Immune Proteins, Itch Mediators Imbalanced in EB, Study Discovers

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by Steve Bryson, PhD |

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An imbalance both of immune signaling proteins and mediators of the itch response was found in the bloodstream of people with epidermolysis bullosa (EB) — for whom itch is a common and debilitating disease symptom — a study discovered.

Given the findings, therapies targeting these proteins may be a potential “beneficial treatment option” for those living with EB, the scientists said.

The study, “New insight of itch mediators and proinflammatory cytokines in epidermolysis bullosa,” was published in the Journal of Cutaneous Immunology and Allergy.

EB is a group of rare skin disorders characterized by fragile skin that easily blisters and tears. Most cases of EB are caused by inherited defects in genes that encode proteins within the layers of skin.

Itch is one of the common symptoms across all types of EB; in fact, in one previous study of three EB types, 85% of participants reported itch, the researchers noted. Itching may occur at the site of blisters or wounds but also in other locations on the body.

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“In EB, the itch is a common symptom with a significant impact on quality of life and is often accompanied by pain and skin infections in the patients,” the team wrote.

In more severe cases of EB, there is an increased risk of kidney or heart disease, in which studies have implicated pro-inflammatory signaling proteins called cytokines.

These findings led researchers at the Niigata University Graduate School of Medical and Dental Science, in Japan, to wonder whether EB is not only a skin disease but also a bodywide (systemic) inflammatory disorder.

To find out, the team collected blood samples from EB patients and measured the levels of cytokines related to systemic inflammation and other immune proteins that mediate the itch response.

Among the EB patients, 14 were diagnosed with dystrophic epidermolysis bullosa (DEB), caused by mutations in the COL7A1 gene, and six with epidermolysis bullosa simplex (EBS), the most common form of EB, which occurs due to KRT5 or KRT14 genetic defects. For comparison, 16 healthy individuals were included as controls.

Blood tests revealed that, compared with controls, several cytokines were significantly elevated in the EB patients, including interleukin-6 (IL-6), IL-8, IL-16, sIL-2R, HGF, M-CSF, SCGF-beta, IFN-gamma, MIF, and MIP-1-alpha.

Cytokines secreted by immune type 2 helper T-cells, which are known to play a role in allergic diseases, were not higher in EB patients compared with the healthy controls.

TSLP, a protein mediator of the itch response, was significantly increased in DEB patients relative to controls. Two other itch mediators, IL-31 and OSM, were higher in those with DEB, but not EBS, although the difference was not statistically significant.

Further analysis discovered that elevated levels of IL-6 — a well-known pro-inflammatory cytokine produced during viral infections — were significantly higher in DEB patients compared with healthy controls. In contrast, there was no significant difference in IL-6 in EBS patients relative to controls.

“These facts suggest that IL-6 can play a [disease-causing] role in triggering serological [blood-based] inflammation in patients with EB,” the researchers wrote.

Two other critical proinflammatory cytokines, IL-1-beta and TNF-alpha, were not found to be elevated.

“Some EBS patients showed a marked increase in serum IL-1β [interleukin-1-beta], which may indicate that elevation of IL-1β specific to a subgroup of EBS,” the scientists wrote. “In addition, the present study did not show any tendency for severe DEB patients to have particularly high levels of IL-1β, and further research is needed on the role of IL-1β in EB patients.”

Of the cytokines produced by type 1 helper T-cells, a cell type known to be involved in the development of diseases in which the immune system attacks healthy tissue, or autoimmune diseases, only IFN-gamma was elevated in DEB patients, compared with healthy controls. It was not elevated in EBS patients.

“Further investigation is needed to determine whether cytokines such as TSLP, IL-31, and IL-6, which were found to be elevated in EB patients in this study, could be targets for biologic therapy for EB patients,” the team wrote.

“The accumulation of these findings is expected to open up new avenues for the treatment of EB which often leads to life-threatening complications and reduced quality of life due to intense pruritus [itch],” they concluded.