Salivary gland response to type I interferons is independent of circulating cytokine levels: Implications for understanding Sjögren’s syndrome pathogenesis

Abstract Sjögren’s syndrome (SS) is a chronic autoimmune disorder affecting the salivary glands. Viral infection-mediated activation of innate immunity and elevated type I IFNs are considered risk factors for SS. However, the frequency of individuals developing SS is far lower than those infected with viruses. To address the role of genetic susceptibility for SS development, we treated 9 inbred strains of mice covering a diverse genetic repertoire with the TLR3 agonist poly (I:C). Serum cytokines were measured by bead-based assays, and salivary gland immune cell populations were studied by spectral flow cytometry. Primary salivary gland cell cultures were stimulated with IFNα, and the expression of IFN-responsive genes was analyzed. Poly (I:C) induced circulating cytokine levels were widely different between the mouse strains, and they correlated with the presence of a CD11b+ macrophage population in the peritoneum. All poly (I:C) treated mice showed significantly increased frequencies of salivary gland NKp46+ (NK and ILC1) innate immune cells compared to saline-treated controls. IFNα-treated primary salivary gland cultures showed strain-specific differences in IFN-responsive gene expression. Surprisingly, the IFN-responsive gene signature score and elevated frequency of NKp46+ cells in salivary glands did not correlate with the levels of circulating cytokines. These data show that the magnitude of salivary gland responses to type I IFNs are not concordant with the systemic innate immune response. Our study suggests that following a viral infection, genes dictating salivary gland response to type I IFNs might play a critical role in SS development. Identifying such genes will lead to a better understanding of SS etiopathogenesis. Supported by grants from NIH (NIDCR DE031166)