What Causes Sjögren Syndrome
Sjögren syndrome is a multifactorial autoimmune disease caused by the interplay of genetic susceptibility, environmental triggers (particularly viral infections), and hormonal factors that lead to lymphocytic infiltration and destruction of exocrine glands. 1, 2, 3
Autoimmune Pathophysiology
The fundamental mechanism involves chronic inflammatory cellular infiltration of exocrine glands by lymphocytes, particularly affecting the lacrimal and salivary glands, which results in progressive glandular dysfunction and the characteristic sicca symptoms. 4, 1, 2
- The histological hallmark is focal lymphocytic infiltration of exocrine glands, determined by minor labial salivary gland biopsy showing a focus score ≥1 foci/4 mm². 4, 2
- T cells predominate in early/mild lesions, while B cells become dominant in advanced disease stages. 5
- The immune response involves multiple T cell subsets (Th1, Th2, Th17, follicular helper T cells) and regulatory cells, with Th1 and Th17 cells initiating the disease and Th2/Tfh cells predominating as it progresses. 5
Key Contributing Factors
Genetic Susceptibility
- Specific genetic mutations, including TAP gene variants, predispose individuals to developing Sjögren syndrome. 6
- There is a strong female predominance with a 20:1 female-to-male ratio, suggesting hormonal influences on disease susceptibility. 2, 7
Environmental Triggers (Viral Infections)
- Epstein-Barr virus (EBV) infection shows the strongest association, with immune response against EBV early antigen (IgG anti-EBVEA) conferring a 4-fold increased risk (OR 4; 95% CI: 1.82-8.83). 6
- The presence of anti-Ro/SSA and anti-La/SSB autoantibodies correlates significantly with anti-EBV EA IgG (OR 3.1 and 3.9 respectively). 6
- Other implicated viruses include human T-cell lymphotropic virus type 1, HIV, and hepatitis C. 4
- Interestingly, cytomegalovirus (CMV) infection appears protective (OR 0.3; 95% CI: 0.16-0.74). 6
Hormonal Factors
- The overwhelming female predominance and typical onset in postmenopausal women strongly implicate hormonal influences in disease pathogenesis. 4, 2
Critical Immune Mediators
B-Cell Activating Factor (BAFF)
- Elevated BAFF levels are a key driver of disease, promoting B-cell growth and autoantibody production, particularly anti-SSA/Ro antibodies. 3
- BAFF represents an important therapeutic target for future interventions. 3
Autoantibody Production
- Anti-Ro/SS-A antibodies are the most specific markers and score 3 points in diagnostic criteria. 4, 2
- Anti-La/SS-B, antinuclear antibodies, and rheumatoid factor are commonly present. 4, 6
- Cryoglobulins and hypocomplementemia (particularly decreased C4) serve as prognostic markers, with low C4 associated with increased lymphoma risk. 4, 1
Important Clinical Pitfalls
- Do not overlook Sjögren syndrome in younger patients or males presenting with dry eye, as the condition is most common in postmenopausal women but can affect any demographic. 4
- Maintain high suspicion when dry eye occurs with systemic symptoms like fatigue, arthralgia, or recurrent parotid swelling. 4, 2
- In children, ocular symptoms may appear before cutaneous manifestations, leading to misdiagnosis as chronic blepharokeratoconjunctivitis. 4
- Approximately 10% of patients with clinically significant aqueous deficient dry eye have underlying primary Sjögren syndrome, warranting low threshold for serological workup. 4, 2