Monocyte NOTCH2 expression predicts IFN-β immunogenicity in multiple sclerosis patients

Area of Science:

• Immunology
• Neuroimmunology
• Cell Biology

Background:

• Multiple sclerosis (MS) is a CNS autoimmune disease impacting myelin and axons.
• Interferon-beta (IFN-β) is a standard MS therapy, but up to 30% of patients develop neutralizing antidrug antibodies (nADA).
• nADA reduce IFN-β bioactivity and efficacy, yet predictors and mechanisms remain unclear.

Purpose of the Study:

• To identify baseline biomarkers predicting nADA development in MS patients undergoing IFN-β treatment.
• To elucidate the mechanisms underlying antidrug immunogenicity in MS patients.

Main Methods:

• High-throughput flow cytometry was used to analyze monocyte NOTCH2 expression and subset frequencies.
• Validation was performed in two independent cross-sectional MS cohorts and one prospective cohort.
• NOTCH2 activation markers, gene expression, monocyte phenotype, and IL-6 production were assessed.

Main Results:

• Baseline NOTCH2 expression on CD14+ monocytes and increased proinflammatory monocyte subsets predicted nADA development.
• Reduced monocyte NOTCH2 expression in nADA+ patients correlated with NOTCH2 pathway activation.
• NOTCH2 activation was T cell-dependent and serum-dependent from nADA+ patients, indicating a pre-existing proinflammatory environment.

Conclusions:

• A specific monocyte profile, including NOTCH2 expression and subset frequency, can predict nADA development in MS patients treated with IFN-β.
• NOTCH2 pathway activation, driven by a proinflammatory environment, precedes and potentially drives nADA formation.
• These findings offer potential biomarkers for predicting immunogenicity and guiding MS treatment strategies.