Pathogenic role of endogenous TNF-α in the development of Sjögren’s-like sialadenitis and secretory dysfunction in non-obese diabetic mice

Patients with Sjögren’s syndrome (SS), an autoimmune disease primarily affecting the exocrine glands, exhibit enhanced TNF-α expression in the saliva and salivary glands. However, the precise in vivo role of TNF-α during the initiation and development of SS is not clearly defined. The present study is undertaken to determine the function of endogenously produced TNF-α in the pathogenesis of SS in non-obese diabetic (NOD) mice, a model of this human disease. Administration of a neutralizing anti-TNF-α antibody to female NOD mice during the stage prior to disease onset significantly improved salivary secretion, indicating a remission of clinical symptoms of SS. TNF-α blockade also decreased the number of leukocyte foci and reduced the number of T cells and B cells in the submandibular glands. Moreover, TNF-α blockade reduced T-bet protein level in the submandibular glands, suggesting a decrease in T helper 1- and T cytotoxic 1 cells. These cellular changes induced by TNF-α neutralization were associated with a reduction in T and B cell chemoattractants CXCL9 and -13. In addition, TNF-α blockade markedly increased the expression level of tight junction protein claudin-1 and water channel protein aquaporin-5, two key factors required for normal salivary secretion, in the submandibular glands. Collectively, these findings indicate that endogenous TNF-α plays a pathogenic role in the development of SS in the NOD model of this disease.