Study Suggests Blocking mTOR Signaling Pathway as Sjogren’s Strategy

Targeting the mTOR signaling pathway may prevent the increased activation and proliferation of immune cells in the salivary glands of patients with primary Sjögren’s syndrome (pSS), according to new research.

The study, “Increased mTORC1 activation in salivary gland B cells and T cells from patients with Sjögren’s syndrome: mTOR inhibition as a novel therapeutic strategy to halt immunopathology?,” appeared in the journal RMD Open.

Excess activity of immune B cells is a hallmark feature of pSS, and includes the formation of autoantibodies — those targeting the body’s own tissues — and an increased number of B cells in salivary glands.

The mTOR pathway regulates the growth, survival, and proliferation of T and B cells. mTOR complex 1 (mTORC1) integrates the enzyme mTOR and plays a role in protein production, cell growth, proliferation, and metabolism.

In other autoimmune diseases where B cells play an active role, such as rheumatoid arthritis and systemic lupus erythematosus, blocking mTOR causes a significant reduction in immune cell activity.

The role of this pathway in pSS, however, had not been addressed. Thus, researchers at the University Medical Centre Utrecht, Netherlands, addressed this gap and analyzed whether targeting mTOR could have therapeutic potential.

The study included 13 patients with pSS (10 women, mean age 52 years), 17 with dry eyes and mouth but without Sjögren’s (non-SS sicca; all women, 53 years) and nine healthy controls (also all women, 57 years).

Researchers found that mTORC1 activation was lower in circulating immune cells from Sjögren’s patients. However, immune cells inside labial salivary glands had higher mTOR activation, which correlated with excess B-cell activity.

“We hypothesized that reduced mTOR activity in circulating B cells may reflect migration of activated B cells to the salivary glands,” the scientists stated.

The team then found that activation of immune cells in circulation increased mTOR activity, providing further evidence that mTOR activation increased the division rate of B cells and some T cells. This was also associated with the production of the inflammatory activator interferon (IFN)-gamma and of IgG — the most common class of antibodies, involved in Sjögren’s.

Thus, rapamycin — an antibiotic compound that blocks mTOR activity — reduced the proliferation of these immune subsets and lowered the production of IFN-gamma and IgG.

“Our data indicate a role for mTOR activity in B-cell hyperactivity in pSS and identify mTOR inhibition as a novel potential therapeutic strategy for this disease,” the scientists said. “As such, studying the efficacy of [combination] therapy using mTOR inhibitors with favorable toxicity profiles in patients with pSS should be pursued.”