Role of the STAT6-IgG1 Signaling Pathway in Salivary Gland Dysfunction

Introduction: NOD mice represent an excellent model of Sjögren's syndrome (SjS), exhibiting salivary and lacrimal gland dysfunction concomitant with lymphocyte infiltrations. B lymphocytes play a central role in the onset of SjS with clinical manifestations dependent on appearance of autoantibodies reactive to multiple components of acinar cells. Previous data suggested that antibodies reactive with muscarinic-acetylcholine-type-3-receptors (M3Rs) may be effectors of glandular dysfunction, and confirmed using interleukin-4 (IL4) gene knockout SjS mice which fail synthesize IgG1-isotype-specific anti-M3R autoantibodies. Here we have investigated the molecular mechanisms by which IL-4 controls SjS development utilizing Stat6 gene knockout mice incapable of IgG1-isotype class-switching.

Methods: A NOD.B10-H2b.C-Stat6^-/- mouse strain was constructed, its disease profile defined and compared to that of NOD.B10-H2b.IL4^-/- mice. Between 4-24 weeks of age, stimulated saliva and tear flow rates were measured, sera analyzed for autoantibodies, tissues examined for biochemical/physiological alterations, and exocrine glands examined immunohistologically. Differentially-expressed genes were identified by microarray analyses.

Results: NOD.B10-H2b.C-Stat6^-/- mice, like NOD.B10-H2b.IL4^-/- mice, exhibited identical pathophysiological profiles of SjS exhibited by NOD mice (e.g., leukocyte infiltration of exocrine glands, production of ANAs, loss and gain of saliva-associated proteolytic enzymes), but failed to develop glandular dysfunction (i.e., maintained saliva flow rates comparable to wild-type control mice). NOD.B10-H2b.C-Stat6^-/- mice possessed no IgG1-isotype-specific anti-M3R autoantibodies. Microarray analyses point to the importance of STAT6-regulated, not IRS-regulated signal transduction pathways.

Conclusion: NOD.B10-H2b.C-Stat6^-/- and NOD.B10-H2b.IL4^-/- mice, unable to synthesize IgG1 antibodies, fail to develop end-stage clinical SjS-like disease, implying a requirement for the STAT6-pathway, a concept supported by differentially-expressed signal transduction pathway genes.

Supported by NIH grants DE55304, DE014344 and DE015152