally, STAT signaling was assessed in human and mouse SGEC s. Results Expression of the DEG s IFNG and BAFF increased in SG s from patients with primary SS , as assessed by focus score. There was a significant correlation between IFIT 2 and BAFF expression. JAK inhibitor suppressed interferon ( IFN )–induced transcription of DEG s and BAFF in human primary SGEC s. Knockdown of DEG s or inhibition of JAK caused reduced secretion of BAFF in human SG organoid cultures. In addition, filgotinib‐treated mice exhibited increased salivary flow rates and marked reductions in lymphocytic infiltration of SG s. JAK inhibitor regulated IFN α‐ and IFN γ‐induced pSTAT ‐1 Y701 , pSTAT ‐3 Y705 , and protein inhibitor of activated STAT ‐3 ( PIAS ‐3) in human SGEC s as well as IFN γ‐induced pSTAT ‐1 Y701 , pSTAT ‐3 S727 , and PIAS ‐1 in mouse SGECs. Conclusion JAK inhibition controls aberrant activation of SGEC s and may be a novel therapeutic approach for primary SS .