Molecular mechanisms of salivary gland destruction in patients with Sjögren's syndrome

Abstract

IFN γ plays an important role to induce several functional molecules on salivary epithelial cells, including class II MHC, Fas and CD40 in salivary glands from patients with Sjögren's syndrome (SS). IFN γ also contributes to the development of lymphocytic infiltrates by inducing T cell attracting chemokines in SS salivary epithelial cells, such as IP- 10(CXCL10), Mig (CXCL9), and I-TAC (CXCL11). IFN γ dysregulation in SS salivary gland may attribute to the decreased production of TGF β from salivary epithelial cells in some patients. Expression of Fas and CD40 was significantly higher in SS salivary epithelial cells than in normal cells after IFN γ stimulation. Although neither anti-Fas (CH11) nor anti-CD40 mAb alone could induce typical apoptosis, the two together and preincubation with IFN γ effciently induced apoptosis in SS salivary epithelial cells. This apoptosis was almost completely blocked by neutralizing anti-Fas mAb (ZB4). c-FLIP, an important inhibitory molecule in the Fas death pathway, was strongly expressed in SS salivary epithelial cells, but its expression was downregulated, at the protein level, by anti-CD40 mAb. CD40 signals promote Fas-dependent death of SS salivary epithelial cells by downregulating c-FLIP expression. The presence of c-FLIP in these cells may explain their resistance to undergo apoptosis in response to either anti-Fas or anti-CD40 mAb, despite their surface expression of both proteins. These findings suggest that SS salivary epithelial cell death requires the cooperation of Fas and CD40. © 2005, The Japan Society for Clinical Immunology. All rights reserved.