Sjögren’s syndrome is an autoimmune disorder where the body’s immune system mistakenly attacks its own healthy tissues, particularly the glands that produce moisture, such as those in the eyes and mouth. This attack leads to characteristic symptoms like dry eyes and a dry mouth, though other organs can also be affected. While not inherited in the same way as single-gene disorders, understanding the development of Sjögren’s syndrome involves exploring the intricate relationship between genetics and other contributing factors.
The Genetic Connection to Sjögren’s Syndrome
Sjögren’s syndrome is not a condition passed down directly from parents to children through a single gene. Instead, individuals can inherit a predisposition. This susceptibility involves multiple genes working together rather than a single inherited flaw.
The human leukocyte antigen (HLA) system, a group of genes on chromosome 6, plays a central role in immune system function. These genes help the immune system distinguish between the body’s own cells and foreign invaders like bacteria or viruses. Specific HLA Class II gene variants, notably HLA-DR and HLA-DQ, are strongly linked to an increased risk of Sjögren’s syndrome. For instance, alleles such as DQA105:01, DQB102:01, and DRB103:01 have been identified as risk factors in various populations.
These HLA gene variations may influence how the immune system presents self-antigens, potentially leading it to misidentify the body’s own tissues as threats. While these genetic markers increase susceptibility, they do not guarantee that an individual will develop Sjögren’s syndrome. The presence of these genes indicates a higher likelihood, but other factors are generally required to trigger the onset of the disease.
Environmental and Hormonal Triggers
Genetic predisposition alone is often insufficient to cause Sjögren’s syndrome; an external trigger is typically involved. Viral or bacterial infections are considered potential environmental triggers. Viruses like Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Hepatitis C virus (HCV) have been studied for their possible roles in activating the immune system in susceptible individuals.
EBV is particularly implicated, with research suggesting it may contribute by increasing immune cells with autoimmune functions. The virus might cause T-cells to infiltrate salivary and tear glands, supporting the hyperactivity of B-cells that produce self-antibodies. This “molecular mimicry” hypothesis suggests that viral proteins can resemble the body’s own proteins, causing the immune system to attack both the virus and the similar self-tissue.
Hormonal factors also play a significant role, explaining why Sjögren’s syndrome affects women far more frequently than men, with onset often occurring around perimenopause. Estrogen appears to have a protective effect, and a decrease in estrogen levels, such as during menopause, is associated with an increased likelihood of developing the syndrome. Androgens, like testosterone and DHEA, may also offer protection, with lower levels potentially contributing to disease development.
Familial Risk and Autoimmune Clustering
Having a first-degree relative with Sjögren’s syndrome does increase an individual’s risk, but the overall chance of developing the condition remains low for most relatives. Studies indicate that a family history of autoimmune diseases in first-degree relatives can be associated with a significantly higher risk for primary Sjögren’s syndrome. Despite this elevated familial risk, it is not a direct inheritance pattern.
A broader concept relevant to familial risk is “familial autoimmunity” or “autoimmune clustering.” This refers to the observation that families with a history of one autoimmune disease frequently have members affected by other distinct autoimmune conditions. For example, individuals with Sjögren’s syndrome often have family members with other autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, or autoimmune thyroid disease.
This clustering suggests a shared genetic susceptibility across various autoimmune conditions, where certain genes, like those in the HLA system, might increase the likelihood of developing an autoimmune response in general, rather than specifically Sjögren’s syndrome. The presence of such a family history indicates a generalized predisposition to immune system dysregulation, making individuals more prone to developing any of a range of autoimmune diseases, including Sjögren’s syndrome, when combined with environmental or hormonal triggers.