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1.
Proc Natl Acad Sci U S A ; 121(39): e2408324121, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39288173

RESUMO

Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism.


Assuntos
Miastenia Gravis , Junção Neuromuscular , Receptores Proteína Tirosina Quinases , Receptores Colinérgicos , Animais , Receptores Proteína Tirosina Quinases/imunologia , Receptores Proteína Tirosina Quinases/metabolismo , Camundongos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/imunologia , Receptores Colinérgicos/imunologia , Receptores Colinérgicos/metabolismo , Miastenia Gravis/imunologia , Miastenia Gravis/tratamento farmacológico , Humanos , Proteínas Relacionadas a Receptor de LDL/imunologia , Autoanticorpos/imunologia , Feminino , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Anticorpos/imunologia , Anticorpos/farmacologia , Modelos Animais de Doenças , Ácidos Graxos Monoinsaturados
2.
Eur J Immunol ; : e2451268, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39285833

RESUMO

Follicular helper (Tfh), peripheral helper (Tph), and regulatory (Treg) T cells are involved in myasthenia gravis (MG) pathogenesis, an autoimmune disorder arising from autoantibodies targeting neuromuscular junction proteins. This study explores the impact of low-dose IL-2 on Tfh, Tph, and Treg cells in vitro in MG. Acetylcholine-receptor antibody-positive MG (AChR-MG), muscle-specific kinase antibody-positive MG (MuSK-MG) patients, and healthy controls (HC) were studied. Blood cells were cultured with/without IL-2 and compared by the ratios of IL-2 stimulated/unstimulated cultures. In both AChR-MG and MuSK-MG patients, CD25+FoxP3+Tregs were lower, while CXCR5+PD-1+ or ICOS+Tfh and CXCR5-PD-1+ or ICOS+Tph cells were higher compared with HC. Among the MG group, the FoxP3+ Treg cells in AChR-MG patients were even lower compared with MuSK-MG patients. In vitro IL-2 stimulation increased Tregs in all groups while decreasing PD-1+/ICOS+Tfh and PD-1+/ICOS+Tph populations. The fold-increase ratio of Tregs and the fold-decrease ratio of PD-1+ or ICOS+Tfh and ICOS+Tph cells in AChR-MG and MuSK-MG patients were greater than in HCs. Low-dose IL-2 treatment may balance Tfh, Tph, and Treg cells in MG patients, offering a potential opportunity for disease modulation.

3.
Hum Genomics ; 18(1): 43, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38659056

RESUMO

OBJECTIVE: Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits from novel biological agents. We performed a drug-targeted Mendelian randomization (MR) study to identify novel therapeutic targets of MG. METHODS: Cis-expression quantitative loci (cis-eQTL), which proxy expression levels for 2176 druggable genes, were used for MR analysis. Causal relationships between genes and disease, identified by eQTL MR analysis, were verified by comprehensive sensitivity, colocalization, and protein quantitative loci (pQTL) MR analyses. The protein-protein interaction (PPI) analysis was also performed to extend targets, followed by enzyme-linked immunosorbent assay (ELISA) to explore the serum level of drug targets in MG patients. A phenome-wide MR analysis was then performed to assess side effects with a clinical trial review assessing druggability. RESULTS: The eQTL MR analysis has identified eight potential targets for MG, one for early-onset MG and seven for late-onset MG. Further colocalization analyses indicated that CD226, CDC42BPB, PRSS36, and TNFSF12 possess evidence for colocalization with MG or late-onset MG. pQTL MR analyses identified the causal relations of TNFSF12 and CD226 with MG and late-onset MG. Furthermore, PPI analysis has revealed the protein interaction between TNFSF12-TNFSF13(APRIL) and TNFSF12-TNFSF13B(BLyS). Elevated TNFSF13 serum level of MG patients was also identified by ELISA experiments. This study has ultimately proposed three promising therapeutic targets (TNFSF12, TNFSF13, TNFSF13B) of MG. CONCLUSIONS: Three drug targets associated with the BLyS/APRIL pathway have been identified. Multiple biological agents, including telitacicept and belimumab, are promising for MG therapy.


Assuntos
Análise da Randomização Mendeliana , Miastenia Gravis , Locos de Características Quantitativas , Humanos , Miastenia Gravis/genética , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/patologia , Miastenia Gravis/sangue , Locos de Características Quantitativas/genética , Mapas de Interação de Proteínas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética
4.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35074870

RESUMO

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.


Assuntos
Predisposição Genética para Doença/genética , Miastenia Gravis/genética , Polimorfismo Genético/genética , Transdução de Sinais/genética , Adulto , Feminino , Expressão Gênica/genética , Frequência do Gene/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Músculo Esquelético/patologia , Receptores Colinérgicos/genética , Receptores Nicotínicos/genética
5.
J Neurochem ; 168(9): 2751-2761, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38822659

RESUMO

The relationship between peripheral inflammatory markers, their dynamic changes, and the disease severity of myasthenia gravis (MG) is still not fully understood. Besides, the possibility of using it to predict the short-term poor outcome of MG patients have not been demonstrated. This study aims to investigate the relationship between peripheral inflammatory markers and their dynamic changes with Myasthenia Gravis Foundation of America (MGFA) classification (primary outcome) and predict the short-term poor outcome (secondary outcome) in MG patients. The study retrospectively enrolled 154 MG patients from June 2016 to December 2021. The logistic regression was used to investigate the relationship of inflammatory markers with MGFA classification and determine the factors for model construction presented in a nomogram. Finally, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were utilized to evaluate the incremental capacity. Logistic regression revealed significant associations between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), aggregate index of systemic inflammation (AISI) and MGFA classification (p = 0.013, p = 0.032, p = 0.017, respectively). Incorporating dynamic changes of inflammatory markers into multivariable models improved their discriminatory capacity of disease severity, with significant improvements observed for NLR, systemic immune-inflammation index (SII) and AISI in NRI and IDI. Additionally, AISI was statistically associated with short-term poor outcome and a prediction model incorporating dynamic changes of inflammatory markers was constructed with the area under curve (AUC) of 0.953, presented in a nomograph. The inflammatory markers demonstrate significant associations with disease severity and AISI could be regarded as a possible and easily available predictive biomarker for short-term poor outcome in MG patients.


Assuntos
Biomarcadores , Inflamação , Miastenia Gravis , Índice de Gravidade de Doença , Humanos , Miastenia Gravis/sangue , Miastenia Gravis/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Adulto , Estudos Retrospectivos , Inflamação/sangue , Neutrófilos/metabolismo , Idoso , Prognóstico
6.
J Neurochem ; 168(3): 224-237, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38214332

RESUMO

Serum amyloid A (SAA) is a clinically useful inflammatory marker involved in the pathogenesis of autoimmune diseases. This study aimed to explore the SAA levels in a cohort of patients with myasthenia gravis (MG) in relation to disease-related clinical parameters and myasthenic crisis (MC) and elucidate the effects of SAA on immune response. A total of 82 MG patients including 50 new-onset MG patients and 32 MC patients were enrolled in this study. Baseline data and laboratory parameters of all enrolled MG patients were routinely recorded through electronic medical systems. SAA levels were measured by enzyme-linked immunosorbent assay (ELISA) kit. CD4+ T and CD19+ B cell subsets were analyzed by flow cytometry. In vitro, human recombinant SAA (Apo-SAA) was applied to stimulate peripheral blood mononuclear cells (PBMCs) from MG patients to observe the effect on T and B cell differentiation. Our results indicated that SAA levels in new-onset MG patients were higher than those in controls and were positively correlated with QMG score, MGFA classification, plasmablast cells, IL-6, and IL-17 levels. Subgroup analysis revealed that SAA levels were increased in generalized MG (GMG) patients than in ocular MG (OMG), as well as elevated in late-onset MG (LOMG) than in early-onset MG (EOMG) and higher in MGFA III/IV compared with MGFA I/II. The ROC curve demonstrated that SAA showed good diagnostic value for MC, especially when combined with NLR. In vitro, Apo-SAA promoted the Th1 cells, Th17 cells, plasmablast cells, and plasma cells differentiation in MG PBMCs. The present findings suggested that SAA was increased in MG patients and promoted expansion of CD4+ T cell and CD19+ B cell subsets, which implicated in the severity of MG patients.


Assuntos
Subpopulações de Linfócitos B , Miastenia Gravis , Humanos , Leucócitos Mononucleares , Miastenia Gravis/diagnóstico , Proteína Amiloide A Sérica , Células Th1
7.
Eur J Neurosci ; 59(12): 3292-3308, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38650308

RESUMO

Muscle-specific kinase myasthenia gravis (MuSK MG) is caused by autoantibodies against MuSK in the neuromuscular junction (NMJ). MuSK MG patients have fluctuating, fatigable skeletal muscle weakness, in particular of bulbar muscles. Severity differs greatly between patients, in spite of comparable autoantibody levels. One explanation for inter-patient and inter-muscle variability in sensitivity might be variations in compensatory muscle responses. Previously, we developed a passive transfer mouse model for MuSK MG. In preliminary ex vivo experiments, we observed that muscle contraction of some mice, in particular those with milder myasthenia, had become partially insensitive to inhibition by µ-Conotoxin-GIIIB, a blocker of skeletal muscle NaV1.4 voltage-gated sodium channels. We hypothesised that changes in NaV channel expression profile, possibly co-expression of (µ-Conotoxin-GIIIB insensitive) NaV1.5 type channels, might lower the muscle fibre's firing threshold and facilitate neuromuscular synaptic transmission. To test this hypothesis, we here performed passive transfer in immuno-compromised mice, using 'high', 'intermediate' and 'low' dosing regimens of purified MuSK MG patient IgG4. We compared myasthenia levels, µ-Conotoxin-GIIIB resistance and muscle fibre action potential characteristics and firing thresholds. High- and intermediate-dosed mice showed clear, progressive myasthenia, not seen in low-dosed animals. However, diaphragm NMJ electrophysiology demonstrated almost equal myasthenic severities amongst all regimens. Nonetheless, low-dosed mouse diaphragms showed a much higher degree of µ-Conotoxin-GIIIB resistance. This was not explained by upregulation of Scn5a (the NaV1.5 gene), lowered muscle fibre firing thresholds or histologically detectable upregulated NaV1.5 channels. It remains to be established which factors are responsible for the observed µ-Conotoxin-GIIIB insensitivity and whether the NaV repertoire change is compensatory beneficial or a bystander effect.


Assuntos
Músculo Esquelético , Animais , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/metabolismo , Humanos , Miastenia Gravis/metabolismo , Miastenia Gravis/fisiopatologia , Miastenia Gravis/imunologia , Modelos Animais de Doenças , Feminino , Receptores Colinérgicos/metabolismo , Receptores Colinérgicos/imunologia , Canais de Sódio Disparados por Voltagem/metabolismo , Junção Neuromuscular/metabolismo , Junção Neuromuscular/efeitos dos fármacos , Autoanticorpos , Masculino , Conotoxinas/farmacologia , Imunização Passiva
8.
Clin Immunol ; 260: 109810, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37949200

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) and myasthenia gravis (MG) are autoimmune diseases. Previous case reports and case series suggest an association may exist between these diseases, as well as an increased risk of SLE after thymectomy for MG. We undertook this study to determine whether SLE and MG were associated in large cohorts. METHODS: We searched the IBM Watson Health Explorys platform and the Department of Veterans Affairs Million Veteran Program (MVP) database for diagnoses of SLE and MG. In addition, we examined subjects enrolled in the Lupus Family Registry and Repository (LFRR) as well as controls for a diagnosis of MG. RESULTS: Among 59,780,210 individuals captured in Explorys, there were 25,750 with MG and 65,370 with SLE. 370 subjects had both. Those with MG were >10 times more likely to have SLE than those without MG. Those with both diseases were more likely to be women, African American, and at a younger age than MG subjects without SLE. In addition, the MG patients who underwent thymectomy had an increased risk of SLE compared to MG patients who had not undergone thymectomy (OR 3.11, 95% CI: 2.12 to 4.55). Autoimmune diseases such as pernicious anemia and miscellaneous comorbidities such as chronic kidney disease were significantly more common in MG patients who developed SLE. In the MVP, SLE and MG were also significantly associated. Association of SLE and MG in a large SLE cohort with rigorous SLE classification confirmed the association of SLE with MG at a similar level. CONCLUSION: While the number of patients with both MG and SLE is small, SLE and MG are strongly associated together in very large databases and a large SLE cohort.


Assuntos
Lúpus Eritematoso Sistêmico , Miastenia Gravis , Feminino , Humanos , Masculino , Lúpus Eritematoso Sistêmico/complicações , Miastenia Gravis/epidemiologia , Miastenia Gravis/diagnóstico , Timectomia
9.
Immunol Cell Biol ; 2024 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-39396830

RESUMO

Myasthenia gravis (MG) is the most frequent immune-mediated neurological disorder, characterized by fluctuating muscle weakness. Specific recognition of self-antigens by T-cell receptors (TCRs) and B-cell receptors (BCRs), coupled with T-B cell interactions, activates B cells to produce autoantibodies, which are critical for the initiation and perpetuation of MG. The immune repertoire comprises all functionally diverse T and B cells at a specific time point in an individual, reflecting the essence of immune selectivity. By sequencing the nucleotide sequences of TCRs and BCRs, it is possible to track individual T- and B-cell clones. This review delves into the generation of autoreactive TCRs and BCRs in MG and comprehensively examines the applications of immune repertoire sequencing in understanding disease pathogenesis, developing diagnostic and prognostic markers and informing targeted therapies. We also discuss the current limitations and future potential of this approach.

10.
J Neuroinflammation ; 21(1): 126, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734662

RESUMO

Myasthenia gravis (MG) is an immune-mediated disease frequently associated with thymic changes. Increased T helper 17 (Th17) cell activity and dysfunctional regulatory T (Treg) cells have been demonstrated in subgroups of MG. On the other hand, hypoxia-inducible factor 1 (HIF-1) has been shown to regulate the Th17/Treg balance by inducing Th17 differentiation while attenuating Treg development. To identify the underlying mechanisms of different thymic pathologies in MG development, we evaluated thymic samples from thymoma-associated myasthenia gravis (TAMG), MG with hyperplasia (TFH-MG) and thymoma without MG (TOMA) patients. Differential gene expression analysis revealed that TAMG and TFH-MG cells are associated with different functional pathways. A higher RORC/FOXP3 ratio provided evidence for Th17/Treg imbalance in TAMG potentially related to increased HIF1A. The hypoxic microenvironment in thymoma may be a driver of TAMG by increasing HIF1A. These findings may lead to new therapeutic approaches targeting HIF1A in the development of TAMG.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Miastenia Gravis , Células Th17 , Timoma , Feminino , Humanos , Masculino , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Miastenia Gravis/genética , Miastenia Gravis/imunologia , Miastenia Gravis/patologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/metabolismo , Células Th17/imunologia , Timoma/complicações , Timoma/genética , Timoma/imunologia , Timo/patologia , Neoplasias do Timo/complicações , Neoplasias do Timo/genética
11.
J Neuroinflammation ; 21(1): 197, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39113081

RESUMO

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. The evidence suggests that the regulation of long noncoding RNAs (lncRNAs) that is mediated by transcription factors (TFs) plays a key role in the pathophysiology of MG. Nevertheless, the detailed molecular mechanisms of lncRNAs in MG remain largely undetermined. METHODS: Using microarray analysis, we analyzed the lncRNA levels in MG. By bioinformatics analysis, LINC01566 was found to potentially play an important role in MG. First, qRT‒PCR was performed to verify the LINC1566 expressions in MG patients. Then, fluorescence in situ hybridization was conducted to determine the localization of LINC01566 in CD4 + T cells. Finally, the impact of LINC01566 knockdown or overexpression on CD4 + T-cell function was also analyzed using flow cytometry and CCK-8 assay. A dual-luciferase reporter assay was used to validate the binding of the TF FOSL1 to the LINC01566 promoter. RESULTS: Based on the lncRNA microarray and differential expression analyses, we identified 563 differentially expressed (DE) lncRNAs, 450 DE mRNAs and 19 DE TFs in MG. We then constructed a lncRNA-TF-mRNA network. Through network analysis, we found that LINC01566 may play a crucial role in MG by regulating T-cell-related pathways. Further experiments indicated that LINC01566 is expressed at low levels in MG patients. Functionally, LINC01566 is primarily distributed in the nucleus and can facilitate CD4 + T-cell apoptosis and inhibit cell proliferation. Mechanistically, we hypothesized that LINC01566 may negatively regulate the expressions of DUSP3, CCR2, FADD, SIRPB1, LGALS3 and SIRPB1, which are involved in the T-cell activation pathway, to further influence the cellular proliferation and apoptosis in MG. Moreover, we found that the effect of LINC01566 on CD4 + T cells in MG was mediated by the TF FOSL1, and in vitro experiments indicated that FOSL1 can bind to the promoter region of LINC01566. CONCLUSIONS: In summary, our research revealed the protective roles of LINC01566 in clinical samples and cellular experiments, illustrating the potential roles and mechanism by which FOSL1/LINC01566 negatively regulates CD4 + T-cell activation in MG.


Assuntos
Linfócitos T CD4-Positivos , Ativação Linfocitária , Miastenia Gravis , Proteínas Proto-Oncogênicas c-fos , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Miastenia Gravis/metabolismo , Miastenia Gravis/imunologia , Miastenia Gravis/genética , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Adulto
12.
J Neuroinflammation ; 21(1): 10, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178152

RESUMO

Myasthenia gravis is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. However, some patients also experience autonomic dysfunction, anxiety, depression, and other neurological symptoms, suggesting the complex nature of the neurological manifestations. With the aim of explaining the symptoms related to the central nervous system, we utilized a rat model to investigate the impact of dopamine signaling in the central nervous and peripheral circulation. We adopted several screening methods, including western blot, quantitative PCR, mass spectrum technique, immunohistochemistry, immunofluorescence staining, and flow cytometry. In this study, we observed increased and activated dopamine signaling in both the central nervous system and peripheral circulation of myasthenia gravis rats. Furthermore, changes in the expression of two key molecules, Claudin5 and CD31, in endothelial cells of the blood-brain barrier were also examined in these rats. We also confirmed that dopamine incubation reduced the expression of ZO1, Claudin5, and CD31 in endothelial cells by inhibiting the Wnt/ß-catenin signaling pathway. Overall, this study provides novel evidence suggesting that pathologically elevated dopamine in both the central nervous and peripheral circulation of myasthenia gravis rats impair brain-blood barrier integrity by inhibiting junction protein expression in brain microvascular endothelial cells through the Wnt/ß-catenin pathway.


Assuntos
Dopamina , Miastenia Gravis , Humanos , Ratos , Animais , Dopamina/metabolismo , Células Endoteliais/metabolismo , Encéfalo , Barreira Hematoencefálica/metabolismo , Via de Sinalização Wnt/fisiologia , Miastenia Gravis/metabolismo
13.
J Transl Med ; 22(1): 183, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378668

RESUMO

BACKGROUND: Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4+ T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8+ T cells also play a critical role in the pathogenesis and treatment of MG. MAIN BODY: Herein, we review the literature on CD8+ T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3+CD8+CD20+ T, and CXCR5+ CD8+ T cells. CONCLUSIONS: Further studies on CD8+ T cells in MG are necessary to determine, among others, the real pattern of the Vß gene usage of autoantigen-specific CD8+ cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8+ cells from MG/EAMG, and the subset of autoantigen-specific CD8+ cells (Tc1, Tc17, and IL-17+IFN-γ+CD8+ T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5+ CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.


Assuntos
Linfócitos T CD8-Positivos , Miastenia Gravis Autoimune Experimental , Animais , Humanos , Linfócitos T Auxiliares-Indutores/metabolismo , Miastenia Gravis Autoimune Experimental/metabolismo , Linfócitos T Reguladores , Autoantígenos/metabolismo
14.
J Transl Med ; 22(1): 955, 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39434135

RESUMO

Numerous clinical trials for myasthenia gravis (MG) treatment have been conducted recently, with satisfactory cognitive and clinical results. However, due to the limited evidence for direct comparison of the safety and effectiveness of various drugs, there is a need for further exploration of the advantages and disadvantages of different monoclonal antibodies and immunosuppressants. Thus, in the present network meta-analysis (NMA), we aimed to compare the efficacy and safety of immunosuppressants and monoclonal antibodies in treating MG. We systematically searched for randomized controlled trials published in PubMed, Embase, Web of Science, and the Cochrane Library between January 1, 2000 and March 6, 2024. Statistical analyses were performed using R software (version 4.2.3), JAGS, and STATA (version 15.0). The surface under the cumulative ranking curve (SUCRA) value was calculated to assess the potential efficacy of each drug and the likelihood of adverse events (AEs), with higher SUCRA values indicating better efficacy or a lower likelihood of AEs. This NMA included 21 randomized controlled trials involving 13 drugs and 1,657 patients. Based on changes in Quantitative MG and MG Composite scores, batoclimab was most likely to exert the best therapeutic effects, with SUCRA values of 99% and 92%, respectively. Rozanolixzumab performed better than the other drugs in terms of the MG Activities of Daily Living score (85%). Eculizumab exhibited the highest potential in reducing the 15-item revised version of the MG Quality of Life score (96%). Regarding safety, belimumab had the highest SUCRA value (85%), demonstrating the lowest likelihood of AEs. In conclusion, all immunosuppressants and monoclonal antibodies analyzed in this study were more effective than the placebo in treating MG, with rozanolixzumab and batoclimab potentially being the most effective. Regarding safety, rozanolixzumab exhibited a higher likelihood of AEs than did placebo. The conclusions guide the clinical selection of effective drugs and offer insights for future drug experiments.


Assuntos
Anticorpos Monoclonais , Imunossupressores , Miastenia Gravis , Metanálise em Rede , Humanos , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/imunologia , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Resultado do Tratamento , Adulto , Ensaios Clínicos Controlados Aleatórios como Assunto , Viés de Publicação
15.
J Transl Med ; 22(1): 302, 2024 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-38521921

RESUMO

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG. METHODS: By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk. RESULTS: We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in TH2 cells and MG risk. CONCLUSIONS: This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.


Assuntos
Predisposição Genética para Doença , Miastenia Gravis , Humanos , Multiômica , Estudo de Associação Genômica Ampla , Miastenia Gravis/genética , Locos de Características Quantitativas/genética , Polimorfismo de Nucleotídeo Único/genética
16.
HIV Med ; 25(3): 398-403, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37990629

RESUMO

BACKGROUND: Comorbidity of Myasthenia gravis (MG) and Graves' disease (GD) in treated HIV-infected individuals has rarely been described and little study has been done on the link between HIV-related immune reconstitution and autoimmune diseases occurring post antiretroviral therapy. CASE PRESENTATION: Here we report on a 33-year-old Chinese man with HIV infection who had been virologically suppressed since 2018. The patient was diagnosed with GD and was treated in 2020. Early in 2022, he developed fluctuating weakness and fatigue involving the bilateral extraocular muscles and limbs. With a positive neostigmine test, he was considered to have MG, but showed a poor response to oral medication. After multiple failed medication attempts, a thymectomy was finally performed to resolve his symptoms. The consecutive onset of immunological events may have partially resulted from immune reconstitution after viral control. CONCLUSIONS: This is a rare case of HIV-related immune reconstitution-associated autoimmune disease (IRAD) with comorbidity of MG and GD which was reported initially. Cooperation with multidisciplinary teams is essential to avoid misdiagnosis and to promote the overall health of HIV-infected patients.


Assuntos
Doença de Graves , Infecções por HIV , Síndrome Inflamatória da Reconstituição Imune , Reconstituição Imune , Miastenia Gravis , Masculino , Humanos , Adulto , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Miastenia Gravis/complicações , Miastenia Gravis/tratamento farmacológico , Doença de Graves/complicações , Doença de Graves/tratamento farmacológico , Comorbidade
17.
Cytokine ; 175: 156485, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38159470

RESUMO

OBJECTIVE: To explore the relationship between macrophage migration inhibitory factor (MIF) and disease severity and relapse in patients with myasthenia gravis (MG). METHODS: 145 MG patients including 79 new-onset patients, 30 remission patients and 36 relapse patients were enrolled in this study. The detailed characteristics of all enrolled MG patients were routinely recorded, including gender, age, type, MGFA classification, antibody, thymic status, clinical score, treatment, MGFA-PIS and B cell subsets (memory B cells, plasmablast cells and plasma cells) detected by flow cytometry. Serum MIF levels were measured by enzyme-linked immunosorbent assay (ELISA) kit. The correlation of MIF levels with clinical subtypes, disease severity and B cell subsets were investigated. Moreover, logistic regression analysis was applied to assess the factors affecting relapse of generalized MG (GMG). RESULTS: Serum MIF levels were higher in new-onset MG patients than those in controls and were positively associated with QMG score, MGFA classification and memory B cells. Subgroup analysis revealed that MIF levels were increased in GMG patients than in ocular MG (OMG), as well as elevated in MGFA III/IV compared with MGFA I/II. With the remission of the disease, the expression of serum MIF decreased. The multivariate logistic regression models indicated that high MIF and thymoma was a risk factor for relapse of GMG, and rituximab could prevent disease relapse. CONCLUSIONS: MIF can be used as a novel biomarker to reflect disease severity and predict disease relapse in MG patients.


Assuntos
Miastenia Gravis , Recidiva Local de Neoplasia , Humanos , Anticorpos , Doença Crônica , Macrófagos , Miastenia Gravis/complicações , Gravidade do Paciente
18.
Acta Neuropathol ; 147(1): 15, 2024 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-38214778

RESUMO

Histopathological analysis stands as the gold standard for the identification and differentiation of inflammatory neuromuscular diseases. These disorders continue to constitute a diagnostic challenge due to their clinical heterogeneity, rarity and overlapping features. To establish standardized protocols for the diagnosis of inflammatory neuromuscular diseases, the development of cost-effective and widely applicable tools is crucial, especially in settings constrained by limited resources. The focus of this review is to emphasize the diagnostic value of major histocompatibility complex (MHC) and complement patterns in the immunohistochemical analysis of these diseases. We explore the immunological background of MHC and complement signatures that characterize inflammatory features, with a specific focus on idiopathic inflammatory myopathies. With this approach, we aim to provide a diagnostic algorithm that may improve and simplify the diagnostic workup based on a limited panel of stainings. Our approach acknowledges the current limitations in the field of inflammatory neuromuscular diseases, particularly the scarcity of large-scale, prospective studies that validate the diagnostic potential of these markers. Further efforts are needed to establish a consensus on the diagnostic protocol to effectively distinguish these diseases.


Assuntos
Miosite , Doenças Neuromusculares , Humanos , Estudos Prospectivos , Doenças Neuromusculares/diagnóstico , Complexo Principal de Histocompatibilidade , Antígenos de Histocompatibilidade Classe I/análise
19.
Acta Neuropathol ; 147(1): 102, 2024 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-38888758

RESUMO

Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice.


Assuntos
Biomarcadores , Miastenia Gravis , Proteínas Secretadas Inibidoras de Proteinases , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Autoanticorpos/sangue , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Coortes , Aprendizado de Máquina , Miastenia Gravis/sangue , Miastenia Gravis/diagnóstico , Miastenia Gravis/patologia , Proteínas Secretadas Inibidoras de Proteinases/sangue , Proteômica , Receptores Colinérgicos/metabolismo
20.
Scand J Immunol ; 99(5): e13360, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38605547

RESUMO

Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. Semaphorin 4A (Sema4A) is involved in the activation of T cells in various inflammatory disorders. In this study, we aimed to investigate whether Sema4A is involved in the pathogenesis of MG. We measured serum Sema4A concentrations in 30 treatment-naïve MG patients with acetylcholine receptor (AChR) antibodies, 7 with muscle-specific tyrosine kinase (MuSK) antibodies and 21 normal controls. As a result, serum Sema4A levels were significantly higher in patients with AChR antibody-positive MG and MuSK antibody-positive MG than in controls (p ≤ 0.0001 for both MG groups). Serum Sema4A levels were correlated with AChR antibody levels (Spearman's ρ = 0.39, p = 0.03) and MG Foundation of America clinical classification classes (Spearman's ρ = 0.38, p = 0.04) in patients with AChR antibody-positive MG. In conclusion, high serum Sema4A levels may reflect T-cell activation, and this molecule could be a potential marker of disease activity in MG.


Assuntos
Miastenia Gravis , Semaforinas , Humanos , Miastenia Gravis/diagnóstico , Autoanticorpos
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