Possible Involvement of EBV-Mediated α-Fodrin Cleavage for Organ-Specific Autoantigen in Sjogren’s Syndrome

Abstract

A cleavage product of α-fodrin may be an important organ-specific autoantigen in the pathogenesis of Sjogren’s syndrome (SS), but the mechanisms of α-fodrin cleavage remain unclear. Since EBV has been implicated in the pathogenesis of SS, we determined whether EBV activation could induce the SS-specific 120-kDa autoantigen α-fodrin. ZEBRA mRNA expression, a marker for activation of the lytic cycle of EBV, was found in the salivary gland tissues from SS patients, but not in those from control individuals. ZEBRA-expressing lymphoid cells were also found in the SS glands in double-stained immunohistochemistry. Furthermore, a significant link between production of Abs against 120-kDa α-fodrin and reactivated EBV Ag was found in sera from patients with SS, but not in those from control individuals. EBV-activated lymphoid cells showed specific α-fodrin cleavage to the expected 120-kDa fragments in vitro. Pretreatment with caspase inhibitors inhibited cleavage of α-fodrin. Thus, an increase in apoptotic protease activities induced by EBV reactivation may be involved in the progression of α-fodrin proteolysis in the development of SS.

A decade of caspases

“…For example, cleaved caspases have been detected in AD LeBlanc et al, 1999;Stadelmann et al, 1999), ALS (Pasinelli et al, 1998), Parkinson's disease (Hartmann et al, 2000;Tatton, 2000), HD (Sanchez et al, 1999) and ischemic brain (Namura et al, 1998;Matsushita et al, 2000). Inappropriate caspasemediated fodrin cleavage has been implicated in the pathophysiology of Sjogren's syndrome, an autoimmune disorder associated with excessive tissue destruction (Hayashi et al, 2000;Inoue et al, 2001). Similarly, caspase activation was shown to correlate with spinal/ head trauma (Clark et al, 1999;Springer et al, 1999) and epilepsy (Henshall et al, 2000).…”

Possible Involvement of Oxidative Stress in Salivary Gland of Patients with Sjögren’s Syndrome

“…Furthermore, our previous studies showed an increase in the enzymatic activity of apoptotic protease by EBV activation to be involved in the progression of 120-kDa ␣ -fodrin autoantigen proteolysis during the development of SS [22,23] .…”

Apoptosis and Autoimmune Disorders

“…Because caspase-3 and caspase-7 are effector enzymes, XIAP might protect salivary epithelial cells from apoptotic death in SS (Nakamura et al, 2000b). suggested that treatment with caspase inhibitors might prevent the development of the inflammatory process in salivary glands, and Inoue et al (2001) found that caspase-inhibiting agents could inhibit the cleavage of -fodrin. Increased caspase cascade activity may be involved in the progression of autoantigen proteolysis and tissue destruction in primary SS.…”