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+CD45RB¹⁰) T-cells was also detected; however, naive (CD3⁺CD45RB^hi) T-cell populations as well as a CD3⁺, CD4⁻/CD8⁻double negative population were also present. In addition, a skewing of the TCR Vβ repertoire toward Vβ6⁺ and Vβ8⁺ 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-1β, IL-6, IL-7, IL-10, IFNγ, TNFα, 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.

Key Words:

• Sjogren's Syndrome
• Xerostomia
• Xerophthalmia
• Salivary glands
• Lacrimal glands
• NOD mice