Abstract
The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.
Highlights
A central question in the study of autoimmune disorders concerns the mechanisms that maintain the persistence of autoreactive cells that produce disease
Survivin expression was significantly greater in peripheral blood mononuclear cells (PBMC) from Myasthenia gravis (MG) patients and was strongly associated with CD20, CD27, CD38 and CD138 expression (Fig. 1C–G)
Survivin-positive cells with B lymphocyte and plasma cell markers are present at significant levels in the circulation of humans with MG, but not in controls
Summary
A central question in the study of autoimmune disorders concerns the mechanisms that maintain the persistence of autoreactive cells that produce disease. We hypothesized that certain inhibitor of apoptosis proteins (IAPs) that are expressed in neoplastic diseases might support the pathologic survival of autoreactive immune cells. Survivin’s role as an anti-apoptotic protein is to modulates the function of a number of terminal effector cell death proteases (caspases) leading to inhibition of apoptosis [8,9,10]. Mitogen-stimulated T lymphocytes from patients with active MS display high-level expression of survivin compared to patients with stable disease [18]. These observations indicate that survivin expression may be a common characteristic of autoimmunity and that it is likely to play a direct pathophysiologic role
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