Function of Regulatory T-cells Impaired in Women With Sjögren’s: Study

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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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.

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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.