Blood levels of inflammatory proteins higher in Fabry patients
ERT found to reduce levels of some of these inflammatory cytokines
People with Fabry disease have higher levels of certain inflammatory cytokines — small proteins that act as chemical messengers of the immune system — in their blood than do healthy individuals, according to a study by researchers in China.
Higher blood levels of some of these inflammatory proteins were significantly linked to worse disease severity among patients.
However, more than six months of enzyme replacement therapy, a mainstay Fabry disease treatment, reduced the levels of some inflammatory cytokines in this patient population, the team found.
“In the current study, we … aimed to reveal the relationship between [inflammatory cytokines] and [Fabry disease] characteristics, … as well as the impact of [enzyme replacement therapy] on [inflammatory cytokine] expression,” the researchers wrote.
Their study, “Inflammatory cytokine expression in Fabry disease: impact of disease phenotype and alterations under enzyme replacement therapy,” was published in the journal Frontiers of Immunology.
Understanding the connection between inflammatory cytokines and Fabry
Fabry is a rare, inherited disorder caused by mutations in the GLA gene, which encodes instructions for producing an enzyme called alpha-galactosidase A, or alpha-Gal A. In healthy individuals, alpha-Gal A breaks down fatty molecules, like globotriaosylceramide (Gb3), inside of the cell.
In patients with deficient or absent alpha-Gal A, these fatty molecules toxically accumulate within cells in various tissues. Organs such as the heart, kidneys, and nervous system are damaged by this accumulation, resulting in a diverse array of Fabry symptoms.
Inflammation is known to play a key role in Fabry disease development. Gb3 can interact with specific inflammatory proteins, called cytokines, triggering a cascade of events that leads to chronic inflammation and blood vessel damage. Over time, this sustained inflammation causes tissue damage, scarring, and organ failure.
Cytokines are small proteins that help immune cells communicate with one another, controlling the activity and growth of immune system cells. Those that stimulate an immune response are called inflammatory cytokines.
It remains unclear, however, whether the increased levels of cytokines observed in Fabry patients have a direct impact on the clinical presentation or progression of the disease.
Now, a team led by researchers at the Peking University First Hospital in Beijing sought to better understand the connection between inflammatory cytokines and Fabry disease characteristics, such as severity and type. Further, the researchers wanted to see how ERT might affect the levels of these cytokines.
To that end, the team examined the blood of 67 patients from 47 unrelated families to measure the level of cytokines in the bloodstream. They also tested the blood of 44 healthy people, who served as controls.
Inflammatory proteins linked to higher disease burden for patients
Altogether, 14 distinct cytokines were measured in the participants’ blood samples. An analysis revealed that, in 59 patients who had not started ERT, there were significantly elevated levels of 11 cytokines compared with the healthy controls.
In this patient group, eight of the cytokines — IFN-gamma, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-17F, and IL-22 — were significantly associated with higher disease burden, as measured by the Mainz Severity Score Index (MSSI). When patients were divided into either low or high MSSI groups, the researchers found significantly higher levels of the cytokine IL-8 in the 28 high MSSI patients relative to the 31 low MSSI patients.
“[Inflammatory cytokines] may be a potential candidate biomarker reflecting disease burden and severity in [Fabry disease],” the researchers wrote.
Higher levels of inflammatory cytokines were associated with organ-specific biomarkers, particularly cardiac and renal biomarkers, used to monitor disease progression. However, they were not significantly associated with age at disease onset, disease duration, alpha-Gal A activity, or plasma Gb3 levels.
The researchers found that ERT may help normalize the levels of certain inflammatory cytokines. The levels of IL-2 and IL17a were significantly lower in those who received long-term — more than six months — enzyme replacement therapy, when compared to those who had not received ERT.
Our findings indicated that the inflammatory pathway may be a promising therapeutic target for [Fabry disease].
TNF-beta levels were normalized in those who received treatment for less than six months. Additionally, levels of IL-1beta, IL-4, IL-6, and IL-10 were restored to normal ranges in patients undergoing long-term ERT.
In acknowledging the study’s limitations, researchers called for further research with a larger number of samples from patients before and after receiving ERT to better understand the impact of such treatment on patients’ levels of inflammatory cytokines.
“Our findings indicated that the inflammatory pathway may be a promising therapeutic target for [Fabry disease],” the researchers concluded.
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