Sapropterin (BH4) aggravates autoimmune encephalomyelitis in mice
Katja Schmitz1, Sandra Trautmann1, Lisa Hahnefeld1, Caroline Fischer1, Yannick Schreiber1, Robert Brunkhorst2, Ernst R. Werner3, Katrin Watschinger3, Sabine Wicker4, Dominique Thomas1, Gerd Geisslinger1,5,6, Irmgard Tegeder1
1Institute of Clinical Pharmacology, Goethe-University, Medical Faculty, Frankfurt, Germany
2Department of Clinical Neurology, Goethe-University, Medical Faculty, Frankfurt, Germany
3Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Austria
4Occupational Health Services, Goethe-University, Medical Faculty, Frankfurt, Germany
5Fraunhofer Institute for Molecular Biology and Applied Ecology, Branch Translational Medicine, Frankfurt, Germany
6Fraunhofer Cluster of Excellence for Immune mediated Diseases, Frankfurt, Germany
Correspondence
Irmgard Tegeder, MD
Goethe-University Frankfurt, Medical Faculty
Institute of Clinical Pharmacology
Theodor Stern Kai 7, 60590 Frankfurt, Germany
Ph 49 696301 7621
tegeder@em.uni-frankfurt.de
Key words
Tetrahydrobiopterin, T-cells, GTP cyclohydrolase, nitric oxide, ceramides, omega lipids
Running head
BH4 and EAE
Word count
Abstract: 247
Main body without Methods/References: 2513
Main body without References: 5170
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.
Abbreviations
AGMO, alkyglycerol monooxygenase; BBB, blood brain barrier; BH4, tetrahydrobiopterin; EAE, experimental autoimmune encephalomyelitis; DAHP, diaminohydroxypyrimidine; GCH1, GTP cyclohydrolase 1; MS, multiple sclerosis; NOS, nitric oxide synthase; RRMS, relapsing remitting MS; PPMS, primary progressive MS; SPMS, secondary progressive MS; PTPS, 6-pyrovoyltetrahydropterin synthase; SPR, sepiapterin reductase