What are the causes of Sjögren's syndrome, particularly in women in their 40s and 50s with a history of dry eyes and mouth?

Causes of Sjögren's Syndrome

Primary Pathophysiologic Mechanism

Sjögren's syndrome is fundamentally caused by chronic inflammatory cellular infiltration of exocrine glands by lymphocytes (particularly T-cells, B-cells, and dendritic cells), leading to progressive destruction of lacrimal and salivary glands and resulting in the characteristic sicca symptoms. 1

The disease represents a multifactorial autoimmune process where genetic susceptibility, environmental triggers, and hormonal factors converge to produce glandular dysfunction. 1

Key Etiologic Factors

Genetic Predisposition

• Multiple genetic polymorphisms contribute to disease susceptibility, though each individual variant confers relatively low risk, making this a polygenic disorder. 2
• HLA associations have been consistently reported and confirmed across populations. 2
• Genetics alone cannot account for disease development—environmental factors are essential triggers. 3

Hormonal Influences

• The overwhelming female predominance with a 20:1 female-to-male ratio strongly implicates hormonal factors in disease pathogenesis. 1
• Typical onset occurs in postmenopausal women, further supporting hormonal involvement in disease susceptibility. 1
• Women in their 40s and 50s represent the peak demographic for disease onset. 4

Environmental Triggers

Viral Infections

• Epstein-Barr virus (EBV) has been directly associated with lacrimal gland swelling, dry eye, and Sjögren syndrome development, particularly with primary and persistent infections. 1
• Hepatitis C virus causes decreased tear secretion and reduced lactoferrin concentrations, producing a Sjögren's-like illness. 1
• Human T-cell lymphotropic virus type 1 (HTLV-1) and HIV have both been reported in patients who subsequently developed Sjögren syndrome. 1
• Dry eye was diagnosed in 21% of patients with AIDS, with diffuse infiltrative lymphadenopathy syndrome reported in HIV-infected patients. 1

Other Environmental Factors

• Exposure to solvents and additional chemical compounds may play a role, though evidence is still emerging. 3
• Smoking has been investigated as a potential risk factor. 3

Immunologic Mechanisms

Autoantibody Production

• Production of autoantibodies against ribonucleoprotein particles SS-A/Ro and SS-B/La is central to pathogenesis. 5
• Anti-Ro/SS-A antibodies are the most specific markers and represent the most important diagnostic criterion. 1
• Autoantibodies interfere with muscarinic receptors, disrupting normal glandular function. 5

Cellular Immune Dysfunction

• Infiltrating immune cells destroy glandular elements through cell-mediated mechanisms. 5
• Secretion of cytokines activates pathways bearing the signature of type 1 and 2 interferons. 5
• Persistent activation of the type I interferon system is central to disease pathogenesis. 3
• Secretion of matrix metalloproteinases (MMPs) interferes with the interaction between glandular cells and their extracellular matrix, which is necessary for efficient glandular function. 5

Progressive Disease Mechanism

• As the process advances, mucosal surfaces become sites of chronic inflammation, creating a vicious cycle. 5
• The histological hallmark is focal lymphocytic infiltration of exocrine glands, with a focus score ≥1 foci/4 mm² on minor labial salivary gland biopsy. 1
• Chronic B-cell activation can lead to systemic manifestations or non-Hodgkin's lymphoma development. 6

Clinical Context for Women in Their 40s-50s

• This demographic represents the typical presentation pattern, with peak incidence in postmenopausal women. 1
• Approximately 10% of patients with clinically significant aqueous deficient dry eye have underlying primary Sjögren syndrome, making this a common presentation that should prompt evaluation. 1
• The combination of dry eyes and dry mouth in this age group should trigger low threshold for serological workup. 7

Critical Complications Related to Etiology

• Primary Sjögren's syndrome carries approximately a 5% lifetime risk of lymphoid malignancy, representing an increased incidence of 320 cases per 100,000 patient-years. 7
• Decreased C4 levels at diagnosis are associated with higher lymphoma risk. 4
• The lymphoproliferative risk stems directly from chronic B-cell activation inherent to the disease mechanism. 6