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* Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610;
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610; and
Center for Orphan Autoimmune Diseases, College of Dentistry, University of Florida, Gainesville, FL 32610
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Public Health Service Grants DE013769, DE014344, and DE015152 (to A.B.P.) from the National Institutes of Health. C.Q.N. was supported by a postdoctoral fellowship from Public Health Service Grant T32 DE07200.
2 Address correspondence and reprint requests to Dr. Cuong Q. Nguyen, Department of Oral Biology, College of Dentistry, University of Florida, P.O. Box 100424, Gainesville, FL 32610. E-mail address: nguyen{at}pathology.ufl.edu
3 Current address: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
4 Current address: Schepens Eye Research Institute, Harvard University, Boston, MA 02114.
5 Abbreviations used in this paper: SjS, Sjögren’s syndrome; ANA, anti-nuclear autoantibody; M3R, muscarinic acetylcholine type-3 receptor; KO, knockout; IRS, insulin receptor substrate; PSP, parotid secretory protein; LES, lymphoepithelial sialadenitis.
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