Epstein-Barr Virus Infection May Contribute to Sjögren’s, Study Finds

Infections with the Epstein-Barr virus (EBV), the most common member of the herpes virus family, may contribute to the development of Sjögren’s syndrome by increasing the proportion of immune cells with autoimmune functions, a recent study suggests.

Therapies targeting the interaction between EBV and activated immune cells may be useful in the clinic, the scientists said. 

The study, “Association between EBV serological patterns and lymphocytic profile of SjS patients support a virally triggered autoimmune epithelitis,” was published in the journal Nature, Scientific Reports. 

Sjögren’s syndrome, which predominantly affects middle-aged women, is characterized by mistaken immune attacks on the tear and salivary glands by cells known as lymphocytes, leading to disease symptoms.

The two main types of lymphocytes, B-cells and T-cells, are normally involved in fighting infections from foreign pathogens such as bacteria and parasites. In Sjögren’s, however, evidence suggests that an infection may cause T-cells to enter the salivary and tear glands and support the disease-causing hyperactivity of B-cells, which are responsible for generating self-antibodies.

Recently, follicular helper T-cells (Tfh) have been suggested to play a role in Sjögren’s development because they are found in higher levels in the bloodstream of Sjögren’s patients and are a major source of the immune signaling protein interleukin (IL)-21, which regulates B-cell survival.

Furthermore, Tfh cells can express a receptor called CXCR5, which induces their migration toward B-cell sites. This receptor also has been found on a subset of cytotoxic (CD8+) T-cells thought to be involved in Sjögren’s by regulating B-cell responses and abnormal antibody production. 

While the underlying causes of Sjögren’s are still unclear, infection with EBV is a candidate for triggering the disease. Nevertheless, the impact of EBV infection on the B-cell profile found in Sjögren’s patients needs further examination.

Now, a team of scientists based at the Comprehensive Health Research Centre, in Portugal, investigated subsets of B- and T-cells circulating in the bloodstream of Sjögren’s patients and assessed their relation to EBV infection. 

The study involved 57 people with Sjögren’s, of which 98.2% were women, with a median age of 60.6 years, and a median disease duration of 11.3 years. A group of 20 people with the autoimmune disorder rheumatoid arthritis (RA) and 24 healthy people (controls) also were enrolled for comparison.

Compared with the healthy controls, the Sjögren’s patients had fewer helper T-cell numbers and percentages. The number of Tfh cells expressing CXCR5 was lower in Sjögren’s than in controls and RA patients. 

In contrast, the percentage of helper T-cells secreting IL-21 significantly increased in Sjögren’s participants compared with both RA patients and controls. Moreover, there was a significant correlation between higher IL-21-secreting T-cells and more Tfh cells with CXCR5.

Cytotoxic T-cell percentages were significantly elevated in Sjögren’s compared with controls, but not in overall numbers. In comparison with both controls and RA patients, cytotoxic T-cells secreting IL-21 were increased as well. 

Higher levels of cytotoxic T-cells that express CXCR5 correlated with more disease activity, as assessed with the EULAR Sjögren’s disease activity index (ESSDAI), “suggesting their relevant role” in disease development, the team wrote. 

The percentages of non-activated B-cells (naïve) were significantly higher in Sjögren’s patients when compared with healthy controls and RA patients, and also presented higher absolute counts compared with RA, as “previously reported in the literature,” the team added. 

Next, the researchers divided patients into three subgroups according to their EBV profile, including those with previous infection, recent infection and EBV reactivation, or no evidence of active infection.

Sjögren’s participants with recent infection or EBV reactivation had earlier disease onset and shorter disease duration. A majority of patients with a previous infection and/or a recent infection/reactivation had active disease at the time of recruitment, but patients with a previous infection showed higher disease activity scores. In contrast, the lowest disease activity scores were found in patients without active EBV infection. 

Regarding T-cells, patients with a previous infection and recent infection/activation had increased Tfh cells expressing CXCR5 as compared with those without active infection.

The subset of B-cells that make antibodies also was increased in patients with a previous infection or recent infection/activation, compared with those without active EBV infection. 

“Our results suggest EBV-infection contributes to B- and T-cell differentiation towards the effector [cells] typical of [Sjögren’s syndrome],” the investigators wrote.

“Considering the possible pathogenic role of EBV in the [development] of [Sjögren’s syndrome], therapies directed towards the interaction between EBV and activated effector T-cells and B-cells could halt the EBV-triggered lymphocytic activation, and have a relevant clinical applicability,” they added.