Abstract
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.