The Aryl Hydrocarbon Receptor–Dependent TGF-α/VEGF-B Ratio Correlates With Disease Subtype and Prognosis in Multiple Sclerosis

Abstract

ObjectiveTo evaluate the aryl hydrocarbon receptor (AHR)-dependent transforming growth factor alpha (TGF-α)/vascular endothelial growth factor B (VEGF-B) ratio, which regulates the effects of metabolic, dietary, and microbial factors on acute and chronic CNS inflammation, as a potential marker in multiple sclerosis (MS).MethodsTGF-α, VEGF-B, and AHR agonistic activity were determined in serum of 252 patients with relapsing-remitting (RR) MS, primary and secondary progressive MS, as well as during active disease (clinically isolated syndrome [CIS] and RRMS relapse).ResultsThe TGF-α/VEGF-B ratio and AHR agonistic activity were decreased in all MS subgroups with a stable disease course as compared to controls. During active CNS inflammation in CIS and RRMS relapse, the TGF-α/VEGF-B ratio and AHR agonistic activity were increased. Conversely, in patients with minimal clinical impairment despite long-standing disease, the TGF-α/VEGF-B ratio and AHR agonistic activity were unaltered. Finally, the TGF-α/VEGF-B ratio and AHR agonistic activity correlated with neurologic impairment and time to conversion from CIS to MS.ConclusionsThe AHR-dependent TGF-α/VEGF-B ratio is altered in a subtype, severity, and disease activity–specific manner and correlates with time to conversion from CIS to MS. It may thus represent a novel marker and serve as additive guideline for immunomodulatory strategies in MS.Classification of EvidenceThis study provides Class III evidence that serum levels of AHR, TGF-α, and VEGF-B distinguish subtypes of MS and predict the severity and disease activity of MS.

Birth history is associated with whole-blood and T-cell methylation patterns in relapse onset multiple sclerosis

“…In these studies, AHR agonist activity increase was associated with relapse in CIS and RRMS 56 . A decrease in AHR agonist activity was associated with RRMS remission 56 and progressive MS, 57 thus implicating AHR in neuroinflammatory processes. In our study, AHR was hypomethylated.…”

“…Furthermore, multiple studies have recently correlated AHR agonist activity with MS subtype and prognosis 56,57 . In these studies, AHR agonist activity increase was associated with relapse in CIS and RRMS 56 .…”

“…Furthermore, multiple studies have recently correlated AHR agonist activity with MS subtype and prognosis 56,57 . In these studies, AHR agonist activity increase was associated with relapse in CIS and RRMS 56 . A decrease in AHR agonist activity was associated with RRMS remission 56 and progressive MS, 57 thus implicating AHR in neuroinflammatory processes.…”

Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis

“…While it is possible that this signal was driven by unreported terminations and/or unknown miscarriages, it was identified in peripheral CD8 + T cells only (not whole blood) and is therefore unlikely to be a marker of recurrent spontaneous abortion in this cohort. Furthermore, multiple studies have recently correlated AHR agonist activity with MS subtype and prognosis [ 65 , 66 ]. In these studies, AHR agonist activity increase was associated with relapse in CIS and RRMS [ 65 ].…”

Astrocytes and Microglia in Stress-Induced Neuroinflammation: The African Perspective

“…For instance, microglia can likely produce both positive and negative regulators of astrocyte pathogenic responses (see 80 ). Several molecules have been found to be involved in astrocyte-microglia communication, and the control of these cell-cell interactions by the commensal flora in specific diseases such as MS ( 89 – 96 ). For instance, VEGF-B was identified as a microglial product that boosts disease-promoting astrocyte responses.…”