A Dual Role for Interferon‐γ in the Pathogenesis of Sjögren's Syndrome‐Like Autoimmune Exocrinopathy in the Nonobese Diabetic Mouse

Sjögren's syndrome‐like autoimmune exocrinopathy (AEC) in the nonobese diabetic (NOD) mouse progresses from a preimmune phase to an immune phase, resulting in dry mouth and/or dry eyes. In the present study, the impact of the prototypical T‐helper type 1 cytokine, interferon‐gamma (IFN‐γ), on the onset of AEC was investigated using both the IFN‐γ and the IFN‐γ receptor gene knockout mice, NOD.IFN‐γ–/– and NOD.IFN‐γR–/–, respectively. Neither the NOD.IFN‐γ–/– nor the NOD.IFN‐γR–/– mice exhibited increased acinar cell apoptosis and abnormal salivary protein expression, typically observed in parental NOD mice prior to disease. Without these preimmune phase abnormalities, NOD.IFN‐γ–/– and NOD.IFN‐γR–/– mice showed no subsequent autoimmune responses against the salivary glands at 20 weeks. Interestingly, real‐time polymerase chain reaction and electrophoretic gel mobility shift assays suggested that IFN‐γ and STAT1, as well as the transcriptional activity of STAT1 in NOD glands, were increased at birth. Unlike the neonatal submandibular glands of NOD or NOD‐scid mice that show abnormal glandular morphogenesis at birth, the submandibular glands of the newly constructed congenic strain, NOD‐scid.IFN‐γ–/–, were found to be normal. Taken together, IFN‐γ appears to play a critical role not only during the later immune phase of AEC, but also the early preimmune phase, independent of effector functions of immune cells. How exactly IFN‐γ functions during this period remains speculative.