What triggers Sjogren syndrome?

What Triggers Sjögren Syndrome

Sjögren syndrome is triggered by a multifactorial interplay of genetic susceptibility, environmental factors (particularly viral infections), and hormonal influences that converge to cause aberrant lymphocytic infiltration and autoimmune destruction of exocrine glands. 1

Genetic Susceptibility

• Specific genetic risk factors have been identified, including STAT-4, ILT6, and the HLA-B8/DR3 haplotype, which predispose individuals to developing the autoimmune response characteristic of Sjögren syndrome 2
• The overwhelming female predominance (20:1 female-to-male ratio) strongly implicates sex-linked genetic factors in disease susceptibility 3, 1

Viral Infections as Environmental Triggers

Viral infections are the most strongly implicated environmental trigger, with multiple viruses associated with Sjögren syndrome development:

• Epstein-Barr virus (EBV) is the most frequently implicated, with activated aryl hydrocarbon receptor potentially interacting with latent EBV infection to predispose to disease development 4
• Lacrimal gland swelling, dry eye, and Sjögren syndrome have been directly associated with primary and persistent EBV infections 5
• Hepatitis C virus has been reported to cause decreased tear secretion and reduced tear concentrations of lactoferrin, and clearly causes a Sjögren's-syndrome-like illness 5, 4
• Human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV) have both been reported in patients who subsequently developed Sjögren syndrome 5, 1
• Dry eye was diagnosed in 21% of patients with AIDS, and diffuse infiltrative lymphadenopathy syndrome has been reported in HIV-infected patients 5

Proposed Viral Mechanisms

The mechanisms by which viruses may trigger Sjögren syndrome include:

• Antigen mimicry, where viral proteins resemble self-antigens, leading to cross-reactive autoimmune responses 4
• Polyclonal lymphocyte activation, causing widespread immune system dysregulation 4
• Infection-mediated innate end-organ inflammation, with activated interferon-1 (IFN-1) pathway playing an important role in the autoimmune disease process 4, 6

Hormonal Factors

• Postmenopausal status and female sex hormones are critical triggers, as evidenced by the typical onset in postmenopausal women and the 20:1 female predominance 1
• The hormonal influence is so strong that it represents one of the three major pathogenic pillars alongside genetic and environmental factors 1

Immune System Dysregulation

Once triggered, the disease progresses through:

• Emergence of aberrant autoreactive B-lymphocytes, leading to autoantibody production (particularly anti-Ro/SS-A and anti-La/SS-B) and immune complex formation 7
• Chronic lymphocytic infiltration of exocrine glands, with T and B cells infiltrating salivary and lacrimal glands 2
• Cytotoxic T cell-mediated destruction of glandular cells, combined with cytokine production and autoantibodies that inhibit glandular function 2

Clinical Implications and Pitfalls

• Approximately 10% of patients with clinically significant aqueous deficient dry eye have underlying primary Sjögren syndrome, warranting a low threshold for serological workup when dry eye presents with systemic symptoms like fatigue, arthralgia, or recurrent parotid swelling 1
• Do not overlook Sjögren syndrome in younger patients or men despite the strong female and postmenopausal predominance, as the disease can occur in all demographics 5
• Maintain high suspicion when sicca symptoms occur following viral infections, particularly EBV, hepatitis C, or HIV 5, 1