Patients with familial amyloid polyneuropathy (FAP) are in a constant pro-inflammatory state, with increased levels of interleukin-6 (IL-6) driven by a mutated form of the protein transthyretin (TTR), which characterizes this disease.
These findings were featured in a study published in the journal Scientific Reports.
FAP is caused by the slowly progressive abnormal deposition of complexes formed by mutated TTR in several organs, caused by a genetic mutation.
FAP patients normally present lower levels of TTR in circulation in the blood than their healthy counterparts. This phenomenon has been suggested to be caused by bad nutrition and increased inflammation. However, many FAP patients are underweight, which rules out that hypothesis and points the blame towards inflammation instead.
The involvement of inflammation in FAP development is not clear. Some studies have showed that pro-inflammatory signaling proteins may be triggered by mutated TTR. But these signals seemed to have a more local behavior, not systemic, which would not entirely explained the lower levels of the mutated protein in the blood.
In the study, “Inflammatory state exists in familial amyloid polyneuropathy that may be triggered by mutated transthyretin,” researchers at Kumamoto University in Japan analyzed the systemic inflammatory state of FAP carriers and patients, and evaluated a potential association with the presence of the mutated TTR protein.
They examined blood samples collected from 66 FAP patients, 21 FAP carriers, and 57 healthy volunteers. FAP carriers were determined by genetic analysis, and FAP diagnosis was confirmed based on clinical evaluation, detection of TTR complexes deposition, and genetic analysis.
The researchers found that the blood levels of IL-6 – a well-known pro-inflammatory component involved in several illnesses, were higher than those detected in healthy individuals. These results were similar between FAP carriers and patients, and independent of disease stage.
Next, they built a statistical model to assess the influence of mutated TTR in the observed IL-6 inflammatory state. This analysis showed that only FAP carriers presented a positive association with IL-6 levels.
“These findings suggest that native mutated TTR may induce IL-6 in FAP carriers,” the authors wrote.
To further confirm these findings they conducted a detailed ex vivo analysis of immune cells — responsible for the production of IL-6 — that were collected from the FAP patients and carriers. They confirmed that in the presence of the mutated protein, immune cells would increase the production of IL-6, but the same would not happen in the presence of normal TTR.
“These results suggest that unlike wild-type TTR, mutated TTR easily initiates a pro-inflammatory state, and this phenomenon in FAP carriers may be a potential risk for FAP onset,” they wrote.
Additional studies are needed to fully understand the underlying mechanisms of FAP that IL-6 may be involved in, and its potential risk for FAP development.
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