Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in ...Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in their serum, targeting acetylcholine receptor, muscle-specific kinase, or related proteins. Current treatment for myasthenia gravis involves symptomatic therapy, immunosuppressive drugs such as corticosteroids, azathioprine, and mycophenolate mofetil, and thymectomy, which is primarily indicated in patients with thymoma or thymic hyperplasia. However, this condition continues to pose significant challenges including an unpredictable and variable disease progression, differing response to individual therapies, and substantial longterm side effects associated with standard treatments(including an increased risk of infections, osteoporosis, and diabetes), underscoring the necessity for a more personalized approach to treatment. Furthermore, about fifteen percent of patients, called “refractory myasthenia gravis patients”, do not respond adequately to standard therapies. In this context, the introduction of molecular therapies has marked a significant advance in myasthenia gravis management. Advances in understanding myasthenia gravis pathogenesis, especially the role of pathogenic antibodies, have driven the development of these biological drugs, which offer more selective, rapid, and safer alternatives to traditional immunosuppressants. This review aims to provide a comprehensive overview of emerging therapeutic strategies targeting specific immune pathways in myasthenia gravis, with a particular focus on preclinical evidence, therapeutic rationale, and clinical translation of B-cell depletion therapies, neonatal Fc receptor inhibitors, and complement inhibitors.展开更多
Domestic pigs are shaped by artificial and natural selection into obese and lean types that are closely related to muscle tissue.However,the key genes and regulatory mechanisms behind these developments remain largely...Domestic pigs are shaped by artificial and natural selection into obese and lean types that are closely related to muscle tissue.However,the key genes and regulatory mechanisms behind these developments remain largely unknown.Here,we pinpoint GRB10 specificity in muscle tissue and cells between obese and lean pigs by combining genomics,transcriptomics,epigenomics,and single-cell transcriptomics.GRB10 shows notable differences in divergent selection on haplotype blocks and expression levels between obese and lean pig breeds,with its expression profiles varying significantly by tissue and development stage.Notably,we identify a muscle-specific promoter of GRB10 and its transcription factor KLF15.This TF-promoter binding is verified by dual luciferase and chromatin immunoprecipitation(Ch IP)assays,and is suggested to be conserved in humans.Single-nucleus RNA sequencing further highlights differential expression patterns of GRB10 between obese and lean pig breeds across various cell types.Type IIa myonuclei and TTN+FAPs,which are more predominant in lean pigs,play a crucial role in myofibril assembly and muscle tissue development.These findings offer insights into the regulatory mechanisms controlling muscle growth.They highlight the tissue-and cell type-specific effects of GRB10 on muscle heterogeneity,which has potential applications in livestock breeding and human obesity research.展开更多
Background Retroviral vectors have been widely used to introduce foreign into various target cells in vitro,thus showing relatively high systemic delivery efficiency of various transgene products. The authors investig...Background Retroviral vectors have been widely used to introduce foreign into various target cells in vitro,thus showing relatively high systemic delivery efficiency of various transgene products. The authors investigated the stability and efficiency of skeletal muscle-specific hybrid retroviral vectors in expression of human factor IX (FIX) in vitro and iv vivo. Methods FIX cDNA in LIXSN vector was replaced with a FIX minigene containing splicing donor and splicing acceptor sequence of first intron of human FIX gene. Two copies of muscle creatine kinase enhancer (MCK,Me2) were inserted in forward or reverse orientation at NheI site of 3’ long terminal repeat (LTR),resulting in two hybrid vectors,which were designated as LMe2IXm_2SN(F) and LMe2IXm_2SN(R),respectively. The vectors were tested in vitro and in vivo for stability and muscle-specificity of factor IX expression with SCID mice. Results Muscle cells carrying vector with Me2 expressed significantly higher levels of FIX (up to 1800 ng/106.24h) than those without Me2, thus suggesting that Me2 could specifically increase expression level of FIX in muscle cells. Myoblasts transduced with LMe2IXm_2SN(R) produced much less FIX in vivo in SCID mice than LMe2IXm_2SN(F). One or two copies of Me2 sequence were deleted in myoblasts transduced with LMe2IXm2SN(R) without changing the orientation of Me2. Conclusions LTR inserted with MCK enhancers can specifically increase human FIX expression in skeletal muscle cells in vitro and in vivo,and MCK enhancer should be positioned in the same orientation as that of LTR promoter.展开更多
Introduction Different autoimmune conditions have been described in human immunodeficiency virus(HIV)patients on antiretroviral therapy(ART),but muscle-specific kinase(MuSK)myasthenia gravis(MG)coexisting with HIV is ...Introduction Different autoimmune conditions have been described in human immunodeficiency virus(HIV)patients on antiretroviral therapy(ART),but muscle-specific kinase(MuSK)myasthenia gravis(MG)coexisting with HIV is rare.We report a case of a Chinese patient with an asymptomatic HIV infection who presented with newly-onset MuSK MG and was managed successfully with the acetylcholinesterase inhibitor pyridostigmine.展开更多
文摘Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in their serum, targeting acetylcholine receptor, muscle-specific kinase, or related proteins. Current treatment for myasthenia gravis involves symptomatic therapy, immunosuppressive drugs such as corticosteroids, azathioprine, and mycophenolate mofetil, and thymectomy, which is primarily indicated in patients with thymoma or thymic hyperplasia. However, this condition continues to pose significant challenges including an unpredictable and variable disease progression, differing response to individual therapies, and substantial longterm side effects associated with standard treatments(including an increased risk of infections, osteoporosis, and diabetes), underscoring the necessity for a more personalized approach to treatment. Furthermore, about fifteen percent of patients, called “refractory myasthenia gravis patients”, do not respond adequately to standard therapies. In this context, the introduction of molecular therapies has marked a significant advance in myasthenia gravis management. Advances in understanding myasthenia gravis pathogenesis, especially the role of pathogenic antibodies, have driven the development of these biological drugs, which offer more selective, rapid, and safer alternatives to traditional immunosuppressants. This review aims to provide a comprehensive overview of emerging therapeutic strategies targeting specific immune pathways in myasthenia gravis, with a particular focus on preclinical evidence, therapeutic rationale, and clinical translation of B-cell depletion therapies, neonatal Fc receptor inhibitors, and complement inhibitors.
基金supported by the National Natural Science Foundation of China(32172765)。
文摘Domestic pigs are shaped by artificial and natural selection into obese and lean types that are closely related to muscle tissue.However,the key genes and regulatory mechanisms behind these developments remain largely unknown.Here,we pinpoint GRB10 specificity in muscle tissue and cells between obese and lean pigs by combining genomics,transcriptomics,epigenomics,and single-cell transcriptomics.GRB10 shows notable differences in divergent selection on haplotype blocks and expression levels between obese and lean pig breeds,with its expression profiles varying significantly by tissue and development stage.Notably,we identify a muscle-specific promoter of GRB10 and its transcription factor KLF15.This TF-promoter binding is verified by dual luciferase and chromatin immunoprecipitation(Ch IP)assays,and is suggested to be conserved in humans.Single-nucleus RNA sequencing further highlights differential expression patterns of GRB10 between obese and lean pig breeds across various cell types.Type IIa myonuclei and TTN+FAPs,which are more predominant in lean pigs,play a crucial role in myofibril assembly and muscle tissue development.These findings offer insights into the regulatory mechanisms controlling muscle growth.They highlight the tissue-and cell type-specific effects of GRB10 on muscle heterogeneity,which has potential applications in livestock breeding and human obesity research.
文摘Background Retroviral vectors have been widely used to introduce foreign into various target cells in vitro,thus showing relatively high systemic delivery efficiency of various transgene products. The authors investigated the stability and efficiency of skeletal muscle-specific hybrid retroviral vectors in expression of human factor IX (FIX) in vitro and iv vivo. Methods FIX cDNA in LIXSN vector was replaced with a FIX minigene containing splicing donor and splicing acceptor sequence of first intron of human FIX gene. Two copies of muscle creatine kinase enhancer (MCK,Me2) were inserted in forward or reverse orientation at NheI site of 3’ long terminal repeat (LTR),resulting in two hybrid vectors,which were designated as LMe2IXm_2SN(F) and LMe2IXm_2SN(R),respectively. The vectors were tested in vitro and in vivo for stability and muscle-specificity of factor IX expression with SCID mice. Results Muscle cells carrying vector with Me2 expressed significantly higher levels of FIX (up to 1800 ng/106.24h) than those without Me2, thus suggesting that Me2 could specifically increase expression level of FIX in muscle cells. Myoblasts transduced with LMe2IXm_2SN(R) produced much less FIX in vivo in SCID mice than LMe2IXm_2SN(F). One or two copies of Me2 sequence were deleted in myoblasts transduced with LMe2IXm2SN(R) without changing the orientation of Me2. Conclusions LTR inserted with MCK enhancers can specifically increase human FIX expression in skeletal muscle cells in vitro and in vivo,and MCK enhancer should be positioned in the same orientation as that of LTR promoter.
基金This study was supported by the Natural Science Foundation of China(81500491)the National Science Foundation of China(Key Program,2017ZX10202102,2018ZX10715014).
文摘Introduction Different autoimmune conditions have been described in human immunodeficiency virus(HIV)patients on antiretroviral therapy(ART),but muscle-specific kinase(MuSK)myasthenia gravis(MG)coexisting with HIV is rare.We report a case of a Chinese patient with an asymptomatic HIV infection who presented with newly-onset MuSK MG and was managed successfully with the acetylcholinesterase inhibitor pyridostigmine.
