Sjögren’s Syndrome: Etiology and Overview

Sjögren’s Syndrome Overview

• Sjögren’s syndrome is an autoimmune disorder characterized by dry eyes and dry mouth.
• The exact cause is unknown, but it primarily affects women.
• Key concerns are the etiology, epidemiology, and pathogenesis of the syndrome.

Definition and Etiology

• Sjögren’s syndrome is an autoimmune disorder initially found in women with chronic arthritis and dry eyes and mouth.
• The precise cause remains unclear, sharing this characteristic with many autoimmune diseases.
• Genetic predisposition is indicated by associations with MHC haplotypes like HLA-DQA1 and HLA-DQB1.
• These MHC class II molecules (HLA-DQ, HLA-DR) may present self-antigens to CD4+ T-helper cells.
• Individuals with these genetic risk factors are more likely to exhibit increased MHC class II expression in epithelial cells under inflammatory conditions.
• Specific HLA haplotypes, such as HLA-DR3, are prone to misidentifying self-antigens from exocrine glands, like salivary and lacrimal glands, triggering an autoimmune response.
• Systemic autoimmune features can develop, but exocrine glands are often the primary targets due to their expression of immune-related molecules.
• Genetic mutations in exocrine gland cells favor MHC class II expression, leading to early autoantigen presentation.
• Exocrine gland cells, which do not normally express MHC class II, abnormally upregulate it under inflammatory conditions, presenting autoantigens and initiating an autoimmune response.
• Exocrine glands are vulnerable due to constant exposure to external factors and intrinsic immune signaling pathways.
• Environmental factors and viruses like Epstein-Barr Virus (EBV) may contribute to disease development.

Environmental Triggers

• Viral infections, including EBV, CMV, HCV, and HTLV-1, may trigger immune dysfunction.
• Molecular mimicry where viral antigens resemble self-antigens can also cause dysfunction.
• Hormonal factors, particularly estrogen, are thought to have a protective role, which may explain the higher prevalence in females.
• Estrogen enhances the immune response but excessive activation can lead to autoimmune diseases such as Sjögren's syndrome affecting exocrine glands.

Epidemiology

• Sjögren’s syndrome affects 0.5% to 1% of the population.
• Approximately half of those with rheumatoid arthritis are also diagnosed with Sjögren’s syndrome.
• Prevalence is estimated to be up to 3 million people.
• Onset typically occurs after age 25, most commonly in middle-aged women.
• The female-to-male ratio is about 9:1.
• There is no observed ethnic or geographic bias in its occurrence.

Pathogenesis and Characteristic Lesion

• The characteristic lesion of Sjögren’s syndrome is Focal Lymphocytic Sialadenitis (FLS).
• FLS occurs in exocrine glands.
• The disorder causes exocrine gland dysfunction, leading to infiltration by mononuclear cells like T cells, B cells, and plasma cells.
• Production of autoantibodies and cytokines diminishes tear production in lacrimal glands.
• Exocrine gland dysfunction results in skin dryness and tracheal irritation.
• Vasculitis can occur due to immune complex deposition in the skin, joints, and other organs.

Immune Mechanism

• Immune system dysfunction in exocrine glands.
• Antigen-presenting cells (APCs) such as macrophages and dendritic cells engulf pathogens and present antigens on MHC class II molecules.
• APCs then activate T cells, which secrete pro-inflammatory cytokines.
• Genetic predisposition involves HLA-DRW52, HLA-DQA1, HLA-DQB1.
• Environmental factors like infections can damage exocrine gland cells.
• Cell damage releases DNA, RNA, and histones, picked up by APCs and presented to T cells.
• In Sjögren’s syndrome, T cells react inappropriately, activating B cells to produce anti-nuclear antibodies (ANAs).
• The main ANAs are anti-SSA (Ro) and anti-SSB (La).
• T cells and autoantibodies reach the exocrine glands.
• T cells secrete cytokines, recruiting more immune cells and increasing inflammation.
• Fibroblasts are activated, leading to fibrosis and loss of secretory function in glands.

Classification

• Primary Sjögren’s syndrome (Sicca syndrome) occurs alone.
• Secondary Sjögren’s syndrome occurs with other autoimmune diseases like rheumatoid arthritis.

Clinical Presentation

• Dry eyes (Keratoconjunctivitis Sicca) occur due to immune targeting of lacrimal glands, causing insufficient tear production and symptoms like blurred vision, itching, redness, and burning.
• Dry mouth (Xerostomia) results from dysfunctional salivary glands, leading to difficulty in tasting and swallowing, with cracks and fissures in the mouth.
• Respiratory and speech issues arise from dryness in the upper respiratory tract, causing ulceration or perforation of the nasal septum, crusting, and bleeding, affecting speech.
• Other dryness issues: Includes dry skin and vaginal dryness, leading to irritation and discomfort.
• Swollen glands, particularly the parotid glands, can cause pain by compressing nearby nerves.
• There is an increased risk of infections due to lack of moisture and proper lubrication, making mucous membranes vulnerable.
• Digestive problems arise due to reduced saliva, making it harder to digest food, particularly dry food, and can impact the digestive tract.
• Joint pain, similar to arthritis, is caused by the immune system attacking joints, leading to inflammation, pain, and stiffness.
• Muscle pain and weakness from the immune system's attack on muscle tissue.
• There is an increased risk of recurrent bronchitis due to dryness in the respiratory tract, impairing mucus clearance.
• Abnormal liver function can occur as the immune system targets the liver, causing inflammation and damage.

Diagnosis

• Tests for decreased gland secretion include sialometry to measure salivary flow.
• Blood tests to check for the presence of Anti-SSA (Ro) and Anti-SSB (La) antibodies.
• A confirmatory lip biopsy examines minor salivary glands for CD4+ T cells, plasma cells, and macrophages.