The pathogenic effect of TNF-α on development of Sjögren’s syndrome in non-obese diabetic mice

Abstract

Abstract Tumor necrosis factor-alpha (TNF-α), is a proinflammatory cytokine involved in the pathogenesis of various autoimmune diseases including rheumatoid arthristis, inflammatory bowel disease and psoriasis. Previous studies showed that patients with Sjögren’s syndrome(SS), a prevalent systemic autoimmune disease primarily affecting tear and saliva secretion, exhibit enhanced expression of TNF-α in saliva and salivary gland. However, the exact role of TNF-α in SS disease development is not yet fully determined. Our current study employed non-obese diabetic (NOD) mice, a model of SS-like diseases, to investigate the function of endogenous TNF-α in pathogenesis of SS. We observed that administration of a neutralizing anti-TNF-α antibody significantly improved salivary secretion in female NOD mice, indicating a remission of clinical symptom of SS. TNF-α neutralization also decreased the number of leukocytic foci and reduced the number of total and activated CD4 T cells and B cells in the submandibular gland of NOD mice. Moreover, neutralization of TNF-α reduced the number of CXCR3-expressing CD4 T cells and T-bet protein level in the submandibular gland, suggesting a decrease in the infiltrating T helper 1 and T cytotoxic 1 cells. In addition, the decrease in CXCR3+ CD4 T cells was associated with reduced expression of CXCR3 ligand CXCL9. Overall, the results presented here indicate that endogenous TNF-α plays a pathogenic role in the initiation and development of SS disease and neutralization of TNF-α may be greatly beneficial for the prevention and treatment of this prevalent autoimmune disease.