Blood Proteins Profiles May Serve as Biomarkers of Scleroderma Severity

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by Steve Bryson, PhD |

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Distinct levels of proteins in the bloodstream of scleroderma patients matched altered gene activity in their skin, a large-scale molecular analysis showed.

Researchers said these blood proteins could prove to be much-needed biomarkers for this chronic disease.

“These results indicate that [blood] proteins are attractive surrogate markers for tracking disease severity at the diseased organ level,” the researchers wrote.

The findings were published in the journal Arthritis Research & Therapy, in a study titled “Multiomic study of skin, peripheral blood, and serum: is serum proteome a reflection of disease process at the end-organ level in systemic sclerosis?

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Scleroderma, also known as systemic sclerosis or SSc, is characterized by the buildup of scar tissue on the skin, as well as in other organs such as the lungs. The disease is caused by an altered immune response resulting in inflammation and excessive scar formation.

Because the course of SSc is highly variable, reliable biomarkers that predict future outcomes are still needed — especially those found in the bloodstream.

To investigate further, scientists at Momenta Pharmaceuticals, in collaboration with the University of Texas Health Science Center at Houston, explored the relationship between the global molecular profile in blood collected from SSc patients and changes in gene expression (activity) in affected skin samples and peripheral blood cells (PBCs) — red blood cells, white blood cells, and platelets.

The study enrolled 49 people with SSc, with a mean age of 52, of whom 35 (71%) were female. Among the patients, 65% had diffuse cutaneous (skin) involvement, and 40% had significant lung disease. A control group of 25 healthy people who did not have an autoimmune rheumatologic disease was included as a comparison. The control group had similar demographic backgrounds to the patients in the study.

Comparing SSc with control PBC gene activity identified 78 genes that were expressed differently. There was no difference in PBC gene expression between samples collected from those with diffuse cutaneous involvement versus limited cutaneous disease.

The expression of genes associated with pathways related to the immune signaling proteins interferon-alpha and interferon-gamma were significantly higher (upregulated) in SSc versus controls.

A comparison of SSc with control gene expression in biopsied skin samples revealed 540 differentially expressed genes. The most significantly upregulated pathway in SSc skin was related to the transition of surface epithelial cells to mesenchymal cells, a process that underlies scar formation or fibrosis.

Large-scale analysis of proteins in the bloodstream indicated that SSc patients had a distinct profile compared with controls.

Proteins found at higher levels in patients included those involved in pro-fibrotic processes, the movement of immune cells through blood vessel walls, blood vessel growth, and the production of the extracellular matrix (ECM) — a scaffold outside cells made of molecules and proteins such as collagen, that accumulates in SSc.

Notably, the levels of several receptor proteins involved in fibrosis and blood vessel disease were significantly lower (downregulated) in SSc than controls, which may “imply general upregulation of EGF receptor pathways,” implicated in the development of lung and kidney fibrosis, the scientists noted.

A total of 39 proteins found in blood samples significantly correlated with the severity of skin involvement, as assessed by the modified Rodnan Skin Score (mRSS).

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Higher levels of several blood proteins positively correlated with worse mRSS scores, including extracellular matrix proteins. Likewise, low levels of other blood proteins negatively correlated with worse mRSS scores. Overall, the average differences between patients and controls were strongly associated with the entire set of blood proteins.

Of the 911 proteins measured in blood, 314 had corresponding RNA molecules (produced from the respective genes) present in PBCs, and 448 in skin gene expression data. Differences in the blood protein profiles found in patients significantly correlated with the differential expression of corresponding genes in the SSc skin dataset. In contrast, a correlation between SSc blood profiles and PBC gene expression did not reach statistical significance.

Moreover, the interactions networks between proteins found at different levels in patients versus controls were more connected to protein networks in the skin dataset compared with PBCs, which suggests that “the SSc [blood] protein profile is reflective of the dysregulations at the skin level,” the researchers wrote.

Finally, similarities among controls and patients in blood protein profiles and gene expression in PBCs and skin samples were compared.

The most significant similarities were found between blood protein profiles and PBC gene expression data in controls, which suggested a “strong influence of PBC [gene expression] profile onto the levels of circulating proteins in serum [blood] for healthy controls,” the scientists wrote.

Also, in controls, there were no similarities between skin and PBC gene expression, nor between blood protein profiles and skin gene expression data, which suggested that “for healthy controls, the genome-wide similarity of skin [gene expression] levels has very little, if any, relevance to the genome-wide similarity of PBC [gene expression] levels and to serum protein level similarities,” they added.

Conversely, in patients, similarities between blood protein profiles and skin gene expression data were significantly aligned.

“Our multilevel comparative analysis indicates that the serum protein profile in SSc correlates more closely with molecular dysregulations of skin than PBCs and might serve as a reflection of disease severity at the end-organ level,” the team concluded.