Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

Area of Science:

• Neuroimmunology
• Autoimmune Diseases
• Biochemistry

Background:

• Tetrahydrobiopterin (BH4) cofactor depletion in T-cells prevents proliferation, suggesting a role in driving autoimmunity.
• The BH4 drug, sapropterin, is clinically available, raising concerns about its potential to increase autoimmune disease risk.
• Multiple Sclerosis (MS) serves as a model for central nervous system (CNS) autoimmune diseases.

Purpose of the Study:

• To investigate the implications of BH4 replenishment for multiple sclerosis (MS).
• To assess whether sapropterin treatment exacerbates or ameliorates experimental autoimmune encephalomyelitis (EAE) in a mouse model.

Main Methods:

• Assessed plasma biopterin and neopterin levels in MS patients.
• Treated EAE mice with sapropterin and monitored disease scores.
• Analyzed T-cell populations in spleen and blood.
• Measured plasma lipid profiles, focusing on ceramides and fatty acids.
• Examined gene expression related to ceramide synthesis in brain endothelial cells.

Main Results:

• MS patients exhibited low plasma biopterin and elevated neopterin, suggesting BH4 imbalance.
• Sapropterin treatment in EAE mice led to higher disease scores and increased spinal cord T-cell infiltration.
• Sapropterin treatment altered lipid profiles, increasing long-chain ceramides and decreasing linolenic acid.
• Gene expression analysis confirmed upregulation of ceramide synthesis pathways in brain endothelial cells of EAE mice.

Conclusions:

• BH4 supplementation appears to fortify autoimmune CNS disease, exemplified by EAE.
• The mechanism involves lipid deregulation, specifically ceramide accumulation and altered fatty acid levels.
• These lipid changes are implicated in blood-brain barrier disruption, contributing to EAE pathology.