Function of Regulatory T-cells Impaired in Women With Sjögren’s: Study
The function of immune regulatory T-cells (Tregs) — cells that play a key role in dampening the body’s immune response — is impaired in women with Sjögren’s syndrome, a study suggests.
Moreover, blood levels of a protein called sIL-2R were elevated in those with more severe disease.
According to researchers, this suggests that “sIL-2R could potentially act as a useful biomarker for [Sjögren’s syndrome] and disease severity and thereby assist in an earlier diagnosis and treatment.”
The study, “Impaired activation of STAT5 upon IL-2 stimulation in Tregs and elevated sIL-2R in Sjögren’s syndrome,” was published in the journal Arthritis Research & Therapy.
Sjögren’s syndrome is an autoimmune disease characterized by a misdirected immune response against the salivary glands and those responsible for tear production (lachrymal glands). It primarily results in dry mouth and eyes, though other tissues can be affected.
Several immune cell types, including B- and T-cells, have been shown to fuel the immune attack driving Sjögren’s syndrome and other autoimmune diseases.
A group of regulatory T-cells, called Tregs, works by keeping immune responses in check and avoiding uncontrolled responses that can harm the body. Interleukin-2 (IL-2), a cytokine or chemical signal that plays a key role in immune responses, is essential for their survival.
IL-2 binds to its receptor, IL-2R, which is located in Tregs. But defects in IL-2 signaling can impair Tregs function, fostering the development of autoimmunity.
Prior studies have shown that IL-2 and IL-2R are central in the development and progression of Sjögren’s. High levels of circulating, or soluble IL-2R (sIL-2R), have been detected in the blood and saliva of Sjögren’s patients. However, how high levels of sIL-2R impact the function of Tregs in these patients remains unknown.
To answer this, researchers at the University of Bergen, in Norway, measured the levels of sIL-2R in blood samples collected from women with Sjögren’s, and healthy age- and sex-matched volunteers, who served as controls. Altogether, the study involved 97 women with Sjögren’s and 49 healthy women, who had a mean age of 50.6.
The Sjögren’s patients were divided into two groups, based on disease severity. A total of 42 participants, with a mean age of 54.1, were in the non-severe disease group. Meanwhile, 54 women, with a mean age of 58.3, comprised the severe disease group. Those in the non-severe disease group had a normal-to-high salivary flow — above 3.5 milliliters every five minutes (mL/5 min) — while women in the severe disease group had a salivary flow of 3.5 mL/5 min or lower.
Levels of sIL-2R were significantly higher in women with Sjögren’s compared with controls. sIL-2R increased gradually with Sjögren’s severity, as reflected by a lower saliva flow. In other words, higher levels of sIL-2R were associated with a low salivary flow.
Researchers then assessed IL-2-mediated Treg function by measuring the levels of a specific protein, called STAT5. That protein undergoes a chemical modification — called phosphorylation, meaning the addition of a phosphate group — that activates it, following the binding of IL-2 to IL-2R.
The team measured the levels of phosphorylated STAT5 (pSTAT5) in 51 randomly selected women from each group. Results showed that women with Sjögren’s had a significantly lower frequency of Tregs positive for pSTAT5 after IL-2 stimulation, compared with controls. No differences were seen in other T-cell populations, indicating a specific impact of Sjögren’s on Tregs.
The lower activation of STAT5 in Tregs also was more pronounced in women with non-severe Sjögren’s.
However, at the start of the analysis (baseline) and without IL-2 stimulation, women with Sjögren’s had a higher frequency of pSTAT5-positive Tregs, compared with healthy women. This increase was associated with the presence of anti-SSA/Ro and anti-SSB/La autoantibodies — self-reactive antibodies associated with Sjögren’s — and elevated levels of sIL-2R.
Overall, these findings suggest that Treg function is impaired in people with Sjögren’s as a result of disruptions in IL-2/IL-2R signaling.
Moreover, the data support previous findings that the levels of sIL-2R are significantly increased in Sjögren’s patients, with higher levels of sIL-2R being correlated with severe disease.
These findings suggest that “sIL-2R could act as a useful indicator for [Sjögren’s] and disease severity,” the researchers wrote.
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