Serum Levels of Aryl Hydrocarbon Receptor Plasma Agonist Activity Are Reduced in Patients With NMOSD and Correlate With Disease Activity

Abstract

Background and objectives: Neuromyelitis optica spectrum disorders (NMOSDs) are severe autoimmune diseases characterized by recurrent CNS inflammation and high risk of persistent disability. Effective disease monitoring is essential for timely intervention and relapse prevention. While biomarkers such as soluble glial fibrillary acidic protein and neurofilament light chain indicate astrocytic and neuronal damage, additional markers are needed to improve disease monitoring and treatment strategies. The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) is a key immune regulator in autoimmune diseases such as multiple sclerosis, where its ligands correlate with disease activity. Given overlapping immunologic pathways, AHR signaling may also influence NMOSD pathophysiology. In this context, this study examines serum levels of AHR ligand in NMOSD, assessing their regulation and association with disease activity. Elucidating the role of AHR signaling may pave the way to explore novel markers of disease activity and therapeutic intervention in NMOSD.

Methods: AHR agonistic activity was assessed in the serum of 102 patients with aquaporin-4 antibody-positive NMOSD across various stages of the disease. As control, serum samples from 36 patients with noninflammatory diseases were evaluated for AHR agonistic activity. In addition, we measured AHR activity longitudinally in 10 individuals at 3 distinct time points-during a quiescent phase preceding relapse, at relapse, and during a postrelapse quiescent phase-to evaluate the dynamic changes in AHR activity over time.

Results: Serum AHR agonistic activity was globally decreased in the NMOSD cohort compared with the control group. AHR agonistic activity was further reduced during or near relapses. Finally, we conducted longitudinal analyses on individual serum samples obtained from patients with NMOSD. Our findings reveal that AHR activity significantly decreases during the relapse phase compared with the quiescent phase, with a subsequent recovery after relapse.

Discussion: Serum AHR agonistic activity is reduced in patients with NMOSD compared with controls and further modulated in temporal vicinity to a relapse. Furthermore, our longitudinal analysis confirmed that AHR activity is markedly reduced during relapse, underscoring its dynamic modulation in relation to disease activity. AHR agonist activity might represent a potential tool to monitor disease activity and develop novel therapeutic strategies.

Classification of evidence: This study provides Class III evidence that serum levels of AHR agonistic activity are reduced in patients with NMOSD compared with noninflammatory controls, and that these levels are further modulated across different stages of the disease.

Figure 1. AHR Agonistic Activity Is Decreased in Patients With NMOSD

AHR agonistic activity was assessed in serum samples from patients with noninflammatory disease (controls; n = 36) and those with AQP4-IgG seropositive NMOSD (n = 102). Values represent the median of technical duplicate measurements, with lines indicating the median and error bars showing the interquartile range (IQR). Statistical significance was determined using the Mann-Whitney U test (****p < 0.0001). AHR = aryl hydrocarbon receptor; NMOSD = neuromyelitis optica spectrum disorder.

Figure 2. AHR Agonistic Activity Is Modulated Over the Disease Course in Patients With NMOSD

(A) Schematic overview illustrating the definition of disease stages relative to relapse onset. (B) AHR agonistic activity was measured in serum samples from patients with noninflammatory neurologic diseases (controls; n = 36) and from patients with AQP4-IgG–seropositive NMOSD across 3 clinical stages: (1) near relapse (n = 40), defined as the interval between 30 and 90 days before relapse onset, representing a phase of potential subclinical disease activity; (2) relapse (n = 18), defined as the period spanning 30 days before to 30 days after the onset of a clinically confirmed relapse; and (3) remission (n = 44), defined as a stable phase of disease activity occurring more than 90 days before or after a relapse event. Values represent the median of duplicate measurements, with lines indicating the median and interquartile range (IQR). Statistical significance was assessed using a nonparametric Kruskal-Wallis test with the Dunn multiple comparison test for correction of multiple comparisons. Significance levels: ****p < 0.0001, **p < 0.001, *p < 0.01, n.s. = nonsignificant. AHR = aryl hydrocarbon receptor; NMOSD = neuromyelitis optica spectrum disorder.

Figure 3. Serum AHR Agonistic Activity Is Negatively Correlated With Relapse Rate

(A) Solid line shows linear regression with correlation of AHR agonistic activity and annual relapse rate as determined using negative binomial models in patients with NMOSD (n = 102). Values represent the median of technical duplicate measurements. Numbers indicated R and p value of linear regression analysis. p < 0.05 is considered as statistically significant. (B and C) Serial analysis of AHR agonistic activity in 10 individual patients. Measurements were obtained during a quiescent phase preceding relapse, at relapse or near, and in the postrelapse phase. AHR = aryl hydrocarbon receptor; NMOSD = neuromyelitis optica spectrum disorder.