Characterization of the Changing Lymphocyte Populations and Cytokine Expression in the Exocrine Tissues of Autoimmune Nod Mice

Abstract

NOD mice develop chronic lymphocytic invasion of the pancreas, submandibular, and lacrimal glands leading to loss of insulin secretion, salivary flow, and tear production. In this study, we have used flow cytometric analyses and RT-PCR to track glandular lymphocyte populations and cytokine expression spanning the initiation of autoimmune infiltration through the development of widespread autoimmune destruction of the salivary and lacrimal glands of NOD mice. Results demonstrate a predominance of CD4+ to CD8+ lymphocytes and a similar predominance of T-cells versus B-cells in both the submandibular and lacrimal gland infiltrates. A temporal increase in memory (CD3+CD45RBlo) T-cells was also detected; however, naive (CD3+CD45RBhi) T-cell populations as well as a CD3+, CD4-/CD8- double negative population were also present. In addition, a skewing of the TCR Vbeta repertoire toward Vbeta6+ and Vbeta8+ lymphocytes was evident in both glandular infiltrates. Analyses of cytokine mRNA expression in the submandibular glands demonstrated an increase between 12 and 16 wk of age of several proinflammatory cytokines including IL-1beta, IL-6, IL-7, IL-10, IFNgamma, TNFalpha, and inducible Nitric Oxide Synthase (iNOS). IL-4 synthesis was notably absent in both tissues. Cytokine mRNA transcripts detected in lacrimal tissue were similar to those seen in the submandibular glands but appeared both earlier and more intensely. These findings depict the progressive development of autoimmune exocrinopathy and can be used as a foundation to explore the similarities and potential differences in the immunopathogenic lesions of several distinct tissues within the same host.

Reduced Oral Wound Healing in the NOD Mouse Model for Type 1 Autoimmune Diabetes and Its Reversal by Epidermal Growth Factor Supplementation

“…Mice in the Department of Pathology Mouse Colony become overtly diabetic starting at 12 Ϯ 2 weeks of age. For the current experiments, mice 10 -12 weeks of age were used to minimize xerostomic conditions related to the development of Sjö gren's syndrome-like exocrine tissue pathology, which does not develop before 12-16 weeks of age (31,32). Diabetic mice were maintained on daily intramuscular insulin injections (1 unit of Humulin/animal/24 h; Novo Nodisk, Bagsvaerd, Denmark) for 2 weeks before the initiation of the wound-healing experiments.…”

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

“…C57BL/6 carrying either the NOD-derived genetic interval on chromosome 3 encompassing Idd3 , 10, 17, 18, or the Idd6 genetic intervals on chromosome 6 retained normal disease-free physiology. Conversely, NOD mice, containing chromosome regions of Hu et al ., 1992Hu and Humphreys-Beher, 1995;Humphreys-Beher et al ., 1993, 1994Kerr et al ., 1995;Yamamoto et al ., 1996Yamamoto et al ., , 1997Robinson et al ., 1996Robinson et al ., , 1997Robinson et al ., , 1998aRobinson et al ., , 1998bRobinson et al ., , 1998cYamachika et al ., 1998Yamachika et al ., , 2000Kong et al ., 1998a. c Konttinen et al ., 1994;Wu et al ., 1997. d Haneji et al ., 1997.…”

Chemokines and Cell Trafficking in Sjögren's Syndrome

“…Ductal epithelial cells are activated in PSS, expressing elevated levels of HLA-DR [29] and secreting high levels of proinflammatory cytokines [4,30,31]. Comparable data have also been derived from the NOD mouse model of salivary gland inflammation [32]. Several studies have reported increased ductal epithelial cell turnover and consequent cell death (apoptosis) in the salivary glands of SS patients [36±40], although one study did not corroborate these observations [41].…”