IL-4-STAT6 Signal Transduction-Dependent Induction of the Clinical Phase of Sjögren’s Syndrome-Like Disease of the Nonobese Diabetic Mouse

Abstract

NOD.B10-H2b and NOD/LtJ mice manifest, respectively, many features of primary and secondary Sjögren’s syndrome (SjS), an autoimmune disease affecting primarily the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). B lymphocytes play a central role in the onset of SjS with clinical manifestations dependent on the appearance of autoantibodies reactive to multiple components of acinar cells. Previous studies with NOD.IL4−/− and NOD.B10-H2b.IL4−/− mice suggest that the Th2 cytokine, IL-4, plays a vital role in the development and onset of SjS-like disease in the NOD mouse model. To investigate the molecular mechanisms by which IL-4 controls SjS development, a Stat6 gene knockout mouse, NOD.B10-H2b.C-Stat6−/−, was constructed and its disease profile was defined and compared with that of NOD.B10-H2b.C-Stat6+/+ mice. As the NOD.B10-H2b.C-Stat6−/− mice aged from 4 to 24 wk, they exhibited leukocyte infiltration of the exocrine glands, produced anti-nuclear autoantibodies, and showed loss and gain of saliva-associated proteolytic enzymes, similar to NOD.B10-H2b.C-Stat6+/+ mice. In contrast, NOD.B10-H2b.C-Stat6−/− mice failed to develop glandular dysfunction, maintaining normal saliva flow rates. NOD.B10-H2b.C-Stat6−/− mice were found to lack IgG1 isotype-specific anti-muscarinic acetylcholine type-3 receptor autoantibodies. Furthermore, the IgG fractions from NOD.B10-H2b.C-Stat6−/− sera were unable to induce glandular dysfunction when injected into naive recipient C57BL/6 mice. NOD.B10-H2b.C-Stat6−/− mice, like NOD.B10-H2b.IL4−/− mice, are unable to synthesize IgG1 Abs, an observation that correlates with an inability to develop end-stage clinical SjS-like disease. These data imply a requirement for the IL-4/STAT6-pathway for onset of the clinical phase of SjS-like disease in the NOD mouse model.

Salivary gland tissue expression of interleukin‐23 and interleukin‐17 in Sjögren's syndrome: Findings in humans and mice

“…In contrast, expression of both Gata3 and Ror␥t did not increase until after age 12 weeks, peaked at age ϳ16 weeks, and returned to normal by age 20 weeks. These data are highly indicative of the disease profile described for C57BL/6.NOD-Aec1Aec2 mice, in which IFN␥ expression is essential early in the disease, but IL-4 expression is essential in the onset of clinical disease (32). The current data indicate that IL17 gene expression is coordinate with IL4 gene expression as well as with production of IgG1 isotypic autoantibodies postulated to effect SS-like disease.…”

Systemic manifestations of primary Sjögren's syndrome in the NOD.B10Sn-H2/J mouse model

“…SS pathogenesis in NOD.B10 mice shares many similarities with the human disease. Specifically, NOD.B10 mice exhibit a female disease predilection, have anti-nuclear autoantibodies (ANA), and develop the disease spontaneously [7–9]. Moreover, exocrine tissue from female NOD.B10 mice shows histopathologic features of human disease and mice lose salivary flow with disease progression, similar to pSS patients [7–9].…”

Age-related Defects in Ocular and Nasal Mucosal Immune System and the Immunopathology of Dry Eye Disease

“…The appearance of autoimmune diabetes before autoimmune exocrinopathy in the NOD mouse suggests that it can be used as a model of secondary, but not primary Sjögren syndrome. 107,108 However, the complex immunopathological mechanisms involved in the NOD mouse remain to be fully elucidated. Evidence also indicates that the immunopathology of lacrimal and salivary glands is secondary to metabolic changes, unrelated to primary diseases (i.e., rheumatoid arthritis, autoimmune thyroiditis, and system lupus erythematosus), that typically give rise to secondary Sjögren syndrome.…”