Interleukin‐12 induces salivary gland dysfunction in transgenic mice, providing a new model of Sjögren's syndrome

Abstract

Objective. Interleukin-12 (IL-12) is a pleiotropic cytokine that is elevated in the affected organs of patients with Sjögren's syndrome (SS). We have previously reported that overexpression of IL-12 in CBA mice leads to mononuclear infiltration of salivary and lacrimal glands, as well as to expansion of bronchial lymphoid tissue and decreased mucociliary clearance. Because xerostomia is one of the most important clinical features in SS patients, our main objective in the current study was to evaluate salivary gland function in IL-12-transgenic mice. Our secondary objective was to further characterize this animal model and to determine if the changes observed in these mice are representative of those observed in patients with SS overall.Methods. Pilocarpine-stimulated salivary flow was used to address salivary gland function in a large group of IL-12-transgenic mice bred onto the autoimmune-prone SJL background. Furthermore, salivary glands were removed to assess the formation of infiltrates in the glands and gland morphology. Serum was also collected from these animals to investigate the formation of autoantibodies.Results. Pilocarpine-stimulated salivary flow was significantly lower in IL-12-transgenic mice than in wild-type controls. Salivary glands from transgenic mice exhibited an increase in both the number and the size of lymphocytic foci, versus glands from agematched controls. Furthermore, the acini in transgenic mice were fewer in number and larger in size compared with acini in controls. An age-dependent increase in anti-SSB/La antibodies was observed in IL-12-transgenic mice and was accompanied by an increase in antinuclear antibodies.Conclusion. Our findings indicate that a number of conditions associated with SS are exhibited by IL-12-transgenic SJL mice and that this model might be useful in researching multiple aspects of the disease.Sjögren's syndrome (SS) is an autoimmune disease of unknown etiology. Therefore, the development of animal models that mimic the disease in patients is critical not only for understanding the biology of SS but also for validating the safety and efficacy of experimental therapeutic approaches. The nonobese diabetic (NOD) mouse model is one of the most widely used models of SS. These mice develop age-dependent histopathologic changes in the salivary glands and autoantibodies in serum, similar to the features observed in SS patients (1,2). While the development of sialadenitis in NOD mice may be accompanied by a loss of salivary gland function,

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

“…Knockout mice for AQP5, NKCC1, IP3R types 2 and 3, matriptase, and the M3 and M1 muscarinic receptors are all reported to have a decrease in saliva flow (28)(29)(30)(31)(32). The interplay between the epithelia and the immune system adds a further layer of complexity because T-cell knockouts of IP3K, STIM1/STIM2, and ID3 and overexpression of IL-12, BAFF, and sTNFR1 are all also reported to induce loss of gland function and may initiate it by different pathways (33)(34)(35)(36)(37)(38). We report an association between elevated BMP6 protein expression and AQP5 expression, but changes in any of these other factors triggered by environmental stimuli could account for the loss of gland activity in the patients with normal BMP6 expression.…”

The enigmatic role of interleukin‐12 in the pathogenesis of Sjögren's syndrome: Comment on the article by Vosters et al

“…Second, it is important to note that the 2 animal models of SS are not identical. For example, the Il-12rb2-KO mice used by Airoldi et al (1) do not develop anti-SSA/Ro or anti-SSB/La antibodies, a key component of human SS that was also manifested in our IL-12-transgenic mice.…”

“…Airoldi, Di Carlo, and Pistoia for their interesting comments. We described a model of SS that was established by increasing IL-12 signaling, whereas Dr. Airoldi and colleagues established a similar phenotype by abolishing IL-12 signaling (1). How can these observations be reconciled?…”

Mechanisms of Salivary Gland Secretory Dysfunction in Sjögren’s Syndrome

“…IL-12 transgenic mice showed decreased stimulated salivary flow by pilocarpine than in wild type controls. Also, IL-12 transgenic mice exhibited increased number and size of lymphocytic foci with increased anti-SSB/La antibodies, compared to glands from age-matched controls (Vosters et al 2009). …”