Treg-associated oligomannose N-glycans trigger immune dysregulation in myasthenia gravis

Abstract

Myasthenia gravis (MG) is an autoimmune neurological disease driven by the production of autoantibodies against components of the neuromuscular junction, resulting in fatigable muscle weakness, and in more severe cases, leading to life-threatening complications. This breakdown of immune tolerance has been associated with an impaired suppressive function and altered frequency of Regulatory T cells (Tregs) in autoimmune diseases, including MG. As key egulators of immune tolerance, Tregs play a pivotal role in maintaining immune homeostasis through their ability to suppress other immune cells, controlling inflammation. Nevertheless, the mechanisms underlying Tregs dysfunction in MG pathogenesis are not fully understood. Here, we reveal the impact of Treg N-glycosylation on their immunoregulatory activity and function in the MG context. Glycan profiling by flow cytometry of circulating Tregs from MG patients (n = 72) and healthy controls (HCs; n = 24) revealed increased presence of oligomannose N-glycans in disease. Moreover, this specific Treg N-glycome profile was associated with disease severity, distinguishing between active disease and remission, being more pronounced in MG patients with additional autoimmune diseases, highlighting its potential as a disease biomarker. Functionally, in vitro abrogation of the N-glycosylation pathway in Tregs (mimicking the oligomannose enrichment found in the patients) resulted in impaired suppressive capacity over conventional T cells. Consistently, in the Experimental Autoimmune Myasthenia Gravis (EAMG) model, mice with altered Treg N-glycosylation exhibited worse clinical features and a reduced frequency of effector Tregs compared to wild-type controls. Altogether, these findings identify N-glycosylation as a mechanism underlying Treg dysfunction in MG, in which abnormal expression of mannose-enriched N-glycans in Tregs associates with compromised Treg suppressive function and increased disease severity, proposing Treg N-glycosylation as both a mechanistic driver of MG pathogenesis and a potential avenue for therapeutic intervention.