Sjögren’s Syndrome (SS) is a chronic, systemic autoimmune disorder where the immune system mistakenly targets the body’s healthy tissues. Like many autoimmune conditions, it does not follow a simple Mendelian pattern of inheritance where a single gene determines the trait. Instead, Sjögren’s is hereditary due to a strong genetic predisposition that interacts with external factors to cause the disease. This multifactorial nature means that while a person may inherit a heightened risk, they will not necessarily inherit the condition itself. Understanding the interplay between genetic susceptibility and non-genetic triggers is necessary to grasp the development of this disorder.
Defining Sjögren’s Syndrome
Sjögren’s Syndrome is characterized primarily by the immune-mediated destruction of exocrine glands, which produce moisture, such as tears and saliva. This inflammation is caused by the infiltration of immune cells, specifically lymphocytes, into the glandular tissue, leading to dysfunction and reduced fluid production. The resulting symptoms of persistent dry eyes (xerophthalmia) and dry mouth (xerostomia) are collectively known as sicca symptoms. The condition is classified into two forms: primary SS occurs as a standalone disease, while secondary SS is diagnosed when associated with another underlying autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus.
Understanding Genetic Predisposition
Sjögren’s Syndrome is not directly passed down like a single-gene disorder, but a significant genetic predisposition exists. Studies show that individuals with an affected first-degree relative (a parent, sibling, or child) have a substantially increased chance of developing the disease compared to the general population. One study indicated that having an affected first-degree relative results in a relative risk 12.37 times greater than the risk for those without a family history. Having a first-degree relative with any autoimmune disease is also associated with a nearly six-fold higher risk of developing primary SS.
The inheritance pattern is polygenic, meaning numerous genes each contribute a small amount to the overall risk. This genetic background, which accounts for approximately 30% of the overall risk, makes the family more susceptible to autoimmune disorders in general, not just Sjögren’s. The heritability of Sjögren’s Syndrome has been estimated to be around 0.54, suggesting that over half of the disease liability can be attributed to genetic factors.
Specific Genetic Markers of Susceptibility
The strongest genetic signal for Sjögren’s Syndrome risk is found within the Human Leukocyte Antigen (HLA) complex, which controls the immune system’s ability to recognize foreign invaders. The HLA class II genes, specifically HLA-DR and HLA-DQ haplotypes, show the most consistent association with the disease. Certain alleles like HLA-DRB1\03 and HLA-DQB1\02:01 are risk factors, thought to influence the presentation of self-proteins to T cells, leading to the autoimmune attack that characterizes SS.
The association between HLA markers and SS is often linked to the presence of specific autoantibodies, such as anti-SSA/Ro and anti-SSB/La. These antibodies are markers of the disease, and HLA genes may contribute more to their production than to the disease itself. Beyond the HLA region, non-HLA genes also play a role, though with a smaller effect size. Genes like STAT4 and IRF5, involved in immune regulation and the interferon system, have been consistently associated with increased risk for primary SS.
Non-Genetic Factors in Disease Manifestation
The fact that many people carry high-risk genetic markers without developing Sjögren’s Syndrome points to the requirement of non-genetic, or environmental, factors for disease manifestation. This is often described as the “two-hit” model, where a genetically susceptible individual encounters an external trigger. Viral infections are widely studied as potential triggers, with agents like the Epstein-Barr Virus (EBV) and Hepatitis C Virus (HCV) hypothesized to initiate the autoimmune response. These infections may prompt epithelial cells to activate the innate immune system or lead to molecular mimicry, where viral proteins resemble the body’s own proteins, causing the immune system to attack healthy tissue.
Hormonal influence is another significant non-genetic factor, evidenced by the striking female-to-male ratio, with women being up to ten times more likely to develop Sjögren’s. The onset of the disease often occurs around menopause, suggesting that the natural drop in sex hormones, particularly estrogen, may affect immune system function. Estrogen is thought to play a protective role in the moisture-secreting glands, and its decrease may diminish that protection, contributing to the glandular destruction.