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Treatment of Myasthenia Gravis Based on Its Immunopathogenesis
김지영,박기덕,David P. Richman 대한신경과학회 2011 Journal of Clinical Neurology Vol.7 No.4
The prognosis of myasthenia gravis (MG) has improved dramatically due to advances in criticalcare medicine and symptomatic treatments. Its immunopathogenesis is fundamentally a T-cell-dependent autoimmune process resulting from loss of tolerance toward self-antigens in the thymus. Thymectomy is based on this immunological background. For MG patients who are inadequately controlled with sufficient symptomatic treatment or fail to achieve remission after thymectomy, remission is usually achieved through the addition of other immunotherapies. These immunotherapies can be classified into two groups: rapid induction and long-term maintenance. Rapid induction therapy includes intravenous immunoglobulin (IVIg) and plasma exchange (PE). These produce improvement within a few days after initiation, and so are useful for acute exacerbation including myasthenic crisis or in the perioperative period. High-dose prednisone has been more universally preferred for remission induction, but it acts more slowly than IVIg and PE, commonly only after a delay of several weeks. Slow tapering of steroids after a high-dose pulse offers a method of maintaining the state of remission. However, because of significant side effects, other immunosuppressants (ISs) are frequently added as “steroid-sparing agents”. The currently available ISs exert their immunosuppressive effects by three mechanisms: 1) blocking the synthesis of DNA and RNA, 2) inhibiting T-cell activation and 3) depleting the B-cell population. In addition, newer drugs including antisense molecule, tumor necrosis factor alpha receptor blocker and complement inhibitors are currently under investigation to confirm their effectiveness. Until now, the treatment of MG has been based primarily on experience rather than gold-standard evidence from randomized controlled trials. It is hoped that well-organized studies and newer experimental trials will lead to improved treatments.
Han, Kihoon,Chen, Hogmei,Gennarino, Vincenzo A.,Richman, Ronald,Lu, Hui-Chen,Zoghbi, Huda Y. IRL Press 2015 Human molecular genetics Vol.24 No.7
<P>Silencing of fragile X mental retardation 1 (<I>FMR1</I>) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here, we generated and characterized <I>Cyfip2</I>-mutant (<I>Cyfip2<SUP>+/−</SUP></I>) mice. We found that <I>Cyfip2<SUP>+/−</SUP></I> mice exhibited behavioral phenotypes similar to <I>Fmr1</I>-null (<I>Fmr1<SUP>−/y</SUP></I>) mice, an animal model of FXS. Synaptic plasticity and dendritic spines were normal in <I>Cyfip2<SUP>+/−</SUP></I> hippocampus. However, dendritic spines were altered in <I>Cyfip2<SUP>+/−</SUP></I> cortex, and the dendritic spine phenotype of <I>Fmr1<SUP>−/y</SUP></I> cortex was aggravated in <I>Fmr1<SUP>−/y</SUP></I>; <I>Cyfip2<SUP>+/−</SUP></I> double-mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both <I>Fmr1<SUP>−/y</SUP></I> and <I>Cyfip2<SUP>+/−</SUP></I> cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in <I>Fmr1<SUP>−/y</SUP></I> or <I>Cyfip2<SUP>+/−</SUP></I> neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS.</P>