58 results on '"Fulvio Baggi"'
Search Results
2. Complement Activation Profile in Myasthenia Gravis Patients: Perspectives for Tailoring Anti-Complement Therapy
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Nicola Iacomino, Fiammetta Vanoli, Rita Frangiamore, Marta Ballardini, Letizia Scandiffio, Federica Bortone, Francesca Andreetta, Fulvio Baggi, Pia Bernasconi, Carlo Antozzi, Paola Cavalcante, and Renato Mantegazza
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myasthenia gravis ,autoimmunity ,biomarkers ,complement system ,anti-complement therapy ,Biology (General) ,QH301-705.5 - Abstract
The complement system plays a key role in myasthenia gravis (MG). Anti-complement drugs are emerging as effective therapies to treat anti-acetylcholine receptor (AChR) antibody-positive MG patients, though their usage is still limited by the high costs. Here, we searched for plasma complement proteins as indicators of complement activation status in AChR-MG patients, and potential biomarkers for tailoring anti-complement therapy in MG. Plasma was collected from AChR-MG and MuSK-MG patients, and healthy controls. Multiplex immunoassays and ELISA were used to quantify a panel of complement components (C1Q, C2, C3, C4, C5, Factor B, Factor H, MBL, and properdin) and activation products (C4b, C3b, C5a, and C5b-9), of classical, alternative and lectin pathways. C2 and C5 levels were significantly reduced, and C3, C3b, and C5a increased, in plasma of AChR-MG, but not MuSK-MG, patients compared to controls. This protein profile was indicative of complement activation. We obtained sensitivity and specificity performance results suggesting plasma C2, C3, C3b, and C5 as biomarkers for AChR-MG. Our findings reveal a plasma complement “C2, C3, C5, C3b, and C5a” profile associated with AChR-MG to be further investigated as a biomarker of complement activation status in AChR-MG patients, opening new perspectives for tailoring of anti-complement therapies to improve the disease treatment.
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- 2022
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3. A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146
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Alessandra Consonni, Sapna Sharma, Karin Schön, Cristina Lebrero-Fernández, Elena Rinaldi, Nils Yngve Lycke, and Fulvio Baggi
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tolerance ,adjuvant ,vaccination ,dendritic cells ,myasthenia gravis ,autoimmune disease ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1–T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGFβ, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1–T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1–T146 is a promising candidate for clinical evaluation in myasthenia gravis patients.
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- 2017
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4. Role of autoantibody levels as biomarkers in the management of patients with myasthenia gravis: A systematic review and expert appraisal
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Andreas Meisel, Fulvio Baggi, Anthony Behin, Amelia Evoli, Anna Kostera‐Pruszczyk, Renato Mantegazza, Raul Juntas Morales, Anna Rostedt Punga, Sabrina Sacconi, Michael Schroeter, Jan Verschuuren, Louise Crathorne, Kris Holmes, and Maria‐Isabel Leite
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myasthenia gravis ,Neurology ,Neurologi ,autoantibodies ,Immunoglobulin G ,Activities of Daily Living ,Humans ,biomarkers ,Neurology (clinical) - Abstract
Background and purpose Although myasthenia gravis (MG) is recognized as an immunoglobulin G autoantibody-mediated disease, the relationship between autoantibody levels and disease activity in MG is unclear. We sought to evaluate this landscape through systematically assessing the evidence, testing the impact of predefined variables on any relationship, and augmenting with expert opinion. Methods In October 2020, a forum of leading clinicians and researchers in neurology from across Europe (Expert Forum for Rare Autoantibodies in Neurology in Myasthenia Gravis) participated in a series of virtual meetings that took place alongside the conduct of a systematic literature review (SLR). Results Forty-two studies were identified meeting inclusion criteria. Of these, 10 reported some correlation between a patient's autoantibody level and disease severity. Generally, decreased autoantibody levels (acetylcholine receptor, muscle-specific kinase, and titin) were positively and significantly correlated with improvements in disease severity (Quantitative Myasthenia Gravis score, Myasthenia Gravis Composite score, Myasthenia Gravis Activities of Daily Living score, Myasthenia Gravis Foundation of America classification). Given the limited evidence, testing the impact of predefined variables was not feasible. Conclusions This first SLR to assess whether a correlation exists between autoantibody levels and disease activity in patients with MG has indicated a potential positive correlation, which could have clinical implications in guiding treatment decisions. However, in light of the limited and variable evidence, we cannot currently recommend routine clinical use of autoantibody level testing in this context. For now, patient's characteristics, clinical disease course, and laboratory data (e.g., autoantibody status, thymus histology) should inform management, alongside patient-reported outcomes. We highlight the need for future studies to reach more definitive conclusions on this relationship.
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- 2022
5. 242nd ENMC International Workshop: Diagnosis and management of juvenile myasthenia gravis Hoofddorp, the Netherlands, 1-3 March 2019
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Pinki Munot, Stephanie A. Robb, Erik H. Niks, Jacqueline Palace, Erik Niks, Stephanie Robb, Amelia Evoli, Andrea Klein, Pedro Rodriquez Cruz, Bruno Eymard, Heinz Jungbluth, Corrie Erasmus, Adela Della Marina, Fulvio Baggi, Nancy Kuntz, Malene Børresen, Imelda Hughes, Sithara Ramdas, Monique Ryan, and Matthew Pitt
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Pediatrics ,medicine.medical_specialty ,business.industry ,Juvenile ,Guidelines ,medicine.disease ,Myasthenia gravis ,Settore MED/26 - NEUROLOGIA ,Neurology ,Pediatrics, Perinatology and Child Health ,Myasthenia Gravis ,medicine ,Neurology (clinical) ,business ,Genetics (clinical) - Published
- 2020
6. Toll-like receptors 7 and 9 in myasthenia gravis thymus: amplifiers of autoimmunity?
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Paola Cavalcante, Claudia Barzago, Lorenzo Maggi, Pia Bernasconi, Fulvio Baggi, Carlo Antozzi, and Renato Mantegazza
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0301 basic medicine ,Innate immune system ,business.industry ,General Neuroscience ,TLR9 ,TLR7 ,medicine.disease_cause ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Myasthenia gravis ,Autoimmunity ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,History and Philosophy of Science ,Autoimmune Process ,Immunology ,medicine ,business ,Receptor ,B cell - Abstract
Pathogen infections and dysregulated Toll-like receptor (TLR)-mediated innate immune responses are suspected to play key roles in autoimmunity. Among TLRs, TLR7 and TLR9 have been implicated in several autoimmune conditions, mainly because of their ability to promote abnormal B cell activation and survival. Recently, we provided evidence of Epstein-Barr virus (EBV) persistence and reactivation in the thymus of myasthenia gravis (MG) patients, suggesting an involvement of EBV in the intrathymic pathogenesis of the disease. Considerable data highlight the existence of pathogenic crosstalk among EBV, TLR7, and TLR9: EBV elicits TLR7/9 signaling, which in turn can enhance B cell dysfunction and autoimmunity. In this article, after a brief summary of data demonstrating TLR activation in MG thymus, we provide an overview on the contribution of TLR7 and TLR9 to autoimmune diseases and discuss our recent findings indicating a pivotal role for these two receptors, along with EBV, in driving, perpetuating, and/or amplifying intrathymic B cell dysregulation and autoimmune responses in MG. Development of therapeutic approaches targeting TLR7 and TLR9 signaling could be a novel strategy for treating the chronic inflammatory autoimmune process in myasthenia gravis.
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- 2018
7. Gut microbiota and probiotics: novel immune system modulators in myasthenia gravis?
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Elena Guidesi, Alessandra Consonni, Renato Mantegazza, Elena Rinaldi, Marina Elli, and Fulvio Baggi
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0301 basic medicine ,biology ,General Neuroscience ,Multiple sclerosis ,Gut flora ,medicine.disease ,biology.organism_classification ,Commensalism ,General Biochemistry, Genetics and Molecular Biology ,Myasthenia gravis ,law.invention ,03 medical and health sciences ,Probiotic ,030104 developmental biology ,Immune system ,History and Philosophy of Science ,law ,Immunology ,medicine ,Pathogen ,Dysbiosis - Abstract
Gut microorganisms (microbiota) live in symbiosis with the host and influence human nutrition, metabolism, physiology, and immune development and function. The microbiota prevents pathogen infection to the host, and in turn the host provides a niche for survival. The alteration of gut bacteria composition (dysbiosis) could contribute to the development of immune-mediated diseases by influencing the immune system activation and driving the pro- and anti-inflammatory responses in order to promote or counteract immune reactions. Probiotics are nonpathogenic microorganisms able to interact with the gut microbiota and provide health benefits; their use has recently been exploited to dampen immunological response in several experimental models of autoimmune diseases. Here, we focus on the relationships among commensal bacteria, probiotics, and the gut, describing the main interactions occurring with the immune system and recent data supporting the clinical efficacy of probiotic administration in rheumatoid arthritis, multiple sclerosis, and myasthenia gravis (MG) animal models. The encouraging results suggest that selected strains of probiotics should be evaluated in clinical trials as adjuvant therapy to restore the disrupted tolerance in myasthenia gravis.
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- 2018
8. Epstein-Barr virus in tumor-infiltrating B cells of myasthenia gravis thymoma: an innocent bystander or an autoimmunity mediator?
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Raffaella Ghislandi, Barbara Galbardi, Stefania Marcuzzo, Carlo Antozzi, Pia Bernasconi, Lorenzo Maggi, Teresio Motta, Massimo Barberis, Sara Franzi, Tommaso De Pas, Paola Cavalcante, Luisella Spinelli, Lorenzo Novellino, Fabio Conforti, Antonella Buzzi, Renato Mantegazza, and Fulvio Baggi
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0301 basic medicine ,Thymoma ,medicine.disease_cause ,Virus ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Epstein-Barr virus ,B cell ,myasthenia gravis ,business.industry ,autoimmunity ,thymoma ,medicine.disease ,Epstein–Barr virus ,Myasthenia gravis ,BZLF1 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Lytic cycle ,toll-like receptors ,Immunology ,business ,030217 neurology & neurosurgery ,Research Paper - Abstract
The thymus plays a key role in myasthenia gravis (MG), a B cell-mediated autoimmune disorder affecting neuromuscular junction. Most MG patients have thymic abnormalities, including hyperplasia and thymoma, a neoplasm of thymic epithelial cells. Epstein-Barr virus (EBV) is associated with autoimmune diseases and tumors. Recently, we showed EBV persistence and reactivation in hyperplastic MG thymuses, suggesting that EBV might contribute to intra-thymic B cell dysregulation in MG patients. Here, we investigated EBV involvement in thymoma-associated MG, by searching for EBV markers in MG (n=26) and non-MG (n=14) thymomas. EBV DNA and EBV-encoded small nuclear RNA (EBER) 1 transcript were detected in 14/26 (53.8%) and 22/26 (84.6%) MG thymomas, and only in 3 of 14 (21.4%) non-MG thymomas. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all, but one, thymomas, and early lytic BZLF1 transcript was absent in all samples, suggesting that early infection events and EBV reactivation were very rare in thymomas. EBER1 and 2-positive cells were detected in MG, but not in non-MG, thymomas, as well as cells expressing EBV latency proteins (EBNA1, LMP1, LMP2A), that were mainly of B cell phenotype, indicating EBV association with MG rather than with thymoma. Toll-like receptor (TLR) 3 transcriptional levels were higher in MG than non-MG thymomas and positively correlated with EBER1 levels, suggesting a role for EBERs in TLR3 activation. Our findings show that EBV is commonly present in thymoma-infiltrating B cells of myasthenic patients, indicating a contribution of EBV to B cell-mediated autoreactivity in MG associated with thymic tumor.
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- 2017
9. Validity, reliability, and sensitivity to change of the myasthenia gravis activities of daily living profile in a sample of Italian myasthenic patients
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Matilde Leonardi, Lorenzo Maggi, Renato Mantegazza, Alberto Raggi, Fulvio Baggi, and Carlo Antozzi
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Male ,medicine.medical_specialty ,Activities of daily living ,Correlation coefficient ,Wilcoxon signed-rank test ,Dermatology ,Disability Evaluation ,03 medical and health sciences ,0302 clinical medicine ,Cronbach's alpha ,Rating scale ,Activities of Daily Living ,Myasthenia Gravis ,medicine ,Humans ,Patient Reported Outcome Measures ,030212 general & internal medicine ,Sensitivity to change ,Reliability (statistics) ,Reproducibility of Results ,General Medicine ,Middle Aged ,medicine.disease ,Myasthenia gravis ,Psychiatry and Mental health ,Italy ,Physical therapy ,Female ,Self Report ,Neurology (clinical) ,Psychology ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
The purpose of this study is to report on the validity, reliability, and sensitivity of the myasthenia gravis activities of daily living profile (MG-ADL) in a sample of Italian patients. Patients with myasthenia gravis (MG) completed a protocol that included the MG-ADL, the WHO Disability Assessment Schedule (WHODAS 2.0), the Besta Neurological Institute rating scale for myasthenia gravis, and the MG-composite. Cronbach’s alpha was used to test reliability, Spearman’s correlation and intra-class correlation coefficient (ICC) to test short-term test-retest, Kruskal-Wallis test to assess differences in MG-ADL between patients with different disease severity, and Wilcoxon signed-rank test to assess sensitivity to change. In total, 58 patients were enrolled: 44 were females, mean MG duration 10.5 ± 10.4 years, mean MG-ADL 3.98 ± 3.07. The MG-ADL showed good internal consistency (alpha = .774), stability (test-retest correlation = .98, ICC = .97). It was superior to the WHODAS 2.0 in differentiating patients with different MG type and severity (P
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- 2017
10. A propensity score analysis for comparison of T-3b and VATET in myasthenia gravis
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Cristina Montomoli, Laura Brambilla, Silvia Bonanno, Carlo Antozzi, Confalonieri Paolo, Renato Mantegazza, Fulvio Baggi, Francesca Andreetta, Brenna, G, Antozzi, C, Montomoli, C, Baggi, F, and Mantegazza, R
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Adult ,Male ,Sternum ,medicine.medical_specialty ,medicine.medical_treatment ,Aftercare ,Extended thymectomy ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Myasthenia Gravis ,medicine ,Thoracoscopy ,Humans ,Treatment effect ,In patient ,Propensity Score ,Aged ,Surgical approach ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Middle Aged ,Outcome and Process Assessment (Health Care) ,Thymectomy ,medicine.disease ,Myasthenia gravis ,Myasthenia Gravi ,Surgery ,Outcome and Process Assessment, Health Care ,Propensity score matching ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Human - Abstract
Objective:We performed propensity score (PS) models to compare the outcome of patients with myasthenia gravis (MG) submitted to 2 different surgical approaches: extended transsternal (T-3b) or thoracoscopic extended thymectomy (VATET).Methods:Patients' clinical data were retrieved from the MG database of the C. Besta Neurologic Institute Foundation. In the PS analysis, a matching ratio of 1:1 of the main clinical variables was obtained for the 2 groups of patients and treatment effect was estimated by comparing their outcome.Results:A total of 210 patients met the inclusion criteria, by having a complete set of clinical data, and were included in the PS model; a matched dataset of 122 participants (61 per group) showed an adequate balance of all the covariates. Our analysis demonstrated that 68.9% of patients who had thymectomy by the VATET technique reached the pharmacologic remission/remission status at 2 years from thymectomy compared to 34.4% of those operated on by the T-3b technique (p < 0.001), had a lower INCB-MG score (p < 0.001), and had less muscle fatigability (p = 0.004). Similar results were found considering only nonthymomatous patients with MG. Results were also confirmed by paired statistical tests.Conclusions:Our PS matching analysis showed that VATET is a reliable and effective surgical approach alternative to T-3b in patients with MG who are candidates for thymectomy.Classification of evidence:This study provides Class IV evidence that for patients with MG, VATET is more effective than T-3b thymectomy.
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- 2017
11. Validation of the italian version of the 15‐item Myasthenia Gravis Quality‐of‐Life questionnaire
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Alberto Raggi, Lorenzo Maggi, Carlo Antozzi, Matilde Leonardi, Roberta Ayadi, Renato Mantegazza, and Fulvio Baggi
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Wilcoxon signed-rank test ,SF-36 ,Physiology ,Spearman's rank correlation coefficient ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cronbach's alpha ,Quality of life ,Rating scale ,Surveys and Questionnaires ,Physiology (medical) ,Internal medicine ,Myasthenia Gravis ,medicine ,Humans ,Aged ,business.industry ,Middle Aged ,Translating ,medicine.disease ,Health Surveys ,Myasthenia gravis ,Test (assessment) ,030104 developmental biology ,Italy ,Quality of Life ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Introduction In this study we assess the Italian version of the 15-item Myasthenia Gravis Quality-of-Life questionnaire (MG-QOL15). Methods The validation protocol included the MG-QOL15, the 36-item Short Form (SF-36), the Besta Neurological Institute Rating Scale for Myasthenia Gravis, and the MG-Composite. We used the Cronbach α to test reliability, the Spearman correlation to test short-term test–retest, the Kruskal–Wallis test to assess differences in MG-QOL15 between patients with different disease severity, and the Wilcoxon signed-rank test to assess sensitivity to change. Results Seventy-two patients were enrolled in the study. The mean MG-QOL15 score was 15.2 ± 12.2, with α = 0.93 and test–retest correlation = 0.93. Compared with the SF-36, the MG-QOL15 was superior in differentiating patients with different MG types (P = 0.041) and severity (P = 0.004), showed higher sensitivity to change (P = 0.003 for improved and P = 0.024 for worsened patients), and had higher correlations with the MG-Composite (rho = 0.367 vs. –0.213 and –0.154). Conclusion The Italian version of the MG-QOL15 is valid, reliable, stable, and sensitive to changes. Muscle Nerve 56: 716–720, 2017
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- 2017
12. Increased expression of Toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein–Barr virus infection
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Amelia Biasiucci, Carmelo Giardina, Carlo Antozzi, Claudia Barzago, Silvia Bonanno, Barbara Galbardi, Lorenzo Maggi, Francesca Andreetta, Teresio Motta, Giorgia Camera, Renato Mantegazza, Stefania Marcuzzo, Dimos Kapetis, Pia Bernasconi, Paola Cavalcante, Sara Franzi, Fulvio Baggi, Cavalcante, P, Galbardi, B, Franzi, S, Marcuzzo, S, Barzago, C, Bonanno, S, Camera, G, Maggi, L, Kapetis, D, Andreetta, F, Biasiucci, A, Motta, T, Giardina, C, Antozzi, C, Baggi, F, Mantegazza, R, and Bernasconi, P
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Adult ,Male ,0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Myeloid ,Adolescent ,Immunology ,Myasthenia gravi ,Thymus Gland ,Biology ,Lymphocyte Activation ,03 medical and health sciences ,Antigen ,Interferon ,Myasthenia Gravis ,medicine ,Humans ,Immunology and Allergy ,RNA, Messenger ,Thymu ,Antigens, Viral ,Cell Proliferation ,Autoimmune disease ,B-Lymphocytes ,Innate immune system ,Macrophages ,virus diseases ,TLR9 ,Germinal center ,Toll-like receptor 9 ,Dendritic Cells ,Interferon-beta ,Epstein-Barr viru ,Hematology ,Germinal Center ,medicine.disease ,Myasthenia gravis ,Toll-like receptor 7 ,Ki-67 Antigen ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Female ,Signal Transduction ,medicine.drug - Abstract
Considerable data implicate the thymus as the main site of autosensitization to the acetylcholine receptor in myasthenia gravis (MG), a B-cell-mediated autoimmune disease affecting the neuromuscular junction. We recently demonstrated an active Epstein-Barr virus (EBV) infection in the thymus of MG patients, suggesting that EBV might contribute to the onset or maintenance of the autoimmune response within MG thymus, because of its ability to activate and immortalize autoreactive B cells. EBV has been reported to elicit and modulate Toll-like receptor (TLR) 7- and TLR9-mediated innate immune responses, which are known to favor B-cell dysfunction and autoimmunity. Aim of this study was to investigate whether EBV infection is associated with altered expression of TLR7 and TLR9 in MG thymus. By real-time PCR, we found that TLR7 and TLR9 mRNA levels were significantly higher in EBV-positive MG compared to EBV-negative normal thymuses. By confocal microscopy, high expression levels of TLR7 and TLR9 proteins were observed in B cells and plasma cells of MG thymic germinal centers (GCs) and lymphoid infiltrates, where the two receptors co-localized with EBV antigens. An increased frequency of Ki67-positive proliferating B cells was found in MG thymuses, where we also detected proliferating cells expressing TLR7, TLR9 and EBV antigens, thus supporting the idea that EBV-associated TLR7/9 signaling may promote abnormal B-cell activation and proliferation. Along with B cells and plasma cells, thymic epithelium, plasmacytoid dendritic cells and macrophages exhibited enhanced TLR7 and TLR9 expression in MG thymus; TLR7 was also increased in thymic myeloid dendritic cells and its transcriptional levels positively correlated with those of interferon (IFN)-β. We suggested that TLR7/9 signaling may be involved in antiviral type I IFN production and long-term inflammation in EBV-infected MG thymuses. Our overall findings indicate that EBV-driven TLR7- and TLR9-mediated innate immune responses may participate in the intra-thymic pathogenesis of MG.
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- 2016
13. Validation of the besta neurological institute rating scale for myasthenia gravis
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Greta Brenna, Carlo Antozzi, Renato Mantegazza, Cristina Montomoli, Cristiana Rezzani, Fulvio Baggi, Giorgia Camera, and Lorenzo Maggi
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medicine.medical_specialty ,Scale (ratio) ,Physiology ,Gold standard (test) ,medicine.disease ,Mg composite ,Myasthenia gravis ,Pearson product-moment correlation coefficient ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,symbols.namesake ,0302 clinical medicine ,Cronbach's alpha ,Rating scale ,Physiology (medical) ,medicine ,Physical therapy ,symbols ,030212 general & internal medicine ,Neurology (clinical) ,Psychology ,030217 neurology & neurosurgery ,Reliability (statistics) - Abstract
Introduction: We validated the scale for myasthenia gravis (MG) developed at the Neurological Institute Foundation of Milan (INCB-MG scale). Methods: A total of 174 patients were evaluated with the INCB-MG and compared with the MG Composite (MGC) as the gold standard. Dimensionality, reliability, and validity of the INCB-MG scale were studied by principal component factor analysis, Cronbach alpha, and Pearson correlation coefficients; interobserver reliability was calculated by the weighted Cohen K coefficient. Results: Generalized and bulbar INCB-MG subscales were unidimensional with excellent consistency; the INCB-MG and MGC scales were strongly correlated. Fatigability assessment was correlated with the INCB-MG generalized, bulbar, and respiratory subscales. Conclusions: The INCB-MG scale is a reliable tool to assess MG and is strongly correlated with the MGC. The INCB-MG scale is a valid tool for every day practice and should be further investigated for its application in clinical trials. Muscle Nerve 53: 32–37, 2016
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- 2015
14. Gut microbiota and probiotics: novel immune system modulators in myasthenia gravis?
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Elena, Rinaldi, Alessandra, Consonni, Elena, Guidesi, Marina, Elli, Renato, Mantegazza, and Fulvio, Baggi
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Arthritis, Rheumatoid ,Disease Models, Animal ,Multiple Sclerosis ,Probiotics ,Myasthenia Gravis ,Animals ,Dysbiosis ,Humans ,Immunologic Factors ,Symbiosis ,Gastrointestinal Microbiome - Abstract
Gut microorganisms (microbiota) live in symbiosis with the host and influence human nutrition, metabolism, physiology, and immune development and function. The microbiota prevents pathogen infection to the host, and in turn the host provides a niche for survival. The alteration of gut bacteria composition (dysbiosis) could contribute to the development of immune-mediated diseases by influencing the immune system activation and driving the pro- and anti-inflammatory responses in order to promote or counteract immune reactions. Probiotics are nonpathogenic microorganisms able to interact with the gut microbiota and provide health benefits; their use has recently been exploited to dampen immunological response in several experimental models of autoimmune diseases. Here, we focus on the relationships among commensal bacteria, probiotics, and the gut, describing the main interactions occurring with the immune system and recent data supporting the clinical efficacy of probiotic administration in rheumatoid arthritis, multiple sclerosis, and myasthenia gravis (MG) animal models. The encouraging results suggest that selected strains of probiotics should be evaluated in clinical trials as adjuvant therapy to restore the disrupted tolerance in myasthenia gravis.
- Published
- 2017
15. Administration of bifidobacterium and lactobacillus strains modulates experimental myasthenia gravis and experimental encephalomyelitis in Lewis rats
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Roberta Marolda, Elena Rinaldi, Fulvio Baggi, Alessandra Consonni, Ilaria Ravanelli, Marina Elli, Elena Guidesi, Chiara Cordiglieri, and Renato Mantegazza
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0301 basic medicine ,Encephalomyelitis ,Gut-associated lymphoid tissue ,Immunology ,experimental autoimmune encephalomyelitis ,law.invention ,03 medical and health sciences ,Probiotic ,0302 clinical medicine ,Immune system ,law ,medicine ,experimental autoimmune myasthenia gravis ,Bifidobacterium ,biology ,business.industry ,Experimental autoimmune encephalomyelitis ,Research Paper: Immunology ,medicine.disease ,biology.organism_classification ,Myasthenia gravis ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,probiotics ,business ,030217 neurology & neurosurgery ,Transforming growth factor - Abstract
Probiotics beneficial effects on the host are associated with regulation of the intestinal microbial homeostasis and with modulation of inflammatory immune responses in the gut and in periphery. In this study, we investigated the clinical efficacy of two lactobacillus and two bifidobacterium probiotic strains in experimental autoimmune myasthenia gravis (EAMG) and experimental autoimmune encephalomyelitis (EAE) models, induced in Lewis rats. Treatment with probiotics led to less severe disease manifestation in both models; ex vivo analyses showed preservation of neuromuscular junction in EAMG and myelin content in EAE spinal cord. Immunoregulatory transcripts were found differentially expressed in gut associated lymphoid tissue and in peripheral immunocompetent organs. Feeding EAMG animals with probiotics resulted in increased levels of Transforming Growth Factor-β (TGFβ) in serum, and increased percentages of regulatory T cells (Treg) in peripheral blood leukocyte. Exposure of immature dendritic cells to probiotics induced their maturation toward an immunomodulatory phenotype, and secretion of TGFβ. Our data showed that bifidobacteria and lactobacilli treatment effectively modulates disease symptoms in EAMG and EAE models, and support further investigations to evaluate their use in autoimmune diseases.
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- 2017
16. Diagnostics of myasthenic syndromes: detection of anti-AChR and anti-MuSK antibodies
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Elena Bazzigaluppi, Elena Rinaldi, Alessandro Pini, Francesca Andreetta, Raffella Fazio, Anna Pia Riviera, Emanuela Bartoccioni, Fulvio Baggi, Maria Grazia Giudizi, and Giovanni A. Deiana
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0301 basic medicine ,medicine.medical_specialty ,Dermatology ,AChR ,Laboratory diagnostics ,MuSK ,Myasthenia gravis ,Neurological autoimmune diseases ,03 medical and health sciences ,Anti-MUSK antibodies ,0302 clinical medicine ,Clinical information ,medicine ,Humans ,Receptors, Cholinergic ,Intensive care medicine ,Autoantibodies ,business.industry ,Autoantibody ,Receptor Protein-Tyrosine Kinases ,General Medicine ,medicine.disease ,Psychiatry and Mental health ,030104 developmental biology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Myasthenic syndromes - Abstract
This paper presents the Italian guidelines for autoantibody testing in myasthenia gravis that have been developed following a consensus process built on questionnaire-based surveys, internet contacts and discussions during dedicated workshops of the sponsoring Italian Association of Neuroimmunology (AINI). Essential clinical information on myasthenic syndromes, indications and limits of antibody testing, instructions for result interpretation and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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- 2017
17. Suppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis
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Yanyun Zhang, Rennolds S. Ostrom, Xiaonan Zhao, Congfeng Xu, Xiangjun Chen, Jiefang Huang, Ailian Du, Shuangyan Zhang, Shiqian Huang, Kuan Feng, Fulvio Baggi, and Xiang Miao
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0301 basic medicine ,medicine.medical_specialty ,Biology ,Receptors, Nicotinic ,Neuromuscular junction ,03 medical and health sciences ,Mice ,Postsynaptic potential ,Internal medicine ,medicine ,Autophagy ,Animals ,Molecular Biology ,Cells, Cultured ,Acetylcholine receptor ,Adaptor Proteins, Signal Transducing ,myasthenia gravis ,Chaperone-assisted selective autophagy ,Skeletal muscle ,Muscle weakness ,Cell Biology ,medicine.disease ,Myasthenia gravis ,Carbonic Anhydrase III ,Endocytosis ,Basic Research Paper ,chaperone-assisted selective autophagy ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,carbonic anhydrase 3 ,medicine.symptom ,CHRN, endocytosis ,Carbonic anhydrase 3 ,Apoptosis Regulatory Proteins - Abstract
Myasthenia gravis is an autoimmune disorder of the neuromuscular junction manifested as fatigable muscle weakness, which is typically caused by pathogenic autoantibodies against postsynaptic CHRN/AChR (cholinergic receptor nicotinic) in the endplate of skeletal muscle. Our previous studies have identified CA3 (carbonic anhydrase 3) as a specific protein insufficient in skeletal muscle from myasthenia gravis patients. In this study, we investigated the underlying mechanism of how CA3 insufficiency might contribute to myasthenia gravis. Using an experimental autoimmune myasthenia gravis animal model and the skeletal muscle cell C2C12, we find that inhibition of CAR3 (the mouse homolog of CA3) promotes CHRN internalization via a lipid raft-mediated pathway, leading to accelerated degradation of postsynaptic CHRN. Activation of CAR3 reduces CHRN degradation by suppressing receptor endocytosis. CAR3 exerts this effect by suppressing chaperone-assisted selective autophagy via interaction with BAG3 (BCL2-associated athanogene 3) and by dampening endoplasmic reticulum stress. Collectively, our study illustrates that skeletal muscle cell CAR3 is critical for CHRN homeostasis in the neuromuscular junction, and its deficiency leads to accelerated degradation of CHRN and development of myasthenia gravis, potentially revealing a novel therapeutic approach for this disorder.
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- 2017
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18. Innate immunity in myasthenia gravis thymus: Pathogenic effects of Toll-like receptor 4 signaling on autoimmunity
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Roberta Marolda, Teresio Motta, Sara Franzi, Carmelo Giardina, Paola Cavalcante, Renato Mantegazza, Pia Bernasconi, Cristina Cappelletti, Fulvio Baggi, and Chiara Cordiglieri
- Subjects
Adult ,Male ,Chemokine ,Adolescent ,Regulatory T cell ,T cell ,Immunology ,Autoimmunity ,Cell Communication ,Thymus Gland ,T-Lymphocytes, Regulatory ,Young Adult ,Immune system ,Myasthenia Gravis ,medicine ,Immunology and Allergy ,CCL17 ,Animals ,Humans ,IL-2 receptor ,Cells, Cultured ,Chemokine CCL22 ,Toll-like receptor ,Innate immune system ,biology ,Dendritic Cells ,Middle Aged ,Coculture Techniques ,Immunity, Innate ,3. Good health ,Rats ,Toll-Like Receptor 4 ,medicine.anatomical_structure ,Rats, Inbred Lew ,biology.protein ,Th17 Cells ,Female ,Chemokine CCL17 ,Signal Transduction - Abstract
The thymus is the main site of immune sensitization to AChR in myasthenia gravis (MG). In our previous studies we demonstrated that Toll-like receptor (TLR) 4 is over-expressed in MG thymuses, suggesting its involvement in altering the thymic microenvironment and favoring autosensitization and autoimmunity maintenance processes, via an effect on local chemokine/cytokine network. Here, we investigated whether TLR4 signaling may favor abnormal cell recruitment in MG thymus via CCL17 and CCL22, two chemokines known to dictate immune cell trafficking in inflamed organs by binding CCR4. We also investigated whether TLR4 activation may contribute to immunodysregulation, via the production of Th17-related cytokines, known to alter effector T cell (Teff)/regulatory T cell (Treg) balance. We found that CCL17, CCL22 and CCR4 were expressed at higher levels in MG compared to normal thymuses. The two chemokines were mainly detected around medullary Hassall's corpuscles (HCs), co-localizing with TLR4(+) thymic epithelial cells (TECs) and CCR4(+) dendritic cells (DCs), that were present in higher number in MG thymuses compared to controls. TLR4 stimulation in MG TECs increased CCL17 and CCL22 expression and induced the production of Th17-related cytokines. Then, to study the effect of TLR4-stimulated TECs on immune cell interactions and Teff activation, we generated an in-vitro imaging model by co-culturing CD4(+) Th1/Th17 AChR-specific T cells, naive CD4(+)CD25(+) Tregs, DCs and TECs from Lewis rats. We observed that TLR4 stimulation led to a more pronounced Teff activatory status, suggesting that TLR4 signaling in MG thymic milieu may affect cell-to-cell interactions, favoring autoreactive T-cell activation. Altogether our findings suggest a role for TLR4 signaling in driving DC recruitment in MG thymus via CCL17 and CCL22, and in generating an inflammatory response that might compromise Treg function, favoring autoreactive T-cell pathogenic responses.
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- 2014
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19. Development of the MG-DIS: an ICF-based disability assessment instrument for myasthenia gravis
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Lorenzo Maggi, Alberto Raggi, Matilde Leonardi, Renato Mantegazza, Carlo Antozzi, Fulvio Baggi, and Silvia Schiavolin
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Male ,medicine.medical_specialty ,Patient interview ,Environment ,Disability assessment ,Disability Evaluation ,International Classification of Functioning, Disability and Health ,Surveys and Questionnaires ,Activities of Daily Living ,Myasthenia Gravis ,Outcome Assessment, Health Care ,Humans ,Medicine ,Disabled Persons ,business.industry ,Rehabilitation ,Outcome measures ,Health Status Disparities ,Middle Aged ,humanities ,Physical therapy ,Icf classification ,Female ,Self Report ,business - Abstract
To develop a preliminary version of a disease-specific, patient-reported disability assessment instrument for myasthenia gravis (MG) based on the International Classification of Functioning, Disability and Health (ICF): the MG-DIS.Five consecutive steps were taken: literature review and selection of outcome measures; linking of measures' concepts to ICF categories and selection of those reported by 30% of the instruments; comparison of linking results with a previous selection of MG-relevant ICF categories; patient interview; development of questions based on retained ICF categories.Thirty-one papers containing 21 different outcome measures were found: 13 ICF categories were linked to them. Fifty-five items were retained after the comparison with the list of MG-specific categories, and were used for patient interview. Thirteen interviews were conducted before saturation of data was reached and the final list was composed of 42 categories: based upon them, 44 questions were developed.The preliminary version of the MG-DIS contains more information than each single MG-specific tool, in particular, for the component of environmental factors. Further research is needed to test its psychometric properties.It is important that patient-reported outcome is incorporated in MG patient's assessment. MG features can be evaluated with ICF-based methods. An MG-specific patient-reported disability assessment instrument can be used to monitor changes of functioning in patients on MG-specific treatments, and can be used in clinical trials as outcome measure.
- Published
- 2013
20. Orphan drugs to treat myasthenia gravis
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Lorenzo Maggi, Fulvio Baggi, and Renato Mantegazza
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medicine.medical_specialty ,business.industry ,Health Policy ,medicine.medical_treatment ,Context (language use) ,Immunosuppression ,Pharmacology ,medicine.disease ,Myasthenia gravis ,Clinical Practice ,Orphan drug ,Food and drug administration ,Expert opinion ,medicine ,Pharmacology (medical) ,Intensive care medicine ,business ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Rare disease - Abstract
Introduction: Acquired myasthenia gravis (MG) is a rare disease and according to the EU Register of designated Orphan Medicinal Products only two drugs are registered as orphan drugs for MG while no orphan drug for MG has been approved by the US Food and Drug Administration. The aim of this review is to discuss the role and mechanism of action of the recognized orphan drugs for MG and of other therapies potentially useful for MG treatment, which should be considered as orphan drugs. Areas covered: In the context of an updated overview of MG pathogenesis, the authors discuss current MG treatments available in clinical practice, orphan drugs for MG according to the EU Orphan Drugs Registry and emerging therapies, among which are therapies exclusively developed for MG. Expert opinion: New effective drugs for MG are needed to reduce side effects, mainly those related to steroids or to chronic immunosuppression, and to manage patients not responsive to common treatments. Hence, in recent years drugs potentiall...
- Published
- 2013
21. Patient registries: useful tools for clinical research in myasthenia gravis
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Donald B. Sanders, Fulvio Baggi, Carlo Antozzi, and Renato Mantegazza
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medicine.medical_specialty ,Patient registry ,business.industry ,General Neuroscience ,MEDLINE ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Myasthenia gravis ,Surgery ,Clinical trial ,Rapid identification ,Clinical research ,History and Philosophy of Science ,medicine ,University medical ,business ,Intensive care medicine ,Cohort study - Abstract
Clinical registries may facilitate research on myasthenia gravis (MG) in several ways: as a source of demographic, clinical, biological, and immunological data on large numbers of patients with this rare disease; as a source of referrals for clinical trials; and by allowing rapid identification of MG patients with specific features. Physician-derived registries have the added advantage of incorporating diagnostic and treatment data that may allow comparison of outcomes from different therapeutic approaches, which can be supplemented with patient self-reported data. We report the demographic analysis of MG patients in two large physician-derived registries, the Duke MG Patient Registry, at the Duke University Medical Center, and the INNCB MG Registry, at the Istituto Neurologico Carlo Besta, as a preliminary study to assess the consistency of the two data sets. These registries share a common structure, with an inner core of common data elements (CDE) that facilitate data analysis. The CDEs are concordant with the MG-specific CDEs developed under the National Institute of Neurological Disorders and Stroke Common Data Elements Project.
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- 2012
22. Animal models of myasthenia gravis: utility and limitations
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Alessandra Consonni, Renato Mantegazza, Chiara Cordiglieri, and Fulvio Baggi
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Autoimmune disease ,myasthenia gravis ,business.industry ,AChR ,autoimmunity ,Autoantibody ,General Medicine ,Review ,neuroimmunology ,medicine.disease ,medicine.disease_cause ,Neuromuscular junction ,Myasthenia gravis ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine.anatomical_structure ,Neuroimmunology ,Immunology ,Medicine ,business ,030217 neurology & neurosurgery ,030215 immunology ,Acetylcholine receptor - Abstract
Myasthenia gravis (MG) is a chronic autoimmune disease caused by the immune attack of the neuromuscular junction. Antibodies directed against the acetylcholine receptor (AChR) induce receptor degradation, complement cascade activation, and postsynaptic membrane destruction, resulting in functional reduction in AChR availability. Besides anti-AChR antibodies, other autoantibodies are known to play pathogenic roles in MG. The experimental autoimmune MG (EAMG) models have been of great help over the years in understanding the pathophysiological role of specific autoantibodies and T helper lymphocytes and in suggesting new therapies for prevention and modulation of the ongoing disease. EAMG can be induced in mice and rats of susceptible strains that show clinical symptoms mimicking the human disease. EAMG models are helpful for studying both the muscle and the immune compartments to evaluate new treatment perspectives. In this review, we concentrate on recent findings on EAMG models, focusing on their utility and limitations.
- Published
- 2016
23. A novel infection- and inflammation-associated molecular signature in peripheral blood of myasthenia gravis patients
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Josephine Lum, Paola Cavalcante, Pia Bernasconi, Kandhadayar G. Srinivasan, Claudia Barzago, Silvia Bonanno, Elisa Faggiani, Lucia Mori, Francesca Andreetta, Raffaele A. Calogero, Giorgia Camera, Francesca Zolezzi, Fulvio Baggi, Carlo Antozzi, Renato Mantegazza, Barzago, C, Lum, J, Cavalcante, P, Srinivasan, K, Faggiani, E, Camera, G, Bonanno, S, Andreetta, F, Antozzi, C, Baggi, F, Calogero, R, Bernasconi, P, Mantegazza, R, Mori, L, and Zolezzi, F
- Subjects
0301 basic medicine ,Male ,RNA, Untranslated ,Myasthenia gravi ,medicine.disease_cause ,Autoimmunity ,Pathogenesis ,0302 clinical medicine ,Medicine ,Immunology and Allergy ,Cluster Analysis ,Receptors, Cholinergic ,Age of Onset ,Hematology ,microRNA ,Age Factors ,Middle Aged ,Female ,medicine.symptom ,Adult ,medicine.medical_specialty ,Immunology ,Inflammation ,Infections ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Immune system ,Internal medicine ,Myasthenia Gravis ,Humans ,business.industry ,Gene Expression Profiling ,Muscle weakness ,medicine.disease ,Myasthenia gravis ,MicroRNAs ,Peripheral blood mononuclear cells ,Viral infection ,Whole-transcriptome sequencing ,030104 developmental biology ,Gene Expression Regulation ,Case-Control Studies ,Leukocytes, Mononuclear ,business ,Transcriptome ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Myasthenia gravis (MG) is a T-cell dependent autoimmune disorder of the neuromuscular junction, characterised by muscle weakness and fatigability. Autoimmunity is thought to initiate in the thymus of acetylcholine receptor (AChR)-positive MG patients; however, the molecular mechanisms linking intra-thymic MG pathogenesis with autoreactivity via the circulation to the muscle target organ are poorly understood. Using whole-transcriptome sequencing, we compared the transcriptional profile of peripheral blood mononuclear cells from AChR-early onset MG (AChR-EOMG) patients with healthy controls: 178 coding transcripts and 229 long non-coding RNAs, including 11 pre-miRNAs, were differentially expressed. Among the 178 coding transcripts, 128 were annotated of which 17% were associated with the ‘infectious disease’ functional category and 46% with ‘inflammatory disease’ and ‘inflammatory response-associated’ categories. Validation of selected transcripts by qPCR indicated that of the infectious disease-related transcripts, ETF1, NFKB2, PLK3, and PPP1R15A were upregulated, whereas CLC and IL4 were downregulated in AChR-EOMG patients; in the ‘inflammatory’ categories, ABCA1, FUS, and RELB were upregulated, suggesting a contribution of these molecules to immunological dysfunctions in MG. Data selection and validation were also based on predicted microRNA-mRNA interactions. We found that miR-612, miR-3654, and miR-3651 were increased, whereas miR-612-putative AKAp12 and HRH4 targets and the miR-3651-putative CRISP3 target were downregulated in AChR-EOMG, also suggesting altered immunoregulation. Our findings reveal a novel peripheral molecular signature in AChR-EOMG, reflecting a critical involvement of inflammatory- and infectious disease-related immune responses in disease pathogenesis.
- Published
- 2016
24. Recommendations for myasthenia gravis clinical trials
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Michael, Benatar, Donald B, Sanders, Ted M, Burns, Gary R, Cutter, Jeffrey T, Guptill, Fulvio, Baggi, Henry J, Kaminski, Renato, Mantegazza, Matthew N, Meriggioli, Joanne, Quan, and Gil I, Wolfe
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medicine.medical_specialty ,Physiology ,Advisory Committees ,Alternative medicine ,MEDLINE ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Quality of life (healthcare) ,Physiology (medical) ,Health care ,Myasthenia Gravis ,Outcome Assessment, Health Care ,medicine ,Humans ,Clinical significance ,Intensive care medicine ,Societies, Medical ,030304 developmental biology ,0303 health sciences ,Clinical Trials as Topic ,business.industry ,Clinical study design ,United States ,3. Good health ,Clinical trial ,Clinical research ,Research Design ,Physical therapy ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
The recommendations for clinical research standards published in 2000 by a task force of the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and acceptance of more effective and less noxious therapies for MG.
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- 2012
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25. Naturally Occurring CD4+CD25+ Regulatory T Cells Prevent but Do Not Improve Experimental Myasthenia Gravis
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Chiara Ruocco, Valeria Nessi, Carlo Antozzi, Fulvio Baggi, Sara Nava, Chiara Toscani, and Renato Mantegazza
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medicine.medical_specialty ,T cell ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Biology ,Polymerase Chain Reaction ,T-Lymphocytes, Regulatory ,Neuromuscular junction ,Epitope ,Immunophenotyping ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,Receptors, Cholinergic ,IL-2 receptor ,Receptor ,Autoantibodies ,Acetylcholine receptor ,Immunomagnetic Separation ,medicine.disease ,Myasthenia gravis ,Myasthenia Gravis, Autoimmune, Experimental ,Rats ,medicine.anatomical_structure ,Endocrinology ,Rats, Inbred Lew ,Female - Abstract
In the current study, we investigated whether naturally occurring CD4+CD25+ T cells, separated by immunomagnetic anti-CD4 and anti-CD25 Abs from naive animals, are able to protect from experimental autoimmune myasthenia gravis (EAMG) and modify the progression of ongoing disease when administered to Torpedo californica acetylcholine receptor (AChR)-immunized Lewis rats. Even though CD4+CD25+ and CD4+CD25high T cell frequencies were similar in the spleens and lymph nodes of EAMG and healthy rats, we observed that CD4+CD25+ T cells isolated from the spleens of naive animals inhibited in vitro the Ag-induced proliferation of T cell lines specific to the self-peptide 97–116 of the anti-AChR subunit (R97-116), an immunodominant and myasthenogenic T cell epitope, whereas CD4+CD25+ T cells purified from the spleens of EAMG rats were less effective. CD4+CD25+ T cells from EAMG rats expressed less forkhead box transcription factor P3 but more CTLA-4 mRNA than healthy rats. Naive CD4+CD25+ T cells, obtained from naive rats and administered to T. californica AChR-immunized animals according to a preventive schedule of treatment, reduced the severity of EAMG, whereas their administration 4 wk postinduction of the disease, corresponding to the onset of clinical symptoms (therapeutic treatment), was not effective. We think that the exogenous administration of CD4+CD25+ naive T cells prevents the early events underlying the induction of EAMG, events linked to the T cell compartment (Ag recognition, epitope spreading, and T cell expansion), but fails to ameliorate ongoing EAMG, when the IgG-mediated complement attack to the AChR at the neuromuscular junction has already taken place.
- Published
- 2010
26. Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis
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Massimo Barberis, P. Didò, Maria Cannone, Ferdinando Cornelio, Sonia Berrih-Aknin, Pia Bernasconi, Renato Mantegazza, Carlo Antozzi, Fulvio Baggi, Lorenzo Maggi, M. Barbi, and Paola Cavalcante
- Subjects
Thymoma ,viruses ,Antigens, Differentiation, Myelomonocytic ,Fluorescent Antibody Technique ,Thymus Gland ,Biology ,medicine.disease_cause ,Virus ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, CD ,Predictive Value of Tests ,Myasthenia Gravis ,medicine ,030304 developmental biology ,Autoimmune disease ,0303 health sciences ,Macrophages ,Poliovirus ,medicine.disease ,Immunohistochemistry ,Virology ,Myasthenia gravis ,3. Good health ,Toll-Like Receptor 4 ,Herpes simplex virus ,Immunology ,RNA, Viral ,Capsid Proteins ,Neurology (clinical) ,030217 neurology & neurosurgery ,Poliomyelitis - Abstract
Background: Genetic and environmental factors are thought to contribute to the etiology of the autoimmune disease myasthenia gravis (MG). Viral involvement has long been suspected, but direct evidence of involvement has not been found. We recently reported that Toll-like receptor 4 (TLR4)—a key activator of innate immunity—was overexpressed in the thymus of some patients with MG, suggesting that thymic infection by pathogens might be involved in MG pathogenesis. We searched for evidence of intrathymic infection in patients with MG. Methods: Twenty-seven MG thymuses (6 involuted, 7 hyperplastic, 5 thymitis, and 9 thymoma) previously tested for TLR4 expression, 18 nonpathologic control thymuses, and 10 pathologic control thymuses from patients without MG (8 thymoma and 2 hyperplastic) were analyzed for cytomegalovirus, varicella-zoster virus, herpes simplex virus types 1 and 2, eubacteria, respiratory syncytial virus, and enteroviruses using PCR techniques. Immunohistochemistry and double immunofluorescence were used to detect enterovirus capsid protein VP1 in thymic specimens and analyze TLR4 expression in VP1-positive cells. Results: Poliovirus was detected in 4 MG thymuses (14.8%; 2 thymitis and 2 thymoma). No virus was detected in any control thymus. A linear correlation between plus and minus strand poliovirus RNA levels was observed in all 4 thymuses, suggesting persistent thymic infection. VP1 protein was detected in the cytoplasm of CD68-positive macrophages scattered through thymic medulla in all PV-positive thymuses. VP1 and TLR4 colocalized in infected cells. Conclusions: Poliovirus-infected macrophages are present in thymus of some patients with myasthenia gravis, suggesting a viral contribution to the intrathymic alterations leading to the disease.
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- 2010
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27. Effect of IgG immunoadsorption on serum cytokines in MG and LEMS patients
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Valeria Nessi, Francesca Andreetta, Carlo Antozzi, Lorenzo Maggi, Federica Ubiali, Sara Nava, Renato Mantegazza, A. Rigamonti, and Fulvio Baggi
- Subjects
Adult ,Male ,Adolescent ,medicine.medical_treatment ,Immunology ,Radioimmunoassay ,Enzyme-Linked Immunosorbent Assay ,medicine.disease_cause ,Autoimmunity ,Myasthenia Gravis ,medicine ,Humans ,Immunology and Allergy ,Receptors, Cholinergic ,Immunoadsorption ,Immunosorbent Techniques ,biology ,business.industry ,Growth factor ,Interleukin ,Calcium Channels, P-Type ,Middle Aged ,medicine.disease ,Myasthenia gravis ,Lambert-Eaton Myasthenic Syndrome ,Cytokine ,Neurology ,Immunoglobulin G ,biology.protein ,Cytokines ,Female ,Neurology (clinical) ,Antibody ,business ,Lambert-Eaton myasthenic syndrome ,Follow-Up Studies - Abstract
We investigated the effect of IgG immunoadsorption (IA) on cytokine network in patients with treatment-resistant Myasthenia Gravis (MG) and Lambert-Eaton Syndrome (LEMS). We observed upregulation of interleukin (IL)-10, an anti-inflammatory and B cells growth factor, and reduction of pro-inflammatory factors such as IL-18 and IL-17, in both MG and LEMS after IA. Our observation suggests that the massive removal of antibodies might induce modifications of the cytokine balance linked to T and B cells mediated autoimmunity.
- Published
- 2008
28. Validation of the Besta Neurological Institute rating scale for myasthenia gravis
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Carlo, Antozzi, Greta, Brenna, Fulvio, Baggi, Giorgia, Camera, Lorenzo, Maggi, Cristiana, Rezzani, Cristina, Montomoli, and Renato, Mantegazza
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Male ,Neurologic Examination ,Analysis of Variance ,Disability Evaluation ,Myasthenia Gravis ,Humans ,Reproducibility of Results ,Female - Abstract
We validated the scale for myasthenia gravis (MG) developed at the Neurological Institute Foundation of Milan (INCB-MG scale).A total of 174 patients were evaluated with the INCB-MG and compared with the MG Composite (MGC) as the gold standard. Dimensionality, reliability, and validity of the INCB-MG scale were studied by principal component factor analysis, Cronbach alpha, and Pearson correlation coefficients; interobserver reliability was calculated by the weighted Cohen K coefficient.Generalized and bulbar INCB-MG subscales were unidimensional with excellent consistency; the INCB-MG and MGC scales were strongly correlated. Fatigability assessment was correlated with the INCB-MG generalized, bulbar, and respiratory subscales.The INCB-MG scale is a reliable tool to assess MG and is strongly correlated with the MGC. The INCB-MG scale is a valid tool for every day practice and should be further investigated for its application in clinical trials.
- Published
- 2015
29. Breakdown of Tolerance to a Self-Peptide of Acetylcholine Receptor α-Subunit Induces Experimental Myasthenia Gravis in Rats
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Widmer Scaioli, Monica Milani, Fulvio Baggi, Renato Longhi, Renato Mantegazza, Ferdinando Cornelio, Federica Ubiali, Carlo Antozzi, and Andrea Annoni
- Subjects
medicine.medical_specialty ,Molecular Sequence Data ,Immunology ,Neuromuscular transmission ,Epitopes, T-Lymphocyte ,Receptors, Nicotinic ,Biology ,Lymphocyte Activation ,Autoantigens ,Epitope ,Neuromuscular junction ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,Amino Acid Sequence ,Muscle, Skeletal ,Receptor ,Peptide sequence ,Cells, Cultured ,Autoantibodies ,Acetylcholine receptor ,G alpha subunit ,medicine.disease ,Molecular biology ,Peptide Fragments ,Myasthenia gravis ,Myasthenia Gravis, Autoimmune, Experimental ,Rats ,Protein Subunits ,Self Tolerance ,medicine.anatomical_structure ,Endocrinology ,Rats, Inbred Lew ,Cytokines ,Female ,Lymph Nodes - Abstract
Experimental autoimmune myasthenia gravis (EAMG), a model for human myasthenia (MG), is routinely induced in susceptible rat strains by a single immunization with Torpedo acetylcholine receptor (TAChR). TAChR immunization induces anti-AChR Abs that cross-react with self AChR, activate the complement cascade, and promote degradation of the postsynaptic membrane of the neuromuscular junction. In parallel, TAChR-specific T cells are induced, and their specific immunodominant epitope has been mapped to the sequence 97–116 of the AChR α subunit. A proliferative T cell response against the corresponding rat sequence (R97–116) was also found in TAChR-immunized rats. To test whether the rat (self) sequence can be pathogenic, we immunized Lewis rats with R97–116 or T97–116 peptides and evaluated clinical, neurophysiological, and immunological parameters. Clinical signs of the disease were noted only in R97–116-immunized animals and were confirmed by electrophysiological signs of impaired neuromuscular transmission. All animals produced Abs against the immunizing peptide, but anti-rat AChR Abs were observed only in animals immunized with the rat peptide. These findings suggested that EAMG in rats can be induced by a single peptide of the self AChR, that this sequence is recognized by T cells and Abs, and that breakdown of tolerance to a self epitope might be an initiating event in the pathogenesis of rat EAMG and MG.
- Published
- 2004
30. Myasthenia Gravis (MG): Epidemiological Data and Prognostic Factors
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Fulvio Baggi, Lucia Morandi, Francesca Andreetta, Angela Campanella, Ferdinando Cornelio, Pia Bernasconi, O. Simoncini, Paolo Confalonieri, Renato Mantegazza, Ettore Beghi, and Carlo Antozzi
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Male ,medicine.medical_specialty ,Pediatrics ,Multivariate analysis ,Thymoma ,medicine.medical_treatment ,Population ,General Biochemistry, Genetics and Molecular Biology ,Cohort Studies ,Sex Factors ,History and Philosophy of Science ,Histological diagnosis ,Myasthenia Gravis ,Epidemiology ,Prevalence ,medicine ,Humans ,Life Tables ,Receptors, Cholinergic ,Clinical efficacy ,Age of Onset ,education ,Retrospective Studies ,Neurologic Examination ,education.field_of_study ,Univariate analysis ,Chi-Square Distribution ,Hyperplasia ,business.industry ,General Neuroscience ,Remission Induction ,Age Factors ,Thymus Neoplasms ,Prognosis ,Thymectomy ,medicine.disease ,Precipitin Tests ,Myasthenia gravis ,Surgery ,Databases as Topic ,Female ,business ,Follow-Up Studies - Abstract
Data from 756 myasthenic patients were analyzed for diagnostic criteria, clinical aspects, and therapeutic approaches. The patients were followed up at our institution from 1981 to 2001. Clinical evaluation was performed according to the myasthenia gravis score adopted at our clinic. Clinical features of each patient (comprising demographic, clinical, neurophysiological, immunological, radiological, and surgical data, as well as serial myasthenia gravis scores) were filed in a relational database containing more than 7000 records. Clinical efficacy and variables influencing outcome were assessed by life-table methods and Cox proportional hazards regression analysis. Complete stable remission, as defined by the Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, was the end point for good prognosis. Four hundred and ninety-nine patients (66%) were female and 257 (34%) were male. Mean follow-up was 55.1 +/- 48.1 months. Onset of symptoms peaked in the third decade in females, whereas the male distribution was bimodal with peaks in the third and sixth decades. Modality of myasthenia gravis presentation was as follows: ocular, 39.3%; generalized, 28.5%; bulbar, 31.3%; and respiratory, 0.8%. Thymectomy was carried out on 63.7% of our patients by different approaches: (1) transcervical; (2) transsternal; (3) video-thoracoscopic mini-invasive surgery. The last approach has been preferentially used in more recent years and accounted for 62.4% of the thymectomized myasthenia gravis population. Univariate analysis and Kaplan-Meier analysis showed that variables such as sex (female), age at onset (below 40 years), thymectomy, and histological diagnosis of thymic hyperplasia were significantly associated with complete stable remission, whereas on multivariate analysis only age at onset below 40 years and thymectomy were confirmed.
- Published
- 2003
31. Oral administration of an immunodominant T-cell epitope downregulates Th1/Th2 cytokines and prevents experimental myasthenia gravis
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Elisabetta Caspani, Fulvio Baggi, Renato Mantegazza, Renato Longhi, Ferdinando Cornelio, Francesca Andreetta, Carlo Antozzi, and Monica Milani
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Transcription, Genetic ,T cell ,Administration, Oral ,Down-Regulation ,Epitopes, T-Lymphocyte ,Article ,Epitope ,Mice ,Th2 Cells ,Antigen ,Transforming Growth Factor beta ,Myasthenia Gravis ,Animals ,Medicine ,Receptors, Cholinergic ,Receptor ,Acetylcholine receptor ,Autoimmune disease ,Dose-Response Relationship, Drug ,business.industry ,General Medicine ,Th1 Cells ,medicine.disease ,Myasthenia gravis ,Tolerance induction ,medicine.anatomical_structure ,Immunology ,Cytokines ,Peptides ,business - Abstract
The mucosal administration of the native antigen or peptide fragments corresponding to immunodominant regions is effective in preventing or treating several T cell-dependent models of autoimmune disease. No data are yet available on oral tolerance with immunodominant T-cell peptides in experimental autoimmune myasthenia gravis (EAMG), an animal model of B cell-dependent disease. We report that oral administration of the T-cell epitope alpha146-162 of the Torpedo californica acetylcholine receptor (TAChR) alpha-subunit suppressed T-cell responses to AChR and ameliorated the disease in C57Bl/6 (B6) mice. Protection from EAMG was associated with reduced serum Ab's to mouse AChR and reduced AChR loss in muscle. The effect of Talpha146-162 feeding was specific; treatment with a control peptide did not affect EAMG manifestations. The protective effect induced by peptide Talpha146-162 was mediated by reduced production of IFN-gamma, IL-2, and IL-10 by TAChR-reactive cells, suggesting T-cell anergy. TGF-beta-secreting Th3 cells did not seem to be involved in tolerance induction. We therefore demonstrate that feeding a single immunodominant epitope can prevent an Ab-mediated experimental model of autoimmune disease.
- Published
- 1999
32. Identification of a Novel HLA Class II Association with DQB1*0502 in an Italian Myasthenic Population
- Author
-
Henry A. Erlich, Ferdinando Cornelio, Renato Mantegazza, Ann B. Begovich, Carlo Antozzi, Emilio Ciusani, Francesca Andreetta, Fulvio Baggi, and Paolo Confalonieri
- Subjects
Adult ,Male ,Risk ,Hla class ii ,Population ,Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,History and Philosophy of Science ,HLA-DQ beta-Chains ,HLA-DQ Antigens ,Myasthenia Gravis ,Humans ,Medicine ,Receptors, Cholinergic ,Age of Onset ,education ,Alleles ,Autoantibodies ,Sex Characteristics ,education.field_of_study ,HLA-DQ Antigen ,business.industry ,General Neuroscience ,HLA-DR Antigens ,Thymectomy ,Italy ,Immunology ,Female ,Identification (biology) ,Age of onset ,Oligonucleotide Probes ,business ,HLA-DRB1 Chains - Published
- 1998
33. Plasma Treatment in Diseases of the Neuromuscular Junction
- Author
-
Renato Mantegazza, P. Confalonieri, Fulvio Baggi, Carlo Antozzi, and Ferdinando Cornelio
- Subjects
Adult ,Male ,Plasma Exchange ,business.industry ,General Neuroscience ,Immunoglobulins, Intravenous ,Plasma treatment ,Middle Aged ,General Biochemistry, Genetics and Molecular Biology ,Neuromuscular junction ,Lambert-Eaton Myasthenic Syndrome ,medicine.anatomical_structure ,History and Philosophy of Science ,Recurrence ,Anesthesia ,Myasthenia Gravis ,Humans ,Medicine ,Female ,Receptors, Cholinergic ,Staphylococcal Protein A ,business ,Immunosorbent Techniques ,Autoantibodies ,Retrospective Studies - Published
- 1998
34. Differential targeting of immune-cells by Pixantrone in experimental myasthenia gravis
- Author
-
Chiara Toscani, Chiara Cordiglieri, Renato Mantegazza, Chiara Ruocco, Fulvio Baggi, Carlo Antozzi, and Roberta Marolda
- Subjects
Drug ,media_common.quotation_subject ,Immunology ,Dendritic cell differentiation ,Pharmacology ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Animals ,Topoisomerase II Inhibitors ,Lymphocytes ,Myeloid Progenitor Cells ,Acetylcholine receptor ,media_common ,Pixantrone ,Bortezomib ,business.industry ,Therapeutic effect ,Cell Differentiation ,medicine.disease ,Isoquinolines ,Myasthenia gravis ,3. Good health ,Myasthenia Gravis, Autoimmune, Experimental ,Rats ,Neurology ,chemistry ,Rats, Inbred Lew ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,030215 immunology ,medicine.drug - Abstract
Pixantrone was shown to reduce the severity of clinical manifestation in experimental myasthenia gravis. In the present work we further studied its therapeutic effect. Our results demonstrate that a single administration suppressed AChR-specific immune-responses in primed rats. However, clinical symptoms could be improved only by repeated drug administrations (q7dx6 protocol—8.12 mg/kg); this treatment allowed stable serum drug levels for at least 7 days, as assessed by a functional T-cell bioassay. Pixantrone exerted strong in vitro inhibitory effect only on proliferating T-cells without impairing dendritic cell differentiation and B-cell viability. Our data further demonstrate that Pixantrone is a promising immunosuppressant drug that should be investigated in myasthenia gravis.
- Published
- 2013
35. Patient registries: useful tools for clinical research in myasthenia gravis
- Author
-
Fulvio, Baggi, Renato, Mantegazza, Carlo, Antozzi, and Donald, Sanders
- Subjects
Adult ,Cohort Studies ,Male ,Biomedical Research ,Myasthenia Gravis ,Humans ,Female ,Registries ,Middle Aged ,Aged - Abstract
Clinical registries may facilitate research on myasthenia gravis (MG) in several ways: as a source of demographic, clinical, biological, and immunological data on large numbers of patients with this rare disease; as a source of referrals for clinical trials; and by allowing rapid identification of MG patients with specific features. Physician-derived registries have the added advantage of incorporating diagnostic and treatment data that may allow comparison of outcomes from different therapeutic approaches, which can be supplemented with patient self-reported data. We report the demographic analysis of MG patients in two large physician-derived registries, the Duke MG Patient Registry, at the Duke University Medical Center, and the INNCB MG Registry, at the Istituto Neurologico Carlo Besta, as a preliminary study to assess the consistency of the two data sets. These registries share a common structure, with an inner core of common data elements (CDE) that facilitate data analysis. The CDEs are concordant with the MG-specific CDEs developed under the National Institute of Neurological Disorders and Stroke Common Data Elements Project.
- Published
- 2012
36. Complete stable remission and autoantibody specificity in myasthenia gravis
- Author
-
Lucia Morandi, Massimo Barberis, Francesca Andreetta, Franco Salerno, Renato Mantegazza, Carlo Antozzi, Fulvio Baggi, Pia Bernasconi, Lorenzo Maggi, Cristina Montomoli, and Paolo Confalonieri
- Subjects
Adult ,Male ,medicine.medical_specialty ,Thymus Gland ,Gastroenterology ,Neurosurgical Procedures ,Cohort Studies ,Antibody Specificity ,Internal medicine ,Myasthenia Gravis ,medicine ,Humans ,Receptors, Cholinergic ,Stage (cooking) ,Age of Onset ,Autoantibodies ,Retrospective Studies ,Sex Characteristics ,biology ,Plasma Exchange ,business.industry ,Autoantibody ,Receptor Protein-Tyrosine Kinases ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Myasthenia gravis ,Treatment Outcome ,Data Interpretation, Statistical ,Cohort ,biology.protein ,Disease Progression ,Female ,Neurology (clinical) ,Antibody ,Age of onset ,business ,Cohort study - Abstract
Patients with myasthenia gravis (MG) are subgrouped as acetylcholine receptor (AChR)-positive, muscle-specific kinase (MuSK)-positive, and AChR/MuSK-negative MG (or double negative [DN]) on the basis of autoantibody assay. We investigated the relationships between autoantibody specificity, main clinical features, and outcome of the disease, in particular the occurrence of complete stable remission (CSR), by means of a retrospective study on a cohort of 677 Italian patients with MG.A total of 517 (76%) patients with AChR-positive MG, 55 (8%) patients with MuSK-positive MG, and 105 (16%) patients with DN MG were included in the study. Kaplan-Meier and Cox proportional hazard regression analyses were used to evaluate associations between baseline characteristics, antibody specificity, and CSR.Clinical stage at onset and at maximal worsening was more severe for MuSK-positive patients: bulbar impairment at maximal worsening was found in 83.6% of MuSK-positive patients compared with 58.6% of AChR-positive patients and 43.8% of DN patients (p0.001). Baseline characteristics of AChR-positive and DN patients were similar. CSR was observed in 3.6% of MuSK-positive patients compared with 22.2% of AChR-positive and 21.9% of DN patients. In the whole MG cohort, onset before age 40 (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.27-3.02, p = 0.002) and ocular and generalized clinical stages at maximal worsening were associated with CSR (ocular, HR = 8.05, 95% CI 1.88-34.53, p = 0.005; generalized, HR = 3.71, 95% CI 1.16-11.90, p = 0.023; bulbar, HR = 3.16, 95% CI 1.00-10.05, p = 0.051).MuSK antibodies identify a clinically distinguishable, more severe form of MG since the disease onset, with a lower occurrence of CSR. These features should be considered by the clinician in the management of this particular form of MG.
- Published
- 2012
37. Immunomodulatory Treatments for Myasthenia Gravis: Plasma Exchange, Intravenous Immunoglobulins and Semiselective Immunoadsorption
- Author
-
Carlo Antozzi and Fulvio Baggi
- Subjects
biology ,business.industry ,Autoantibody ,Radioimmunoassay ,medicine.disease ,Neuromuscular junction ,Myasthenia gravis ,medicine.anatomical_structure ,Immunology ,medicine ,biology.protein ,Antibody ,business ,Immunoadsorption ,Tyrosine kinase ,Acetylcholine receptor - Abstract
Myasthenia Gravis (MG) is an autoimmune disorder characterized clinically by fluctuating muscle weakness and fatigability on exertion. The disease is caused by specific autoantibodies against proteins of the neuromuscular junction (NMJ) (Conti-Fine et al, 2002; Sanders & Meriggioli, 2009). Two different autoantibodies are routinely detectable, i.e. antibodies against the acetylcholine receptor (AChR) or to a muscle specific tyrosine kinase (MuSK) (Hoch et al., 2001). Anti acetylcholine receptor autoantibodies are detected in about 80-85% of patients with generalized Myasthenia Gravis. Myasthenia Gravis patients without antibodies to either acetylcholine receptor or MuSK are now defined as affected with “seronegative Myasthenia Gravis”. A recent study reported that a proportion of seronegative patients has low-affinity antibodies to acetylcholine receptor, antibodies that cannot be detected by common radioimmunoassay (Leite et al., 2008).
- Published
- 2012
38. The thymus in myasthenia gravis: Site of 'innate autoimmunity'?
- Author
-
Rozen Le Panse, Carlo Antozzi, Sonia Berrih-Aknin, Pia Bernasconi, Renato Mantegazza, Lorenzo Maggi, Paola Cavalcante, Fulvio Baggi, and Fondazione IRCCS Istituto Neurologico 'Carlo Besta'
- Subjects
animal structures ,Physiology ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Inflammation ,Thymus Gland ,Biology ,medicine.disease_cause ,Neuromuscular junction ,Autoimmunity ,Autoimmune Diseases ,Pathogenesis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Physiology (medical) ,Myasthenia Gravis ,medicine ,Humans ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Acetylcholine receptor ,Autoantibodies ,0303 health sciences ,Autoantibody ,medicine.disease ,Myasthenia gravis ,Immunity, Innate ,3. Good health ,Thymectomy ,medicine.anatomical_structure ,Immunology ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Myasthenia gravis (MG) is an autoimmune disorder caused, in most cases, by autoantibodies against components of the neuromuscular junction, frequently the acetylcholine receptor (AChR), and less often the muscle-specific kinase receptor. The thymus plays a major role in the pathogenesis of MG with anti-AChR antibodies: it shows marked pathologic alterations (hyperplastic or tumoral) in most AChR-positive patients and contains the elements required to initiate and sustain an autoimmune reaction (AChR autoantigen, AChR-specific T cells, and autoantibody-secreting plasma cells). In this study we review early and more recent findings implicating the thymus as site of AChR autosensitization in MG and briefly discuss the therapeutic role of thymectomy. We also summarize data showing that the MG thymus is in a state of chronic inflammation, and we review emerging evidence of a viral contribution to the onset and maintenance of the thymic autoimmune response.
- Published
- 2011
39. Acetylcholine receptor-induced experimental myasthenia gravis: what have we learned from animal models after three decades?
- Author
-
Chiara Toscani, Carlo Antozzi, Chiara Cordiglieri, and Fulvio Baggi
- Subjects
Immunology ,Neuromuscular Junction ,Biology ,medicine.disease_cause ,Neuromuscular junction ,Autoimmunity ,Immune system ,Myasthenia Gravis ,medicine ,Immune Tolerance ,Immunology and Allergy ,Animals ,Humans ,Receptors, Cholinergic ,Acetylcholine receptor ,Autoantibodies ,Autoimmune disease ,General Medicine ,Complement System Proteins ,medicine.disease ,Myasthenia gravis ,Complement system ,Myasthenia Gravis, Autoimmune, Experimental ,Disease Models, Animal ,medicine.anatomical_structure ,Neuroimmunology ,Immunotherapy - Abstract
Myasthenia gravis (MG) is an autoimmune disease caused by an immunological response against the acetylcholine receptor (AChR) at the neuromuscular junction. Anti-AChR antibodies induce degradation of the receptor, activation of complement cascade and destruction of the post-synaptic membrane, resulting in a functional reduction of AChR availability. The pathophysiological role of autoantibodies (auto-Abs) and T helper lymphocytes has been studied in the experimental autoimmune MG (EAMG) models. EAMG models have been employed to investigate the factors involved in the development of MG and to suggest new therapies aimed to preventing or modulating the ongoing disease. EAMG can be induced in susceptible mouse and rat strains, which develop clinical symptoms such as muscular weakness and fatigability, mimicking the human disease. Two major types of EAMG can be induced, passive and active EAMG. Passive transfer MG models, involving the injection of auto-Abs, are helpful for studying the role of complement molecules and their regulatory proteins, which can prevent neuromuscular junction degradation. Active models, induced by immunization, are employed for the analysis of antigen-specific immune responses and their modulation in order to improve disease progression. In this review, we will concentrate on the main pathogenic mechanisms of MG, focusing on recent findings on EAMG experimental models.
- Published
- 2011
40. Presentation of endogenous acetylcholine receptor epitope by an MHC class II-transfected human muscle cell line to a specific CD4+ T cell clone from a myasthenia gravis patient
- Author
-
John Newsom-Davis, Angela Vincent, Hide Matsuo, Fulvio Baggi, Mike Nicolle, and Nick Willcox
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,medicine.medical_specialty ,animal structures ,T cell ,Genes, MHC Class II ,Immunology ,Antigen presentation ,Antigen-Presenting Cells ,In Vitro Techniques ,Receptors, Nicotinic ,Lymphocyte Activation ,Transfection ,Epitope ,Epitopes ,Internal medicine ,Myasthenia Gravis ,MHC class I ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Antigen-presenting cell ,HLA-D Antigens ,MHC class II ,biology ,Antigen processing ,Muscles ,musculoskeletal system ,Molecular biology ,medicine.anatomical_structure ,Endocrinology ,Neurology ,biology.protein ,Neurology (clinical) - Abstract
Muscle or thymic myoid cells, if induced to express MHC class II in addition to endogenous acetylcholine receptor (AChR), might present epitopes derived from the AChR to specific CD4+ T cells. These T cells could in turn initiate or maintain the anti-AChR response that is responsible for AChR loss in myasthenia gravis (MG). We transfected the AChR+ TE671 (rhabdomyosarcoma) cells with HLA-DR4 and co-cultured them with the DR4-restricted, CD4+ T cell clone (PM-A1; raised from a hyperplastic thymus of an MG patient and previously shown to recognise all forms of the AChR that contain the sequence alpha 144-156). Significant T cell activation, demonstrated both by 3H-thymidine incorporation and by lysis of the TE671 cells, was found in the presence of added alpha 144-156 and, more importantly, in the absence of exogenous antigen. These results show that MHC class II-expressing muscle or other AChR-expressing cells could present endogenous AChR to pathogenic T cells. This process may be important in the aetiology of MG.
- Published
- 1993
41. A short plasma exchange protocol is effective in severe myasthenia gravis
- Author
-
Paolo Confalonieri, Marco Gemma, F. Fiacchino, Bruno Regi, D. Peluchetti, Maurizio Marconi, Renato Mantegazza, Fulvio Baggi, Ferdinando Cornelio, Carlo Antozzi, and E. Berta
- Subjects
Adult ,Male ,medicine.medical_specialty ,Neurology ,Adolescent ,medicine.medical_treatment ,Therapeutic Procedure ,Immunopathology ,Myasthenia Gravis ,medicine ,Humans ,Child ,Aged ,Monitoring, Physiologic ,Plasma Exchange ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Myasthenia gravis ,Surgery ,Regimen ,Immunosuppressive drug ,Anesthesia ,Concomitant ,Female ,Plasmapheresis ,Neurology (clinical) ,business - Abstract
Plasma exchange has been reported to be a successful therapeutic procedure for the treatment of severely compromised myasthenic patients, but the optimal regimen in terms of costs or clinical benefit has not so far been determined. We have investigated the efficacy of a short plasmapheresis protocol of two exchanges 1 day apart in a series of 70 patients with severe forms of myasthenia gravis. Patients were evaluated before and 7 days after the first exchange. A positive outcome was observed in 70% of the plasma exchange cycles performed. Disease severity did not seem to be a negative prognostic factor for the efficacy of this short protocol, which was well tolerated by patients. In only 1 case were major side-effects observed. In spite of its short duration, the exchange treatment plus concomitant immunosuppressive drug therapy was not followed by early clinical deterioration.
- Published
- 1991
42. Thymoma-associated myasthenia gravis: outcome, clinical and pathological correlations in 197 patients on a 20-year experience
- Author
-
Paola Cavalcante, Fulvio Baggi, Lorenzo Novellino, Francesca Andreetta, Ferdinando Cornelio, Giuseppe Muscolino, Renato Mantegazza, Carlo Antozzi, Lorenzo Maggi, and Pia Bernasconi
- Subjects
Adult ,Male ,medicine.medical_specialty ,Thymoma ,Multivariate analysis ,medicine.medical_treatment ,Immunology ,Video-Assisted Surgery ,Myasthenia Gravis ,medicine ,Immunology and Allergy ,Humans ,Life Tables ,Longitudinal Studies ,Pathological ,Survival analysis ,Retrospective Studies ,business.industry ,Age Factors ,Retrospective cohort study ,Thymus Neoplasms ,Middle Aged ,medicine.disease ,Thymectomy ,Survival Analysis ,Myasthenia gravis ,Surgery ,Natural history ,Treatment Outcome ,Neurology ,Female ,Neurology (clinical) ,Cholinesterase Inhibitors ,business - Abstract
We studied 197 patients with thymoma-associated myasthenia gravis (T-MG) to identify variables that can influence the natural history of the disease and the therapeutical approaches. Multivariate analysis showed that neither clinical nor pathological variables were associated with a better chance to reach complete stable remission. The video-assisted thoracoscopic extended thymectomy (VATET) was not significantly correlated with a lower chance of achieving complete stable remission compared with the classical transsternal approach (T-3b) (p=0.1090). Thymoma recurrence was not correlated with surgery by VATET or T-3b. VATET was safe and reliable for removal of thymoma. The low chance of achieving remission (9.64%) in T-MG underlines the importance of an early diagnosis as well as the need for more aggressive therapeutic strategies.
- Published
- 2008
43. Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats
- Author
-
Valeria Nessi, Renato Longhi, Sara Nava, Gabriella Pezzoni, Raffaella Capobianco, Fulvio Baggi, Carlo Antozzi, Renato Mantegazza, and Federica Ubiali
- Subjects
medicine.medical_specialty ,T cell ,T-Lymphocytes ,Immunology ,Molecular Sequence Data ,Nicotinic Antagonists ,Pharmacology ,Receptors, Nicotinic ,Lymphocyte Activation ,Torpedo ,Severity of Illness Index ,chemistry.chemical_compound ,Internal medicine ,medicine ,Immunology and Allergy ,Animals ,Amino Acid Sequence ,Acetylcholine receptor ,Cell Proliferation ,Mitoxantrone ,Cardiotoxicity ,Pixantrone ,Immunodominant Epitopes ,medicine.disease ,Isoquinolines ,Myasthenia gravis ,Peptide Fragments ,Myasthenia Gravis, Autoimmune, Experimental ,Rats ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Mechanism of action ,Rats, Inbred Lew ,Female ,medicine.symptom ,Ex vivo ,Immunosuppressive Agents ,medicine.drug - Abstract
Pixantrone (BBR2778) (PIX) and mitoxantrone share the same mechanism of action because both drugs act as DNA intercalants and inhibitors of topoisomerase II. PIX is an interesting candidate immunosuppressant for the treatment of autoimmune diseases because of its reduced cardiotoxicity compared with mitoxantrone. The clinical response to conventional immunosuppressive treatments is poor in some patients affected by myasthenia gravis (MG), and new but well-tolerated drugs are needed for treatment-resistant MG. PIX was tested in vitro on rat T cell lines specific for the immunodominant peptide 97–116 derived from rat acetylcholine receptor (AChR), and showed strong antiproliferative activity in the nanomolar range. We demonstrate in this study that PIX administration reduced the severity of experimental autoimmune MG in Lewis rats. Biological and immunological analysis confirmed the effect of PIX, compared with vehicle-treated as well as mitoxantrone-treated experimental autoimmune MG rats. Anti-rat AChR Abs were significantly reduced in PIX-treated rats, and AChR content in muscles were found increased. Torpedo AChR-induced T cell proliferation tests were found reduced in both in vitro and ex vivo experiments. The effectiveness and the reduced cardiotoxicity make PIX a promising immunosuppressant agent suitable for clinical investigation in MG, although additional experiments are needed to confirm its safety profile in prolonged treatments.
- Published
- 2008
44. Increased incidence of certain TCR and HLA genes associated with myasthenia gravis in Italians
- Author
-
Giuseppe Pellegris, Renato Mantegazza, Jorge R. Oksenberg, Carlo Antozzi, Maria Teresa Illeni, Ferdinando Cornelio, Fulvio Baggi, and Lawrence Steinman
- Subjects
Molecular Sequence Data ,Immunology ,Receptors, Antigen, T-Cell ,Immunogenetics ,Human leukocyte antigen ,In Vitro Techniques ,Biology ,Lymphocyte Activation ,Myasthenia Gravis ,medicine ,Humans ,Immunology and Allergy ,Receptors, Cholinergic ,Amino Acid Sequence ,Typing ,Allele frequency ,HLA-D Antigens ,T-cell receptor ,medicine.disease ,Peptide Fragments ,Myasthenia gravis ,Italy ,Restriction fragment length polymorphism ,DNA Probes ,Polymorphism, Restriction Fragment Length ,Alpha chain - Abstract
In order to study the immunogenetics of myasthenia gravis (MG), we analysed the TCR and HLA-class II genes from Italian and Californian myasthenic patients. We investigated polymorphisms of the TCR using the full length cDNA probes pGA5 and the pT10 for the alpha and beta chains, respectively. The 6.3 kb and 2.0 kb polymorphic markers, revealed by the PssI enzyme and the alpha chain probe, were shown to be significantly associated with MG. Italian MG patients were HLA typed, and allele frequencies showed a significant association of DR3 and DQw2 with MG. The relative risk calculated for DR3 was 7.4. T-cell proliferative responses to peptides of the AchR alpha chain were also studied and no associations with TCR RFLP analysis or HLA-class II typing were observed.
- Published
- 1990
45. Increased Toll-Like Receptor 4 Expression in Thymus of Myasthenic Patients with Thymitis and Thymic Involution
- Author
-
Maria Cannone, Ferdinando Cornelio, Laura Passerini, Elisa Arnoldi, Massimo Barberis, Pia Bernasconi, Fulvio Baggi, Lorenzo Novellino, and Renato Mantegazza
- Subjects
Adult ,Male ,Thymoma ,Receptors, Cell Surface ,Thymus Gland ,Biology ,Pathology and Forensic Medicine ,Immunity ,Myasthenia Gravis ,medicine ,Humans ,RNA, Messenger ,Age of Onset ,Lymphatic Diseases ,Toll-like receptor ,Thymic involution ,Innate immune system ,Membrane Glycoproteins ,Microscopy, Confocal ,Reverse Transcriptase Polymerase Chain Reaction ,Toll-Like Receptors ,Germinal center ,medicine.disease ,Immunohistochemistry ,Myasthenia gravis ,Immunity, Innate ,Original Research Paper ,Toll-Like Receptor 4 ,Immunology ,TLR4 ,Female - Abstract
Thymic abnormalities are present in approximately 80% of myasthenia gravis (MG) patients, and the thymus seems to be the main site of autosensitization to the acetylcholine receptor. In view of findings that the innate immune system can generate an autoimmune response, we studied the expression of Toll-like receptors (TLRs) 2 to 5, key components of innate immunity signaling pathways, in 37 thymuses from patients with autoimmune MG. TLR4 mRNA levels were significantly greater in thymitis (hyperplasia with diffuse B-cell infiltration) and involuted thymus than in germinal center hyperplasia and thymoma. By immunohistochemistry and confocal microscopy, cells positive for TLR4 protein were rarely detected in thymoma. However, in thymitis TLR4 protein was mostly found on epitheliomorphic (cytokeratin-positive) cells located in close association with clusters of acetylcholine receptor-positive myoid cells in thymic medulla and also at the borders between cortical and medullary areas. B cells were never TLR4-positive. TLR4 protein was also present in remnant tissue of involuted thymus. This is the first finding of a possible link between innate immunity and MG. We speculate that in a subgroup of MG patients, an exogenous or endogenous danger signal may activate the innate immune system and give rise to TLR4-mediated mechanisms contributing to autoimmunity.
- Published
- 2005
46. Immunization with rat-, but not Torpedo-derived 97-116 peptide of the AChR alpha-subunit induces experimental myasthenia gravis in Lewis rat
- Author
-
Fulvio Baggi, Renato Longhi, Renato Mantegazza, Andrea Annoni, Federica Ubiali, Ferdinando Cornelio, Monica Milani, and Carlo Antozzi
- Subjects
Time Factors ,Peptide ,Torpedo ,General Biochemistry, Genetics and Molecular Biology ,Antibodies ,law.invention ,History and Philosophy of Science ,Species Specificity ,law ,medicine ,Animals ,Receptors, Cholinergic ,Amino Acid Sequence ,Experimental Myasthenia Gravis ,Acetylcholine receptor ,chemistry.chemical_classification ,Α subunit ,Chemistry ,General Neuroscience ,Body Weight ,medicine.disease ,Molecular biology ,Myasthenia gravis ,Myasthenia Gravis, Autoimmune, Experimental ,Rats ,Protein Subunits ,Immunization ,Rats, Inbred Lew ,Female ,Peptides - Published
- 2003
47. Analysis of SjTREC levels in thymus from MG patients and normal children
- Author
-
Fulvio Baggi, Ferdinando Cornelio, Renato Mantegazza, Laura Passerini, and Pia Bernasconi
- Subjects
Adult ,Time Factors ,Adolescent ,Thymoma ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Thymus Gland ,Gene Rearrangement, T-Lymphocyte ,General Biochemistry, Genetics and Molecular Biology ,Text mining ,History and Philosophy of Science ,Myasthenia Gravis ,Medicine ,Humans ,Child ,Aged ,Hyperplasia ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,General Neuroscience ,Infant ,Middle Aged ,Case-Control Studies ,Child, Preschool ,Immunology ,Normal children ,business - Published
- 2003
48. Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of follow-up
- Author
-
Paolo Confalonieri, Maria Teresa Ferrò, Fulvio Baggi, Ferdinando Cornelio, Luisella Spinelli, Lorenzo Novellino, Renato Mantegazza, Ettore Beghi, Carlo Antozzi, and Pia Bernasconi
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Thymus Gland ,Myasthenia Gravis ,Task Performance and Analysis ,Thoracoscopy ,medicine ,Humans ,Age of Onset ,Retrospective Studies ,Univariate analysis ,Analysis of Variance ,medicine.diagnostic_test ,business.industry ,Thoracic Surgery, Video-Assisted ,Remission Induction ,Retrospective cohort study ,Odds ratio ,Middle Aged ,medicine.disease ,Thymectomy ,Confidence interval ,Myasthenia gravis ,Surgery ,Treatment Outcome ,Neurology ,Cardiothoracic surgery ,Regression Analysis ,Female ,Neurology (clinical) ,Cholinesterase Inhibitors ,Thymus Hyperplasia ,business ,Follow-Up Studies - Abstract
The aims of this study were to assess the efficacy of video-assisted thoracoscopic extended thymectomy (VATET) as a treatment for myasthenia gravis (MG) and to identify prognostic factors for thymectomy success. Clinical efficacy and variables influencing outcome were assessed by life-table and Cox proportional hazards regression analysis. Complete stable remission (CSR), as defined by the MGFA Medical Task Force, was the end point for efficacy. VATET was performed in 159 MG patients and T-3b in 47 MG patients. At 6 years of follow-up, CSR, assessed by life-table analysis, was 50.6% in non-thymomatous VATET patients and 48.7% in non-thymomatous T-3b surgery. By univariate analysis, the presence of thymic hyperplasia (P=0.0002) and treatment only with anticholinesterases (P
- Published
- 2003
49. Immunotherapy of Myasthenia Gravis
- Author
-
Monica Milani, C. Antozzi, Ferdinando Cornelio, A. Annoni, Renato Mantegazza, F. Andreetta, Fulvio Baggi, and Pia Bernasconi
- Subjects
Autoimmune disease ,animal structures ,business.industry ,Neuromuscular transmission ,Muscle weakness ,musculoskeletal system ,medicine.disease ,Neuromuscular junction ,Myasthenia gravis ,Complement system ,Nicotinic acetylcholine receptor ,medicine.anatomical_structure ,Immunology ,Medicine ,medicine.symptom ,business ,tissues ,Acetylcholine receptor - Abstract
Myasthenia gravis (MG) is an acquired autoimmune disease of the neuromuscular junction mediated by antibodies against the nicotinic acetylcholine receptor (anti-AChR Ab). Anti-AChR Ab, by cross-linking AChR molecules and activating the complement cascade, cause destruction of junctional AChR and simplification of the post-synaptic membrane [1, 2]. The reduced number of functional AChR accounts for the impaired neuromuscular transmission, leading to the muscle weakness and fatigability typical of MG patients. For a review of the clinical features of MG, see [3].
- Published
- 2002
50. Oral Administration of Peptide Tαl46-162 Prevents EAMG in Mice
- Author
-
O. Simonicini, Monica Milani, Renato Mantegazza, Francesca Andreetta, Fulvio Baggi, Renato Longhi, Ferdinando Cornelio, E. Caspani, and C. Antozzi
- Subjects
biology ,business.industry ,Muscle weakness ,medicine.disease ,Neuromuscular junction ,Myasthenia gravis ,medicine.anatomical_structure ,Immune system ,Nicotinic agonist ,Immunology ,medicine ,biology.protein ,Nasal administration ,medicine.symptom ,Antibody ,business ,Acetylcholine receptor - Abstract
Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which antibodies to the acetylcholine receptor (anti-AChR Ab) lead to muscle weakness and fatigability [1]. MG is treated with corticosteroids and immunosuppressive drugs which exert a non-specific action on the immune system. Moreover, their efficacy is frequently limited, and sometimes overwhelmed, by drug toxicity [2]. Experimental autoimmune MG (EAMG), the animal model of human myasthenia, is a T cell-dependent, B cell-mediated disorder suitable for the investigation of new therapeutic strategies. Indeed, data available on the structure and immunological recognition of the nicotinic AChR allow the design of antigen-specific approaches potentially able to modulate the autoimmune response to the AChR.
- Published
- 2000
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