Impaired salivary gland function in NOD mice: Association with changes in cytokine profile but not with histopathologic changes in the salivary gland

Abstract

Objective. To characterize the chronologic disease course and possible interrelationships between salivary gland inflammation, hyposalivation, and cytokine levels in NOD mice, a model for Sjögren's syndrome (SS).Methods. NOD mice of different ages were used to mimic different disease stages of SS. Histopathologic findings and rates of salivary secretion were compared between 8-week-old, 17-week-old, and 24-week-old female mice. In addition, 10 cytokines were analyzed in serum and saliva obtained from NOD and BALB/c mice.Results. In NOD mice, the salivary flow rate did not change between 8 weeks and 17 weeks of age, while a significant decrease in the salivary flow rate occurred between 17 weeks and 24 weeks of age (P < 0.001). In contrast, significant histopathologic changes in the salivary glands occurred before 17 weeks of age. Chronic inflammatory cell infiltrates were characterized by T and B cell infiltration. Interestingly, in one-third of the mice, proliferating cells were observed in the focal infiltrates. Significant changes in the levels of interleukin-2 (IL-2), IL-5, and granulocyte-macrophage colony-stimulating factor in serum, and in the levels of IL-4 and tumor necrosis factor ␣ (TNF␣) in saliva occurred contemporarily with the decrease in salivary flow. Correlation analyses revealed a negative association between salivary secretion and the levels of IL-4, interferon-␥, and TNF␣ in saliva obtained from NOD mice, while the correlation with inflammatory changes in the glands was consistently weak.Conclusion. Consistent with previous findings, our results indicate at least 2 phases of SS-like disease in NOD mice. Hyposalivation was preceded by inflammatory changes in the salivary glands, whereas abrupt changes in secretion occurred without significant progression of inflammation. Changes in cytokine levels are an indication of the mechanisms involved in the adaptive immune response in the transition from early to overt disease.

Desiccating environmental stress exacerbates autoimmune lacrimal keratoconjunctivitis in non-obese diabetic mice

“…Histopathologically, the autoimmune inflammation in the secretory glands of NOD mice accelerates acinar cell loss via apoptosis and necrosis and ductal epithelial hyperplasia by local production of cytotoxic auto-and paracrine factors [16,26]. It is characterized by glandular infiltration by T cells and B cells, primarily in periductal and perivascular areas [12].…”

“…Among these, the NOD mouse is the most accurate model, because development of adenitis is accompanied by decreased secretory function in the lacrimal and salivary glands [11]. Lymphocytic infiltration of the exocrine glands of the NOD mouse occurs well before the onset of clinical findings [12]. Although the NOD mouse can also be used as a model for spontaneous type 1 diabetes, the NOD.B10.H2 b strain develops Sjögren's syndrome-like disease, but not diabetes [13].…”

An NZW-Derived Interval on Chromosome 7 Moderates Sialadenitis, But Not Insulitis in Congenic Nonobese Diabetic Mice

“…This morphologic disruption precipitates inflammation with subsequent lymphocytic foci initially consisting of T cells, followed by B cell recruitment. The onset of disease, defined principally by hyposalivation, is then mediated by the combination of acinar destruction, Abs, and proinflammatory cytokines, likely produced by invading lymphocytes (3,6,34,41,43). Conversely, it has been proposed that reduced salivary secretion occurs independently of sialadenitis, but inflammation, once established, exacerbates salivary gland dysfunction (42).…”

“…Previous studies have shown that NOD mice older than 140 d, subsequent to sialadenitis, have a significant reduction in their capacity to produce saliva on stimulation (39)(40)(41). To determine whether the reduction of sialadenitis can ameliorate salivary gland dysfunction observed in NOD mice, we compared saliva flow rate between NOD, NOD.NZW-Chr7, and NZW mice.…”

Inhibition of experimental Sjögren's syndrome through immunization with HSP60 and its peptide amino acids 437–460

“…It spontaneously manifests SS-like histopathologic features and hyposalivation, following a specific time course for the onset of the different SS-related disease manifestations (24). Although some genetic loci related to diabetes have been found to contribute to inflammatory changes in the exocrine glands, diabetes and SS-like disease can develop independently of each other (25).…”