MerTK protein in salivary glands could help track Sjögren’s activity
Study: It could also be useful marker in estimating tissue damage
Levels of the receptor protein Mer tyrosine kinase (MerTK) in small salivary glands may be a useful marker for tracking disease activity and estimating tissue damage in Sjögren’s disease, a study reports.
Researchers found that elevated MerTK, which plays a role in immune inflammation, was significantly associated with more disease activity and tissue damage. They also saw a relationship between MerTK and histopathological, or microscopic, features of immune system involvement in the diseased tissue.
“To the best of our knowledge, this is the first study to establish a significant correlation between increased MerTK [levels] and various histopathologic, clinical, and laboratory parameters, particularly disease activity and organ damage, in SD [Sjögren’s disease] patients,” researchers wrote.
The findings also suggest MerTK may be a potential therapeutic target in Sjögren’s.
The study, “Clinical significance of TAM receptor in the minor salivary glands of patients with Sjögren’s disease,” was published in the journal Scientific Reports.
Potential links between TAM receptors, disease features studied
Sjögren’s is caused by the immune system mistakenly targeting the body’s own cells as potential threats, and launching an inflammatory attack against these cells. It primarily affects the glands that produce tears and saliva, leading to hallmark symptoms of dry eyes and mouth.
“Dysregulation of immune [balance], including impaired clearance of [dying] cells and aberrant type I interferon (IFN) signaling, plays a key role in [Sjögren’s development],” the researchers wrote.
TAM receptors, a group of proteins including MerTK, are key for the clearance of dying cells from tissues and are also involved in the suppression of IFN signaling.
Although this immune signaling is a vital part of the body’s defenses, “sustained type I IFN responses can be detrimental, leading to chronic inflammation and potentially contributing to autoimmune diseases like [Sjögren’s],” the researchers wrote.
While abnormalities in TAM signaling have been linked to certain autoimmune diseases, “there is limited research on the role of TAM signaling in SD patients,” the researchers wrote.
In this study, a team of researchers in South Korea evaluated potential links between levels of TAM receptors — MerTK, Tyro3, and Axl — in tissues samples of small salivary glands and disease features in 74 Sjögren’s patients.
All participants had undergone biopsy of these glands during the Sjögren’s diagnostic process, as infiltration of a type of immune cell called lymphocytes into these tissues is a marker of the disease.
Their average age was 52.1 at the time of the biopsy, and 90.5% of participants were women. They had experienced dry eyes and mouth for an average of 21.8 months, or nearly two years.
The proportion of minor salivary gland cells testing positive for MerTK on a microscope was classified as negative, mild (6% to 25% of positive cells), moderate (26% to 50% of positive cells), and strong (more than 50% of cells were positive).
Higher MerTK levels indicate greater Sjögren’s activity
Two clinical rating scales — the European League Against Rheumatism’s Sjögren’s Syndrome Disease Activity Index (ESSDAI) and the Sjögren’s Syndrome Disease Damage Index (SSDDI) — were used to assess clinical features of the disease.
Results showed that greater percentages of MerTK-positive cells, reflecting higher MerTK levels, were significantly associated with higher ESSDAI and SSDDI scores, indicating greater disease activity and more tissue damage.
Higher MerTK levels were also significantly linked with a higher focus score, a histopathological measure reflecting greater lymphocyte infiltration in salivary gland biopsies.
In terms of laboratory findings, having more MerTK-positive cells was significantly associated with higher levels of immunoglobulin G (IgG), anti-SS-A antibody positivity, and lower C3 levels.
IgG is an antibody commonly found at higher-than-normal levels in Sjögren’s. Anti-SS-A antibodies are a type of self-reactive antibody strongly associated with Sjögren’s. C3 is an immune protein whose low levels in Sjögren’s have been linked to worse outcomes.
These findings highlight the distinctive role of MerTK in the [disease processes] of SD and its potential as a biomarker for assessing disease severity, whereas Tyro3 and Axl appear to have less prominent roles.
When the team repeated this analysis for the other two TAM receptors, Tyro3 and Axl, they didn’t find significant associations between these molecules and clinical or laboratory findings and histopathology.
The only exception was between higher Tyro3 levels and testing positive for anti-SS-B antibody, another type of self-reactive antibody often linked to Sjögren’s.
“These findings highlight the distinctive role of MerTK in the [disease processes] of SD and its potential as a biomarker for assessing disease severity, whereas Tyro3 and Axl appear to have less prominent roles,” the researchers wrote.
They proposed three possible explanations linking high MerTK to Sjögren’s. First, MerTK levels may increase in the glands in response to accumulation of dying cells. Second, the high levels of MerTK may be the result of defective MerTK signaling, which should regulate itself in the presence of certain immune signaling molecules. Finally, there could be mutations in the gene coding for the MerTK receptor that could lead to increased levels in minor salivary glands.
To evaluate these hypotheses, future research could use more complex molecular imaging methods to identify other elements of MerTK pathways, the team noted.
“Further studies are warranted to elucidate the underlying mechanisms regulating MerTK [levels] and to explore its potential as a therapeutic target in SD,” the researchers concluded.
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