What causes Sjögren's Syndrome?

What Causes Sjögren's Syndrome

Sjögren's syndrome is a chronic autoimmune disease caused by aberrant immune responses against self-tissues, where genetic predisposition combines with environmental triggers to produce autoreactive B and T cells that attack the exocrine glands, particularly targeting the autoantigens Ro/SSA and La/SSB. 1, 2

Autoimmune Pathogenesis

The fundamental cause is loss of immune tolerance leading to autoimmune destruction of exocrine glands through lymphocytic infiltration and autoantibody production. 3, 1

• The disease is characterized by infiltration of lacrimal and salivary glands with lymphocytes, resulting in secondary compromise of gland function. 3
• Aberrant autoreactive B-lymphocytes emerge, leading to autoantibody production (particularly anti-SSA/Ro and anti-SSB/La) and immune complex formation, which appears crucial in disease development. 1, 2
• Both B cells and T cells mount abnormal responses against self-antigens, with T cells predominating in mild lesions and B cells predominating in advanced lesions. 4, 2

Multifactorial Etiology

Genetic Factors

• Genetic polymorphisms associate with increased risk of Sjögren's syndrome, though each individual variant contributes relatively low risk. 5
• The disease predominantly affects women with a female-to-male ratio of 20:1, suggesting hormonal influences on genetic susceptibility. 3

Environmental Triggers

• Environmental factors play a critical role since genetics alone cannot account for disease development. 5
• Potential environmental contributors include infections, hormones, smoking, solvents, and additional compounds, though specific causative agents remain under investigation. 5
• Exogenous factors likely interact with genetic predisposition to trigger the autoimmune cascade. 5

Immunologic Mechanisms

Cellular Immune Dysfunction

• Multiple T cell subsets are implicated: Th1 and Th17 cells appear to initiate disease, while Th2 and follicular helper T (Tfh) cells predominate as disease progresses. 4
• Regulatory cell (Tregs/Bregs) dysfunction contributes to tolerance defects, though their exact role in ameliorating or worsening disease remains unclear. 4

Preinflammatory Phase

• Exocrine gland dysfunction may precede autoimmunity or represent a process independent from inflammation. 6
• Nonimmunologic injury can cause functional and morphologic changes in target organs before inflammation develops, potentially linking innate immunity to adaptive immunity. 6

Clinical Context

• The disease can manifest as primary Sjögren's syndrome (occurring alone) or secondary Sjögren's syndrome (associated with other autoimmune diseases such as rheumatoid arthritis, scleroderma, or systemic lupus erythematosus). 3, 1
• The pathogenesis involves persistent activation of the type I interferon system alongside autoreactive lymphocytes. 5

Important Caveats

• The exact sequence of events triggering disease onset remains elusive, with different non-mutually exclusive models proposed involving genetic and environmental interactions. 1
• The mechanisms behind decreased secretion volume are complex and not fully understood, extending beyond simple glandular destruction. 6
• Environmental risk factors require further investigation through prospective studies examining exposures prior to disease onset, as most current evidence comes from prevalent cases. 5