Sjogren's Syndrome: Genetic Factors

• Sjögren’s syndrome, an autoimmune disorder, was initially identified in women with chronic arthritis accompanied by dry eyes and dry mouth.
• The definitive etiology remains unknown, characteristic of most autoimmune diseases.
• Genetic predisposition involving MHC haplotypes is a risk factor

Genetic Factors

• Specific MHC haplotypes like HLA-DQA1, HLA-DQB1, increase susceptibility.
• MHC class II molecules (HLA-DQ, HLA-DR) present self-antigens to CD4+ T-helper cells.
• HLA haplotypes, such as HLA-DR3, may misidentify self-antigens from exocrine glands.
• The loss of self-tolerance triggers an autoimmune response, causing chronic inflammation and leukocyte infiltration.
• Exocrine epithelial cells abnormally express MHC class II under inflammatory conditions.
  • Normally do not express MHC class II, but upregulate it due to IFN signaling, genetic predisposition, or cellular stress
  • This abnormal antigen presentation leads to T-cell activation and inflammation.
• Salivary and lacrimal glands are vulnerable due to continuous exposure to external factors, constant production of secretions, intrinsic immune signaling pathways

Environmental Factors

• Viral infections, like Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis C virus (HCV), and human T-lymphotropic virus-1 (HTLV-1), molecular mimicry, and hormonal factors can all be triggers.
• Estrogen has a protective role, explaining the female predominance.
• Estrogen enhances the immune response, but can lead to autoimmune diseases if overactive.

Epidemiology

• Sjögren’s syndrome affects 0.5%–1% of the population.
• Approximately half of rheumatoid arthritis patients are also diagnosed with Sjögren’s syndrome.
• Affects up to 3 million people.
• Typically presents after 25 years of age.
• Most common in middle-aged women, with a female-to-male ratio of 9:1.
• There is no observed ethnic or geographic bias in incidence.

Characteristic Lesion: Focal Lymphocytic Sialadenitis (FLS)

• FLS, a lesion of exocrine glands, means inflammation of the salivary glands
• Causes exocrine gland dysfunction, leading to:
  • Infiltration by mononuclear cells, including T cells, B cells, and plasma cells
  • Production of autoantibodies and cytokines
  • Diminished tear production by lacrimal glands
• Dysfunction of exocrine glands can result in skin dryness, tracheal irritation, and vasculitis from immune complex deposition.

Immune Mechanism

• Immune system dysfunction occurs in exocrine glands.
  • Antigen-presenting cells (APCs) engulf pathogens and present antigens on MHC class II molecules.
  • APCs activate T cells, which secrete pro-inflammatory cytokines, recruiting more immune cells and causing inflammation.
• Genetic predisposition involves HLA-DRW52, HLA-DQA1, HLA-DQB1.
• Cell damage releases DNA, RNA, and histones, picked up by APCs and presented to T cells.
• T cells react inappropriately, activating B cells to produce anti-nuclear antibodies (ANAs), which include 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.

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)

• Inflammation and alteration of the cornea and conjunctiva
• Dysfunction of lacrimal glands results in dry eyes
• Can cause blurred vision, itching, redness, and burning.

Dry Mouth (Xerostomia)

• Dysfunction of salivary glands results in dry mouth
• Causes difficulty with tasting and swallowing
• Cracks and fissures in the mouth due to reduced moisture.

Respiratory and Speech Issues

• Dryness in the upper respiratory tract, including the nasal passages, causes ulceration or perforation of the nasal septum, crusting, and bleeding.
• Dryness in the mouth and throat impairs speech, causing difficulty in speaking.

Other Symptoms

• Dry Skin: Reduced moisture production leads to dryness and irritation.
• Vaginal Dryness: Dryness and discomfort of mucous membranes in the vagina.
• Digestive Problems which are caused by a difficulty in digestion

Diagnosis

• Tests for decreased gland secretion include sialometry, which measures salivary flow.
• Blood tests confirm 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.