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INTRODUCTION

DEFINITION, INCIDENCE, AND PREVALENCE

Sjögren’s syndrome is a prototype autoimmune disease characterized by lymphocytic infiltration of the exocrine glands resulting in xerostomia, dry eyes (keratoconjunctivitis sicca), and profound B-cell hyperactivity. The syndrome has unique features since it presents with a wide clinical spectrum from organ-specific to systemic disease; can occur alone or in association with other systemic rheumatic diseases, more commonly rheumatoid arthritis, limited scleroderma, and systemic lupus erythematosus; and displays high probability of the development of lymphoma. Because of all these characteristics, it is an ideal model to study not only autoimmunity but also lymphoid malignancy.

Middle-aged women (female-to-male ratio 10-20:1) are primarily affected, although Sjögren’s syndrome may occur at any age, including childhood. Patients with earlier disease onset express a more aggressive disease phenotype manifested by a high occurrence of systemic manifestations and serum autoantibodies. The prevalence of Sjögren’s syndrome is ~0.5–1%, while 5–20% of patients with other autoimmune diseases can express sicca manifestations.

PATHOGENESIS

The autoimmune phenomena observed in Sjögren’s syndrome include lymphocytic infiltration of the exocrine glands (primarily salivary and lachrymal glands) and B lymphocyte hyperreactivity. The latter is mainly manifested by hypergammaglobulinemia and the presence of serum autoantibodies toward non-organ-specific antigens such as immunoglobulins (rheumatoid factors) and extractable cellular antigens (Ro52, Ro60, and La). The major infiltrating cells in the affected exocrine glands are activated T lymphocytes. In labial minor salivary gland tissues with extensive lymphocytic infiltrations, B-cell populations prevail. Other cellular subsets detected in the labial minor salivary gland histopathologic lesion of Sjogren’s syndrome include follicular, myeloid, and plasmacytoid dendritic cells, as well as macrophages. Inflammasome activation and macrophages positive for interleukin (IL) 18 in the salivary gland lesion have been shown to be associated with adverse predictors for lymphoma development.

The interplay of endogenous (e.g., intracellular stress, inappropriate overexpression of endogenous nucleic acids) and exogenous triggers (e.g., viruses, hormonal triggers, stressful life events) in a background of a genetically determined hyperactive immune response seems to be crucial for the initiation and perpetuation of the disease. Ductal and acinar epithelial cells appear to play a significant role in the initiation and perpetuation of autoimmune injury. These cells (1) express inappropriately costimulatory molecules and the intracellular autoantigens Ro and La on their cell surfaces, acquiring the capacity to provide signals essential for lymphocytic activation; (2) produce proinflammatory cytokines and lymphocyte-attracting chemokines necessary for sustaining the autoimmune lesion and allowing the formation of ectopic germinal centers; (3) express functional receptors of innate immunity, particularly Toll-like receptors (TLRs) 3, 7, and 9 molecules, which may account for the initiation of the autoimmune reactivity; and (4) display immunoregulatory molecules such as ICAM and CD40. Glandular epithelial cells also seem to have an active role in the production of B cell–activating factor (BAFF), which is induced after stimulation with type I and II interferons. Circulating BAFF has been found to be ...

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