Thy-1 Protein May Mark Progression of Skin Fibrosis in SSc Over Time
Higher Thy-1 levels correlate with worse skin fibrosis in scleroderma
A protein called Thy-1 is present at higher levels in the skin of patients with systemic sclerosis (SSc) than in healthy skin, and the more Thy-1, the worse the disease, a study has found.
When researchers modeled the disease in lab animals, they observed that mice lacking Thy-1 had less fibrosis in the skin, but not in the lungs, than wild-type (control) mice. Fibrosis is the growth of collagen-rich tissue during scarring, which is what makes skin — and sometimes other tissues — thicken and harden in patients with SSc, also known as scleroderma.
These findings suggest that “Thy-1 may serve as a longitudinal marker to assess skin fibrosis,” the researchers wrote.
The study, “Thy-1 plays a pathogenic role and is a potential biomarker for skin fibrosis in scleroderma,” was published in the journal JCI Insight.
Scleroderma occurs when the immune system becomes overactive and launches an attack against the connective tissue beneath the skin. This causes fibroblasts, a type of cells, to make too much collagen. As a result, the skin will scar.
In the systemic type of scleroderma, there also may be scarring in the connective tissue around the blood vessels and internal organs. When scarring occurs in the lungs, it can make it hard to breathe.
What is Thy-1?
Thy-1, also called CD90, is a protein that can be found on the surface of certain cells such as fibroblasts. It helps them bind to other cells and helps fibroblasts develop into myofibroblasts, which can tighten (contract) in a way similar to muscle cells.
While having no Thy-1 in the lungs can worsen fibrosis and make it last longer, what the protein does in the skin remains an open question.
A team of researchers in the U.S. started to look for answers in samples of skin from 10 patients with SSc.
Compared with samples of healthy skin from eight individuals, those of patients with early-stage disease lasting for less than three years had nearly four times as many Thy-1-positive cells (36.8% vs. 9.3%). In patients with later stages of the disease, the proportion of Thy-1-positive cells was even higher (69.2%).
Thy-1 was present in cells of the dermis — the innermost of the two main layers of cells that make up the skin — and more specifically in those also rich in fibroblast activation protein, a marker of fibroblasts.
To confirm these findings, the researchers checked whether the THY1 gene, which contains the instructions to make the Thy-1 protein, was turned on in samples of skin from two public datasets. To do this, they looked at the levels of mRNA, a molecule that takes the instructions from the genes to the place in a cell where the proteins are made.
How do mRNA levels correlate with disease?
These mRNA levels were found to be higher in samples of skin from patients with either the limited or the diffuse subtype of SSc than in samples of healthy skin. Moreover, they correlated with the modified Rodnan skin score, a measure of skin thickness. This means that the higher the levels of mRNA, the worse the disease.
To better understand the link between Thy-1 levels and the process of fibrosis, the researchers turned to mice in which the disease is triggered by injection of a chemical called bleomycin.
The levels of Thy-1 increased over time and reached their maximum three to four weeks after injection of bleomycin. At the same time, there also was an increase in markers of fibrosis, including skin thickness.
“These findings provide evidence that Thy-1 expression increases during fibrogenesis [abnormal accumulation of fibrous tissue],” the researchers wrote.
To find out what Thy-1 does in the skin, the researchers used mice lacking the protein and compared their skin thickness with that of wild-type (control) mice. After injection of bleomycin, the skin of mice lacking Thy-1 was about half as thick as that of control mice, and their fibroblasts also made less of collagen.
Usually, injection of bleomycin brings about inflammation in the skin, and with it come macrophages, a type of immune cell that can remove dead cells from tissues and prompt other immune cells to take action. Left untreated, both mice with and without Thy-1 had about the same number of macrophages in the skin. After injection of bleomycin, the number of macrophages rose, but those in the skin of mice lacking Thy-1 were about half as many as those in the skin of control mice.
Similar observations were made when looking at the number of myofibroblasts and dead (apoptotic) cells.
“These findings indicate that Thy-1 serves as a marker of fibrosis and is involved in pathways that lead to skin fibrogenesis,” the researchers concluded.
But as observed in previous studies, lung fibrosis was worse in mice lacking Thy-1 than in control mice. “It is intriguing that the effect of loss of Thy-1 in skin is opposite to that seen in lung,” the researchers wrote, adding that “these findings add both clarity and complexity to the actions exerted by Thy-1.”