AHR protein may be a biomarker for NMOSD relapses
Discovery could lead to new monitoring tools and treatments
The activity of an immune-regulating protein is significantly lower just before or during a relapse in people with neuromyelitis optica spectrum disorder (NMOSD), a recent study has found. This discovery could lead to new ways to monitor disease activity and develop treatments.
The protein, called the aryl hydrocarbon receptor (AHR), is a ligand-activated transcription factor. This means that when bound to certain molecules called ligands, it triggers gene activation to produce certain proteins, including some associated with the regulation of the immune system.
“AHR agonist activity might represent a potential tool to monitor disease activity and develop novel therapeutic strategies,” researchers wrote.
The study, “Serum Levels of Aryl Hydrocarbon Receptor Plasma Agonist Activity Are Reduced in Patients With NMOSD and Correlate With Disease Activity,” was published in Neuroimmunology & Neuroinflammation.
Disease activity increases permanent disability risk
NMOSD primarily causes inflammation in the optic nerve — the nerve that sends signals from the eyes to the brain — and the spinal cord. The disease is characterized by relapses, or episodes of inflammation that typically recur periodically, interspersed with periods of remission.
Disease activity increases the risk of permanent disability. Therefore, monitoring NMOSD activity and an early start to disease-modifying therapies are essential.
In the study, researchers assessed whether the activity levels of AHR were associated with NMOSD activity.
“Elucidating the role of AHR signaling may pave the way to explore novel markers of disease activity and therapeutic intervention in NMOSD,” the researchers wrote.
To that end, they analyzed data from 102 individuals diagnosed with NMOSD who were positive for anti-aquaporin-4 (AQP-4) antibodies, and 36 individuals with non-inflammatory neurological conditions. AQP-4 is a protein mainly found on cells that support the nervous system; anti-AQP-4 antibodies are present in most people with NMOSD.
The NMOSD patients were mainly women (84%), and had a mean age of 47.6 years and a mean disease duration of 9.2 years.
AHR agonistic activity, which refers to the receptor’s overall activation when bound to ligands that trigger its activation, was significantly reduced in people with NMOSD compared with controls. AHR ligand levels were not associated with the patients’ age, sex, ethnicity, or the use of immunosuppressants.
AHR signaling and disease stages
AHR activity was evaluated across three clinical disease stages:
- during a relapse, which is characterized by the appearance or worsening of disease symptoms. The relapse period includes the 30 days before and after the onset of symptoms.
- near a relapse, defined as the interval between 30 and 90 days before the onset of the relapse, reflecting a phase of potential subclinical disease activity
- remission phase, characterized by stable disease activity occurring more than 90 days before or after a relapse.
In the period near or during a relapse, AHR activity in patients was significantly lower compared with control participants and with patients in remission.
“Our observation of decreased AHR agonist activity in NMOSD, particularly during relapses, aligns with the hypothesis that impaired AHR signaling may contribute to heightened disease activity,” the researchers wrote.
In seven of the 10 patients in whom AHR activity levels were measured across the three phases, signaling was decreased during or near a relapse compared with periods of remission. In the other three patients, the patterns were inconsistent.
“Our longitudinal analysis confirmed that AHR activity is markedly reduced during relapse, underscoring its dynamic modulation in relation to disease activity,” the researchers wrote.
Additionally, analyses revealed a negative correlation between AHR agonistic activity and annual relapse rates, meaning that higher levels of AHR activity were associated with a lower rate of annual relapses.
According to researchers, “future studies need to solidify whether AHR ligand levels might be of relevance as a marker of disease activity or even point to future research avenues including … treatment-specific effects relevant to AHR signaling, and potentially novel therapeutic approaches.”
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