Pathogenesis and treatment of Sjögren's syndrome.

The criteria for diagnosis of primary Sjögren's syndrome continue to be controversial, leading to confusion in clinical practice and in the research literature. Among Sjögren's syndrome patients who fulfill the European criteria, only 15% of those would fulfill the San Diego criteria. This difference in disease classification leads to difficulty in evaluating clinical trials and in elucidating pathogenetic mechanisms, because different patient populations are evaluated. As a result of the ease and safety of minor salivary gland biopsy, Sjögren's syndrome serves as a prototype model to study the immunopathogenic features of a human organ-specific autoimmune disease. Critical features of pathogenesis include: 1) failure to "delete" autoimmune T cells at the level of thymic selection; 2) "homing" of autoimmune lymphocytes to salivary and lacrimal glands via high endothelial venules; 3) clonal expansion of autoimmune T cells in the glands; 4) upregulation of major histocompatibility antigens and adhesive molecules by epithelial cells in the glands; 5) secretion of proinflammatory cytokines by both lymphocytes and epithelial cells; 6) decreased neural innervation of the glands; 7) failure of residual glandular tissue express secretory functions; and 8) failure to remove autoimmune T cells by normal mechanisms of apoptosis. Each of these steps is regulated by cell-matrix interactions, cytokine and growth factor secretion, cell membrane receptor stimulation, "second" signals in the cytoplasm, and nuclear transcription factors. Recent studies on each of these steps in Sjögren's syndrome have suggested their role in pathogenesis and, consequently, their potential as sites for therapeutic intervention.