Altered B-Cell Balance Linked to Skin, Lung Involvement in SSc: Study

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An altered balance of immune B-cell subtypes was linked to skin and lung involvement in people with more severe systemic scleroderma, a study suggested.

The results indicate that restoring that balance may be a novel therapeutic target in people with severe forms of the condition, the scientists noted.

The study, “Cytokine-producing B-cell balance associates with skin fibrosis in patients with systemic sclerosis,” was published in the Journal of Dermatology.

Systemic scleroderma, also called systemic sclerosis (SSc), is an autoimmune disease marked by scarring of the skin as well as internal organs such as the heart and blood vessels, and the lungs, stomach, and kidneys. More than 90% of people with the condition test positive for autoantibodies, a type of antibody that targets the body’s healthy tissues.

Studies demonstrated that B-cells play an important role in developing SSc. These cells are best known for antibody production, but they also release signaling proteins — called cytokines — that communicate with other immune cells during immune responses.

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Two subtypes of these specialized B-cells have opposing functions: effector B-cells (Beff) and regulatory B-cells (Breg).

Beff cells participate in immune responses by secreting the pro-inflammatory interleukin-6 (IL-6), among other cytokines, and have been shown to promote SSc. The approved SSc therapy Actemra (tocilizumab) works by directly blocking the action of IL-6.

In contrast, Breg cells release anti-inflammatory interleukin-10 (IL-10). Bregs are found in lower numbers or are functionally impaired in various autoimmune diseases, including SSc.

The balance of Beff and Breg cells is thought to help regulate immune responses through the release of these cytokines.

The goal of this study by researchers at the Kanazawa University Graduate School of Medical Sciences, Japan was to compare the balance of Beff and Breg cells in people with SSc to that in healthy individuals then to evaluate the relationship between this balance, clinical characteristics, and disease severity.

Immune cells were collected, sorted, and analyzed from the blood of 30 Japanese people with SSc, ages 47–78 (28 females, two males). Among them, 15 had diffuse cutaneous scleroderma (dcSSc), and 15 had limited cutaneous scleroderma (lcSSc), both subtypes of SSc. Cells were also collected from 21 Japanese people without SSc.

The frequency of IL-6-secreting Beff cells was significantly higher in people with SSc compared to controls, cell analysis showed. Conversely, the frequency of Breg cells that release IL-10 was significantly lower in SSc.

Moreover, those with dcSSc, a more severe form of the disease, had significantly more Beff cells compared to participants with  lcSSs. There were no differences in Bregs between dcSSs and lcSSc patients, however.

Consistently, the ratio of Beff/Breg was significantly higher across all patients with SSc than in healthy controls, and in dcSSc patients over lcSSc patients.

This ratio was higher in those who tested positive for anti-topoisomerase autoantibodies, which are associated with lung involvement and more severe disease. There was no difference in the Beff/Breg ratio between controls and SSc patients with anti-centromere autoantibodies, which are linked with less severe disease.

A comparison of patients with a higher Beff/Breg ratio to those with a normal ratio found no differences with respect to disease duration and treatment history.

As assessed by the modified Rodnan Skin Score (mRSS), skin thickening was worse for patients with an increased Beff/Breg ratio than those with a typical Beff/Breg ratio. Accordingly, worse mRSS scores correlated with the Beff/Breg ratio.

This ratio was not related to symptoms such as pitting scars, finger contractions, pigmentation, dilated blood vessels near the surface of the skin, or involvement in organs such as the esophagus, heart, joint, and muscles.

Although a higher Beff/Breg ratio was not linked to lung function tests, it correlated with more extensive interstitial lung disease (ILD) based on CT scans. ILD is marked by inflammation and scarring of the tissue that surrounds the air sacs in the lungs.

Lastly, immunoglobulin G antibody levels were elevated in those with an increased Beff/Breg ratio, but the difference was not statistically significant.

“Collectively, these findings demonstrated that the Beff/Breg ratio was positively associated with the severity of SSc, such as skin fibrosis and ILD,” the researchers wrote. “This imbalance in the two cytokine-producing B-cell subtypes may promote the development of skin fibrosis, suggesting the Beff/Breg ratio as a new therapeutic target.”