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