Sapropterin (BH4) aggravates autoimmune encephalomyelitis in mice

Background and Purpose: Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4) in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 medication (sapropterin) might increase the risk of autoimmune diseases. Experimental Approach: The present study assessed the implications for multiple sclerosis (MS) as a model autoimmune disease in MS patients and in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis in mice. Key Results: Plasma levels of biopterin were persistently low in MS patients, and the bypass product, neopterin tended to be increased suggesting a relative deficiency of BH4. Ex vivo stimulation of human whole blood indeed led to a drop of biopterin pointing to high consumption. Hence, BH4 replenishment might either further drive the immune response or beneficially restore the BH4 balance. To answer this question, mice were treated with sapropterin in the EAE model. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood, suggesting that BH4 facilitated the invasion of the central nervous system (CNS). Sapropterin-treated EAE mice had increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood brain barrier in EAE mice. Conclusion and Implications: Sapropterin might aggravate autoimmune disease of the CNS through permissive effects at the brain barrier.