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The crucial role of sphingosine-1-phosphate and the therapeutic potential of fingolimod for Graves´ disease and associated orbitopathy
Graves´ disease (GD) is an autoimmune disorder caused by stimulating autoantibodies against the thyrotropin stimulating hormone receptor (TSHR) resulting in hyperthyroidism. The most common complication of GD is Graves´ orbitopathy (GO) as a result of the binding of autoantibodies to TSHR in the orbital tissue. The main features of GO include orbital inflammation, adipogenesis and fibrosis of extraocular muscles. Orbital fibroblasts (OFs) play a crucial role in the pathogenesis of GO and function as effector cells. They can be activated by the binding of antibodies to TSHR or by the ligation of T cells via CD40/CD40L. The activation of OFs results in proliferation, differentiation into adipocytes or myofibroblasts and/or hyaluronan production leading to the characteristics of the disease. While thyroid dysfunction can be efficiently treated with anti-thyroid drugs, current treatments for GO remain unsatisfactory. Since GO has a huge impact on the life quality of patients, there is a strong need for the identification of new therapeutic targets and efficient treatment. The work presented in this thesis addressed the role of the sphingolipid sphingosine-1-phosphate (S1P) in the pathogenesis of GO, especially the impact on T-cell migration towards human OFs. Furthermore, the S1P receptor modulator fingolimod was investigated for its preventive and therapeutic potential in an experimental GD/GO mouse model. In the first part of this thesis, increased S1P levels were found in GO patients´ orbital tissue. Moreover, stimulation of OFs derived from GO patients with CD40L to mimic an inflammatory environment, led to enhancement of S1P levels in comparison to OFs derived from non-GO control persons. Further analyses revealed that the sphingolipid pathway is upregulated in GO OFs upon CD40L stimulation: Other sphingolipids like ceramide and sphingosine, as well as involved enzyme activities such as acid sphingomyelinase (ASM) and sphingosine kinase (SphK) were increased in the diseased cells. Since S1P is well known as a ...
The crucial role of sphingosine-1-phosphate and the therapeutic potential of fingolimod for Graves´ disease and associated orbitopathy
Graves´ disease (GD) is an autoimmune disorder caused by stimulating autoantibodies against the thyrotropin stimulating hormone receptor (TSHR) resulting in hyperthyroidism. The most common complication of GD is Graves´ orbitopathy (GO) as a result of the binding of autoantibodies to TSHR in the orbital tissue. The main features of GO include orbital inflammation, adipogenesis and fibrosis of extraocular muscles. Orbital fibroblasts (OFs) play a crucial role in the pathogenesis of GO and function as effector cells. They can be activated by the binding of antibodies to TSHR or by the ligation of T cells via CD40/CD40L. The activation of OFs results in proliferation, differentiation into adipocytes or myofibroblasts and/or hyaluronan production leading to the characteristics of the disease. While thyroid dysfunction can be efficiently treated with anti-thyroid drugs, current treatments for GO remain unsatisfactory. Since GO has a huge impact on the life quality of patients, there is a strong need for the identification of new therapeutic targets and efficient treatment. The work presented in this thesis addressed the role of the sphingolipid sphingosine-1-phosphate (S1P) in the pathogenesis of GO, especially the impact on T-cell migration towards human OFs. Furthermore, the S1P receptor modulator fingolimod was investigated for its preventive and therapeutic potential in an experimental GD/GO mouse model. In the first part of this thesis, increased S1P levels were found in GO patients´ orbital tissue. Moreover, stimulation of OFs derived from GO patients with CD40L to mimic an inflammatory environment, led to enhancement of S1P levels in comparison to OFs derived from non-GO control persons. Further analyses revealed that the sphingolipid pathway is upregulated in GO OFs upon CD40L stimulation: Other sphingolipids like ceramide and sphingosine, as well as involved enzyme activities such as acid sphingomyelinase (ASM) and sphingosine kinase (SphK) were increased in the diseased cells. Since S1P is well known as a ...
The crucial role of sphingosine-1-phosphate and the therapeutic potential of fingolimod for Graves´ disease and associated orbitopathy
Plöhn, Svenja (author) / Berchner-Pfannschmidt, Utta
2019-04-15
Theses
Electronic Resource
English
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