Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

Abstract

Sjögren's Syndrome (SS) is a chronic autoimmune disease characterized by histological and functional alterations of salivary and lacrimal glands that result in a severe dryness of the mouth and the eyes. The etiology of SS has remained undefined despite investigators' significant efforts to identify the mechanisms of initiation. Based on histopathology, several animal models are available-such as MRL/lpr, NZW/NZB, NFS/sld, graft vs. host, transgenic mouse expressing viral surface antigen, and the nonobese diabetic (NOD) mouse-for investigation of the etiology of SS. Biochemical and immunological similarities between human SS and autoimmune exocrinopathy (AEC) in the NOD mouse, including the loss of secretory function, establish the NOD mouse as an appropriate model to unravel the underlying pathophysiology of SS. Recently, several NOD congenic partner strains have been developed to investigate the roles of genetic intervals, cytokines, and autoantibodies in the disease pathogenesis. Studies on NOD-scid suggest that the pathogenesis of SS occurs in two phases: an asymptomatic phase, in which epithelial cells of exocrine tissues undergo dedifferentiation accompanied by elevated apoptosis; and a second phase in which autoaggression is mounted against target organ autoantigens, resulting in the activation of T-and B-cells, and the generation of autoantibodies. The presence of autoantibodies on the cell-surface signaling receptor, the muscarinic 3 receptor, in both SS patients and the NOD mice correlates with the hallmark clinical symptom of secretory dysfunction. Additionally, the NOD mouse model provides an important example of how both Th1 and Th2 cytokines, as well as non-immune genetic loci, are involved in the maintenance of and progression to the overt disease state. Ultimately, analysis of these data provides insight into potentially novel therapeutic interventions.

STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjögren's syndrome

“…The late disease onset and the diverse genetic background of affected individuals complicate study of the disease mechanism and pathogenesis. Although several mouse models display a pSS-like phenotype (17)(18)(19)(20)(21), no single model can perfectly match the full spectrum of pSS observed in humans.…”

Development of Sjögren’s Syndrome in Nonobese Diabetic-Derived Autoimmune-Prone C57BL/6.NOD-Aec1Aec2 Mice Is Dependent on Complement Component-3

“…Although the underlying cause of SjS remains elusive, a number of studies using the NOD mouse model and its congenic partner strains have led us to propose the concept that this autoimmune exocrinopathy progresses in three continuous, consecutive, yet distinct phases (27,28). In phase 1, a series of aberrant genetic, physiological, and biochemical activities associated with retarded salivary gland organogenesis and acinar cell apoptosis occur before and independent of initiation of an autoimmune attack.…”

Human chorionic gonadotropin prevents Sjögren's syndrome–like exocrinopathy in mice

“…By 12-24 weeks of age, NOD mice exhibit significant impairment of saliva and tear flow, and this is associated with lymphocyte invasion of the exocrine glands. Lymphocytic infiltrates consist mainly of CD4ϩ T lymphocytes and B lymphocytes, and the ratios of these cells are similar to those described in the salivary glands of patients with SS (2). Currently, only palliative treatments of this disease are available (1).…”

“…The NOD mouse is the animal model used most commonly to investigate the disease properties of SS. The NOD mouse presents with both type 1 diabetes and sialadenitis, which are autoimmune processes that develop in the pancreas and the salivary glands, respectively (2). By 12-24 weeks of age, NOD mice exhibit significant impairment of saliva and tear flow, and this is associated with lymphocyte invasion of the exocrine glands.…”