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Development of Sjögren’s Syndrome in Nonobese Diabetic-Derived Autoimmune-Prone C57BL/6.NOD-Aec1Aec2 Mice Is Dependent on Complement Component-3¹

Cuong Q. Nguyen^2,*, Hyuna Kim^*, Janet G. Cornelius and Ammon B. Peck^*,,

^* 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

The role of complement in the etiology of Sjögren’s syndrome (SjS), a human autoimmune disease manifested primarily by salivary and lacrimal gland dysfunction resulting in dry mouth/dry eye syndrome, remains ill-defined. In the present study, we examined the role of complement component-3 (C3) using a newly constructed C3-gene knockout mouse, C57BL/6.NOD-Aec1Aec2.C3^–/–. Inactivation of C3 in the parental C57BL/6.NOD-Aec1Aec2 strain, a model of primary SjS, resulted in a diminished or total absence of both preclinical and clinical manifestations during development and onset of disease, including reduced acinar cell apoptosis, reduced levels of caspase-3, lack of leukocyte infiltration of submandibular glands, reduced synthesis of disease-associated autoantibodies, maintenance of normal glandular architecture, and retention of normal saliva secretion. In addition, C57BL/6-NOD.Aec1Aec2.C3^–/– mice did not exhibit increased numbers of marginal zone B cells, a feature of SjS-prone C57BL/6-NOD.Aec1Aec2 mice. Interestingly, C57BL/6-NOD.Aec1Aec2.C3^–/– mice retained some early pathological manifestations, including activation of serine kinases with proteolytic activity for parotid secretory protein. This improvement in the clinical manifestations of SjS-like disease in C57BL/6.NOD-Aec1Aec2.C3^–/– mice, apparently a direct consequence of C3 deficiency, supports a much more important role for complement in the adaptive autoimmune response than previously recognized, possibly implicating an essential role for innate immunity.

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 (PHS) 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 PHS 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 Abbreviations used in this paper: SjS, Sjögren’s syndrome; CVF, cobra venom factor; C3, complement component-3; KO, knockout; PSP, parotid secretory protein; DAPI, 4',6'-diamidino-2-phenylindole; ANA, anti-nuclear autoantibody; MMP, matrix metalloproteinase; M3R, muscarinic acetylcholine type 3 receptor; ECM, extracellular matrix; FO, follicular; MZ, marginal zone.