Sjögren’s syndrome is caused by the immune system mistakenly attacking the body’s moisture-producing glands, particularly those that make tears and saliva. No single cause has been identified. Instead, a combination of genetic susceptibility, hormonal shifts, viral exposures, and changes in how genes are regulated appears to converge, triggering the immune system to turn against healthy tissue. The condition affects women roughly 4.6 times more often than men, with peak prevalence in the 65-to-69 age range.
How the Immune System Attacks the Glands
The hallmark of Sjögren’s is clusters of immune cells infiltrating the salivary and tear-producing glands. These clusters form around the ducts inside the glands, and they’re made up primarily of a type of white blood cell called T lymphocytes. About 60 to 70% of these T cells are the CD4 “helper” variety, the same cells that coordinate broader immune responses. In more severe cases, B cells and antibody-producing plasma cells join the attack, escalating the damage.
The process works something like a self-reinforcing loop. Gland cells die through programmed cell death (apoptosis), which exposes proteins that are normally hidden inside cells. In a genetically predisposed person, the immune system treats these exposed proteins as foreign threats. It produces antibodies against them, most notably anti-Ro (also called anti-SSA) and anti-La (anti-SSB) antibodies, which are the signature blood markers of the disease. Those antibodies, combined with debris from dying cells, trigger further immune activation, which causes more gland cells to die, and the cycle continues.
Several inflammatory signaling molecules drive this process. Genes regulated by a group of immune signals called type I interferons are abnormally active in the salivary glands of people with Sjögren’s. A protein called BAFF, which helps B cells survive and multiply, is overproduced by the gland’s own lining cells. The result is a gland progressively overrun by immune cells, losing its ability to produce moisture.
Genetic Susceptibility
Sjögren’s syndrome runs in families, and certain gene variants significantly raise a person’s risk. The most studied are in a group of genes called HLA (human leukocyte antigen), which control how the immune system identifies threats. Carrying the HLA-DR8 gene variant, for example, increases the odds of developing Sjögren’s by about 60%. Other HLA variants influence which complications a person is more likely to experience: HLA-DR15 is linked to a roughly 4.7-fold increased risk of interstitial lung disease, while HLA-DR1 and HLA-DR14 are associated with eye complications like uveitis and scleritis.
Beyond HLA genes, genome-wide studies have identified risk variants in genes involved in immune signaling, including IRF5, STAT4, and BLK. These genes affect how aggressively the immune system responds to perceived threats. Having these variants doesn’t guarantee someone will develop Sjögren’s, but it lowers the threshold for the disease to take hold when other triggers are present.
The Role of Estrogen
The overwhelming female predominance of Sjögren’s points strongly to hormones, and estrogen appears to be the key player. The disease typically emerges around menopause, when estrogen levels drop sharply. Research comparing women with Sjögren’s to women with dry eyes from other causes found that those with Sjögren’s had significantly lower lifetime estrogen exposure. Women with higher cumulative estrogen exposure were about half as likely to develop the condition.
Animal studies reinforce this connection. Mice that lack the enzyme needed to produce estrogen develop progressive destruction of salivary gland cells as they age. Normal mice whose ovaries are surgically removed develop programmed cell death in their salivary gland tissue. In mice already genetically predisposed to Sjögren’s-like disease, removing the ovaries accelerates the onset. In humans, breast cancer patients treated with drugs that block estrogen production develop Sjögren’s at higher-than-expected rates. The salivary glands themselves appear to have an impaired ability to convert precursor hormones into estrogen locally, which may compound the problem.
Viral Triggers
Certain viral infections can set the autoimmune process in motion in people who are already genetically vulnerable. Epstein-Barr virus (EBV), the virus that causes mono, is the most studied candidate. EBV has a particular affinity for the organized immune structures that form inside the salivary glands of Sjögren’s patients. When the virus reactivates in these structures, it infects B cells and plasma cells. Some of those infected cells then display Ro52 protein on their surface, the same protein targeted by the hallmark anti-Ro antibodies. In lab experiments, salivary gland tissue from Sjögren’s patients transplanted into mice produced anti-Ro and anti-La antibodies, demonstrating that the gland tissue itself harbors the machinery for this autoimmune response.
EBV’s ability to persist in the salivary glands appears to be aided by weakened immune surveillance: the cytotoxic T cells that normally keep EBV in check don’t function properly in affected tissue. Another virus, HTLV-1 (a virus more common in certain regions of Japan, the Caribbean, and parts of Africa), has an epidemiologically established link to Sjögren’s. HTLV-1 can directly infect salivary gland lining cells, prompting them to release inflammatory molecules that recruit immune cells to the gland.
Epigenetic Changes
Epigenetics refers to chemical modifications that sit on top of DNA and control whether specific genes are turned on or off, without changing the DNA sequence itself. In Sjögren’s, researchers have found that genes involved in the interferon response are abnormally “unlocked” through a process called hypomethylation. Normally, chemical tags called methyl groups keep these genes quiet. In the B cells and blood of people with Sjögren’s, those tags are stripped away from interferon-related genes, leaving them in a state of heightened readiness to fire.
This matters because these same epigenetic changes have been found at known Sjögren’s risk genes, suggesting that genetic susceptibility and epigenetic changes reinforce each other. Variants in risk genes like IRF5 and STAT4 are directly associated with altered methylation patterns at those locations. Environmental exposures, including viral infections and hormonal changes, can drive these epigenetic shifts, which helps explain how a person can carry risk genes for decades without developing the disease until something tips the balance.
Primary Versus Secondary Sjögren’s
When Sjögren’s syndrome develops on its own, it’s called primary Sjögren’s. But it frequently appears alongside other autoimmune conditions, a pattern sometimes called secondary Sjögren’s. The two most common companion diseases are rheumatoid arthritis and systemic lupus erythematosus. Sjögren’s also occurs alongside systemic sclerosis (scleroderma), mixed connective tissue disease, and inflammatory muscle diseases.
In secondary Sjögren’s, the underlying autoimmune condition likely creates an environment of chronic immune activation that makes it easier for the salivary and tear glands to become collateral targets. The dryness symptoms are identical regardless of whether the condition is primary or secondary, but the distinction matters for treatment because managing the associated condition often influences how the Sjögren’s component behaves.
How These Factors Work Together
No single cause is sufficient to produce Sjögren’s syndrome. The current understanding is a multi-hit model: a person inherits immune system genes that make self-attack more likely, then an environmental event, often a viral infection or a hormonal shift like menopause, damages gland cells or activates the immune system in a way that exposes hidden cellular proteins. Epigenetic changes accumulate over time, priming immune genes to overreact. Once the loop of gland cell death, antigen exposure, and immune activation begins, it becomes self-sustaining, and the chronic inflammation gradually destroys the gland’s ability to produce moisture.
This multi-layered causation explains why Sjögren’s can look so different from person to person. Someone with strong HLA-DR8 risk genes may develop prominent antibody production, while someone whose disease is driven more by hormonal changes may have milder serological findings but significant gland dysfunction. The specific combination of causes shapes not just whether someone develops the condition, but how it manifests and which organs beyond the glands may be affected.