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PubMed1982

The ocular signs and symptoms of myasthenia gravis.

Myasthenia gravis is a chronic disease characterized by a fluctuating weakness of voluntary muscles, with a preference for the muscles innervated by the cranial nerves. Ocular symptoms (ptosis, diplopia) were present at onset in 65% of 432 own patients and in 10% of these patients the disease remained confined to the extrinsic eye muscles. A complete remission occurred in 30% of the purely ocular cases within 10 years of onset. The diagnosis depends upon the pattern of weakness, the spontaneous or provoked fluctuation of the symptoms and the favourable response to anticholinesterases. The presence of antibodies against acetylcholine receptor protein is the most recent tool to confirm the diagnosis, but they are absent in 10-20% of the patients with generalized MG and in 20-50% of the purely ocular cases. As the reaction to anticholinesterases in ocular MG is sometimes equivocal or even absent auxillary investigations (electromyography, tonography, nystagmography, curaretest) may be necessary. Oral anticholinesterases (Pyridostigmin, Prostigmin, Ambenomium) usually have a moderate effect on the ptosis and a poor effect on the diplopia so that other measures (ptosishooks, covering one eye) are necessary. In selected patients alternate-day Prednisone is the therapy of choice.

Adolescent↗
PubMed1997

Tolerance to a dominant T cell epitope in the acetylcholine receptor molecule induces epitope spread and suppresses murine myasthenia gravis.

Myasthenia gravis (MG) is a T cell-dependent, Ab-mediated autoimmune disease. T cells reactive to a dominant peptide alpha 146-162 of acetylcholine receptor (AChR) alpha subunit participate in murine MG pathogenesis. To suppress the autoimmune response to AChR, a high dose of alpha146-162 peptide in IFA was administered parenterally as a tolerogen, after the development of a primary T cell immune response to AChR. This form of AChR T cell peptide tolerance suppressed the in vitro T cell proliferative response to AChR and its dominant alpha146-162 and subdominant alpha182-198 peptides through epitope spread. Administration of alpha146-162 peptide in IFA after the primary immune response to AChR also significantly suppressed the serum anti-AChR Ab of the IgG2b isotype and clinical incidence of MG in C57BL/6 mice. Furthermore, the production of IFN-gamma, IL-2, and IL-10 cytokines by AChR, alpha146-162, and alpha182-198 peptide-reactive cells was suppressed by alpha146-162 peptide tolerance, and the epitope spread observed could be attributed to the reduction in the above cytokine production. Therefore, AChR T cell-dominant peptide tolerance could be adapted in the Ag-specific therapy of MG.

Amino Acid Sequence↗
PubMed2000

Decreased mRNA expression of TNF-alpha and IL-10 in non-stimulated peripheral blood mononuclear cells in myasthenia gravis.

Myasthenia gravis (MG) is characterized by T cell-dependent autoantibodies to the acetylcholine receptor on the post-synaptic membrane of the neuromuscular junction. The production of autoantibodies is regulated by T cells via cytokines. To investigate the involvement of interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4) and interleukin-10 (IL-10) in MG, the mRNA levels of these cytokines in peripheral blood mononuclear cells without stimulation in vitro were quantified by competitive reverse transcription polymerase chain reaction technique. The mRNA level of TNF-alpha was significantly lower (P = 0.0004) in the overall group of MG patients compared with controls. IL-10 was also lower in MG patients (P = 0.008), most markedly in non-thymectomized patients (P = 0.016). There were no significant differences in IFN-gamma and IL-4 between patients and healthy controls, but the mRNA levels of IL-4 in non-thymectomized patients was significantly lower than in controls (P = 0.02) and in thymectomized patients (P = 0.03). These results, reflecting the in vivo expression pattern of these cytokines in the periphery, suggest an altered cytokine expression at the systemic level in MG.

Adult↗
PubMed2006

Expression of OX40 (CD134) on CD4+ T-cells from patients with myasthenia gravis.

Myasthenia gravis (MG) is commonly regarded as the prototype of an antibody-mediated, organ-specific autoimmune disease. Antibodies against the acetylcholine receptor (AChR) on the muscle endplate trigger its typical clinical manifestations of weakness and fatiguability. T-B cell interactions are thought to play a crucial role in the pathogenesis of MG. OX40 (CD134), a costimulatory molecule that is expressed on activated CD4+ T-cells, might contribute to the development or pathogenesis of immune-mediated diseases such as rheumatoid arthritis and graft-versus-host disease. In the present study, we investigated the expression of OX40 on CD4+ T-cells from patients with MG and healthy individuals. Results from 36 MG patients and 28 healthy controls revealed that more freshly isolated CD4+ T-cells from MG patients expressed OX40 than cells from healthy individuals. High levels of antibodies against the AChR, thymic hyperplasia and onset at an early age were associated with elevated expression of OX40. Upon activation by various concentrations of anti-CD3 antibodies, CD4+ T-cells from MG patients showed a tendency toward higher levels of OX40 expression than cells from healthy individuals. Given the role of OX40 in the immune system, we conclude that OX40 might contribute to the development of MG.

Adult↗
PubMed2006

The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis.

Myasthenia gravis (MG) is associated with ectopic germinal centers in the thymus. Thymectomy and glucocorticoids are the main treatments but they induce operative risks and side effects, respectively. The aim of this study was to propose new therapies more efficient for MG. We hypothesized that molecules dysregulated in MG thymus and normalized by glucocorticoids may play a key role in thymic pathogenesis. Using gene chip analysis, we identified 88 genes complying with these criteria, the most remarkable being the B-cell chemoattractant (CXCL13). Its expression was increased in thymus and sera of glucocorticoid-untreated patients and decreased in response to treatment in correlation with clinical improvement. Normal B cells were actively chemoattracted by thymic extracts from glucocorticoid-untreated patients, an effect inhibited by anti-CXCL13 antibodies. In the thymus, CXCL13 was preferentially produced by epithelial cells and overproduced by epithelial cells from MG patients. Altogether, our results suggest that a high CXCL13 production by epithelial cells could be responsible for germinal center formation in MG thymus. Furthermore, they show that this gene is a main target of corticotherapy. Thus, new therapies targeting CXCL13 could be of interest for MG and other autoimmune diseases characterized by ectopic germinal center formation.

Adrenal Cortex Hormones↗
PubMed1996

Tumor necrosis factor-alpha, lymphotoxin, interleukin (IL)-6, IL-10, IL-12 and perforin mRNA expression in mononuclear cells in response to acetylcholine receptor is augmented in myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disorder mediated by autoantibodies against the nicotinic acetylcholine receptor (AChR) on the postsynaptic membrane of the neuromuscular junction. The production of antibodies is regulated by T cells by means of immunoregulatory cytokines. To investigate the involvement of TNF-alpha, lymphotoxin (LT), IL-6, IL-10, IL-12 and perforin in MG, numbers of cytokine mRNA expressing blood mononuclear cells (MNC) were examined in patients with MG and controls. LT belongs to the Th1 cell related cytokines, IL-6 and IL-10 to the Th2 type, TNF-alpha is produced by both Th1 and Th2 cells, IL-12 induces T cell switch towards the Th1 type and perforin is an effector molecule inducing cell lysis. Short term culture of MNC with AChR revealed augmented levels of AChR-reactive TNF-alpha, LT, IL-6, IL-10, IL-12 and perforin mRNA expressing cells in MG compared to levels obtained without AChR or in presence of control antigen. AChR-reactive TNF-alpha, IL-6, IL-10, IL-12 and perforin mRNA expressing cells were higher in MG than controls. These findings suggest that the cytokines TNF-alpha, LT, IL-6, IL-10 and IL-12, and the cytolytic effector molecule perforin are also involved in MG.

Adolescent↗
PubMed1998

An acetylcholine receptor alpha subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor (AChR). Although the autoantigen is present in the thymus, it is not tolerated in MG patients. In addition, the nature of the cell bearing the autoantigen is controversial. To approach these questions, we used two lineages of transgenic mice in which the beta-galactosidase (beta-gal) gene is under the control of a 842-bp (Tg1) or a 3300-bp promoter fragment (Tg2) of the chick muscle alpha subunit AChR gene. In addition to expression in muscle cells, thymic expression was observed in both mouse lines (mainly in myoid cells in Tg1 and myoid cells and epithelial cells in Tg2). After challenge with beta-gal, Tg1 mice produced Th2-dependent anti-beta-gal antibodies, while Tg2 mice were almost unresponsive. By contrast, in a proliferation assay both Tg lines were unresponsive to beta-gal. Cells from Tg1 mice produce Th2-dependent cytokine whereas cells from Tg2 mice were nonproducing in response to beta-gal. These data indicate that the level of expression in Tg1 mice could be sufficient to induce tolerance of Th1 cells but not of Th2 cells, while both populations are tolerated in Tg2 mice. These findings are compatible with the hypothesis that AChR expression is not sufficiently abundant in MG thymus to induce a full tolerance.

Animals↗
PubMed2005

Differential estrogen receptor expression in autoimmune myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease associated with thymic hyperplasia and is much more prevalent in women than men. In this study we investigated potential changes in estrogen receptor (ER) expression in thymic hyperplasia. We first quantified by real-time PCR the relative expression of ER alpha and ER beta in normal thymus and found that the ER beta to ER alpha ratio was inverted in thymocytes (8.6 +/- 1.2), compared with thymic epithelial cells (0.18 +/- 0.05). The ER transcript number gradually decreased in thymic epithelial cells during culture, indicating that the thymic environment influences ER expression. CD4+ helper T cells expressed higher level of ERs, compared with CD8+ cells, as assessed by flow cytometry in thymocytes and peripheral blood mononuclear cells. In MG patients, we found an increased expression of ER alpha on thymocytes and both ERs on T cells from peripheral blood mononuclear cells, indicating that the signals provided by thymic and peripheral microenvironments are distinct. Finally, activation of normal thymocytes by proinflammatory cytokines induced increased expression of ERs especially in the CD4+ subset, suggesting that an excess of proinflammatory cytokines could explain the increase of ERs expression on MG lymphocytes. The dysregulation of ER expression in MG lymphocytes could affect the maintenance of the homeostatic conditions and might influence the progression of the autoimmune response.

Adolescent↗
PubMed2004

Immunomodulation by a dual altered peptide ligand of autoreactive responses to the acetylcholine receptor of peripheral blood lymphocytes of patients with myasthenia gravis.

Myasthenia gravis (MG) is a T cell-dependent, antibody-mediated autoimmune disease. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogs of two myasthenogenic peptides was demonstrated to downregulate in vitro and in vivo murine MG associated autoreactive responses. Furthermore, treatment with the dual APL ameliorated the clinical manifestations of an established experimental autoimmune MG in mice. This study was undertaken in order to investigate the ability of the dual APL to immunomodulate MG-associated responses of peripheral blood lymphocytes (PBL) of patients with MG to the native autoantigen acetylcholine receptor (AChR). PBL of 22 of 27 patients with MG tested responded by proliferation to torpedo AChR. The proliferative responses of PBL of 21 of 22 responders were significantly inhibited by the dual APL. The inhibition was specific because a control peptide did not inhibit these proliferative responses. The dual APL also downregulated the levels of the secreted pathogenic cytokine IFN-gamma in supernatants of stimulated PBL of 80% of the tested patients. The latter inhibitions correlated with an upregulated production of the immunosuppressive cytokine, tumor growth factor beta. Thus, the results of our study demonstrate that the dual APL is capable of downregulating in vitro autoreactive responses of patients with MG and suggest that this peptide is a potential candidate for a novel specific treatment of patients with MG.

Adult↗
PubMed2001

Anesthesia and critical care of thymectomy for myasthenia gravis.

Myasthenia gravis is an autoimmune disease resulting from the production of antibodies against the ACh receptors of the neuromuscular synapse. The thymus gland is involved in the autosensitization process, and the disease frequently is associated with thymic morphologic abnormalities. There is a consensus that all adults with generalized MG should have a thymectomy. This recommendation has been propagated by the safety of the procedure and excellent outcome. Removal of as much thymic tissue as possible (anterior mediastinal exenteration) by transsternal approach is the logical goal of thymectomy in the treatment of MG. Transcervical approach and VATS, however, are less invasive and have been used in patients who have MG unaccompanied by thymoma. Optimization of the condition of the myasthenic patients can markedly decrease the risk of surgery and improve the outcome. Two techniques have been recommended for general anesthesia in the myasthenic patient. Because of the unpredictable response to succinylcholine and the marked sensitivity to nondepolarizing muscle relaxants, some anesthesiologists avoid muscle relaxants and depend on deep inhalational anesthesia, such as halothane, isoflurane, or sevoflurane, for tracheal intubation and maintenance of anesthesia. Others, however, use a balanced technique of anesthesia that includes the use of carefully titrated muscle relaxants. The most important preoperative factor predicting the need for postoperative mechanical ventilation is the severity of bulbar involvement (Ossermann group 3 and 4), usually indicated by significant dysphagia and dysarthria associated with borderline respiratory dysfunction. Thymectomy benefits nearly 96% of patients: 46% develop complete remission, 50% are asymptomatic or improve on therapy, and 4% remain the same. The time from diagnosis to surgery is shorter than 8 months, and mild or moderate myasthenic symptoms are the main prognostic factors that predict the best outcome after thymectomy.

Anesthesia↗
PubMed2001

The role of adjuvants in the efficacy of a peptide vaccine for myasthenia gravis.

Myasthenia gravis (MG) and its animal model, experimental autoimmune (EA) MG, are caused by interference with neuromuscular transmission by autoantibodies against the nicotinic acetylcholine receptor (AChR) on muscle. Previously, we have shown that two peptides, denoted RhCA 67-16 and RhCA 611-001, designed to be complementary in structure to the main immunogenic region and the dominant Lewis rat T cell epitope (alpha-chain residues 100-116) of the AChR, respectively, are effective vaccines that prevent EAMG in rats by inducing antiidiotypic/clonotypic antibodies (Ab) and lowering levels of AChR Ab. These studies employed keyhole limpet hemocyanin (KLH) as a carrier and complete Freunds adjuvant (CFA). In advance of a clinical trial the present study tested the efficacy of RhCA 611-001 when combined with different adjuvants that are approved for use in humans. Adjuvants chosen for comparison were incomplete Freunds adjuvant (IFA) and aluminum hydroxide (Alum). As a second goal we evaluated diphtheria toxin (DT) as an alternative carrier protein to KLH. Alum was found to be an effective adjuvant, particularly when used with the peptide conjugated to DT. This combination of carrier and adjuvant provided protection against EAMG comparable with that observed with CFA and KLH. Using enzyme-linked immunosorbent assays for Ab against RhCA 611-001, it was found that disease protection is qualitatively, but not quantitatively, related to the anti-peptide Ab response. Our results demonstrate a vaccine formulation that should be useful in the first soon-to-be-conducted clinical trials of peptide vaccines to specifically correct aberrant T and B cell responses in an autoimmune disease.

Adjuvants, Immunologic↗
PubMed2005

Thoracoscopic thymectomy in the treatment concept for myasthenia gravis.

Myasthenia gravis (MG) is a chronic autoimmune disease that usually responds positively to treatment with thymectomy. Standard surgical procedures have been shown to result in a beneficial outcome. This Chapter includes discussions regarding what are controversial, and opinions as to what constitutes the optimal access to be used for thymectomy. In a prospective study conducted between 8/97 and 12/03, 137 patients with MG underwent thoracoscopic thymectomy, for which a left-sided approach was generally applied. An analysis of the intraoperative and postoperative course was performed, as well as of the impact of the surgical procedure on further development of the disease. The results obtained were compared with those published in the literature, with particular reference to results obtained with open surgery. The patients in this study were 96 females and 41 males, with a mean age of 35.8 (range: 9-83) years. The mean preoperative duration of the disease was 22.9 (range: 1-140) months. In 8 (5.8%) patients, the procedure was converted to an anterolateral thoracotomy or sternotomy. The postoperative morbidity rate was 5.8%, one (0.7) patient died and the mean follow up was 24.7 (range: 1-57) months. Complete remission was noted in 19.4%, and improvements reflected either in a reduction in the medication required or a decrease in symptom severity, in a total of 76.8%. Complete thoracoscopic thymectomy is a technically feasible operation, equally as effective as conventional open surgery. Remissions or symptomatic improvements were observed in more than 70% of the patients. The low morbidity rate, coupled with excellent cosmetic results, have led to increasing acceptance of the operation both by patients and Neurologists. Therefore, thoracoscopic thymectomy represents a new, alternative method for use in patients with MG.

Adolescent↗
PubMed1996

Evidence against chronic antigen-specific T lymphocyte activation in myasthenia gravis.

Myasthenia gravis (MG) is an antigen-specific autoimmune disease caused by antibodies against acetylcholine receptors (AChR) at the post-synaptic membrane of the neuromuscular junction. Clinical and immunological data imply the involvement of AChR-specific T lymphocytes as helper cells for autoantibody production. Direct data to support this hypothesis, however, remain sparse. In the present study, a large population of MG patients was studied for evidence of peripheral blood T cell activation by several assays. Assays based on non-specific measurements of T cell activation as well as assays of antigen-specific clonal expansion were utilized. Levels of soluble IL-2 receptor in serum were modestly elevated in some patients, suggesting T cell activation. However, peripheral blood cells did not show evidence of IL-2 receptor expression or enhanced reactivity to IL-2 in culture. Clonable T cells selected for hypoxanthine phosphoribosyl transferase (hprt) mutation, another non-antigen-specific marker for T cell activation, were not seen with increased frequency except in patients treated with purine analogs. Antigen-specific T cell activation was measured by proliferation assays using heterologous and autologous sources of AChR. Antigen-restimulated peripheral blood cell cultures were cloned by limiting dilution. The vast majority of patients failed to show convincing evidence of AChR specific T cell activation or clonal expansion; only 2 of 44 patients demonstrated clonable autologous AChR-specific T cells. An alternative hypothesis of T cell involvement in MG is proposed in which T cell activation is discontinuous and predominantly directed at antigens other than AChR.

Adult↗
PubMed2002

[Seronegative myasthenia gravis].

Myasthenia gravis (MG) is an acquired autoimmune disorder of neuromuscular transmission in which antibodies to acetylcholine receptor (AChRAB) attack the postsynaptic membrane of the neuromuscular junction. Circulating AChRAB are present in 80-90% of patients with the generalised form of MG and in 55-70% of patients with the ocular form of disease. Contrary in 10-20% of patients with typical symptoms of MG, the standard immunoprecipitation test for AChRAB is negative. Those patients contain a group of seronegative MG (SNMG). The aim of this study was the examination of frequency of SNMG in patients with different types of MG according to Osserman's classification. The establishment a relation between the fact of non-marking AChRAB in the plasma and the clinical state of the patients was also done. 74 patients with diagnosed MG and 30 healthy controls were evaluated. The diagnosis of MG was based on clinical features and one or more of the following factors: response to edrophonium chloride, electrophysiologic studies and demonstration of circulating AChRAB. In all of persons standard neurological examination was performed and measurement of the level of AChRAB was done. AChRAB were determined with a radioimmunoassay using 125-l-alpha-bungarotoxin. The myasthenic patients were classified according to Osserman's classification. The Oosterhuis' personal disability scoring system was used to indicate disease severity. In all of healthy controls the levels of AChRAB were within normal standards. 27% of myasthenic patients were seronegative. Statistically significant differences in the frequency of occurrence cases with SNMG in different types of MG according to Osserman have not been observed. The differences in the frequency of occurrence cases with SNMG in different classes according to Oosterhuis scale were indicated, but they did not reach statistical function. Negative titers of AChRAB can be found in all types of MG irrespective of the clinical state of the patients. It proves the diagnostic difficulties in MG and shows that the results of the measurement of AChRAB should be interpreted in relation with results of other examinations used in MG diagnosis.

Adult↗
PubMed1999

Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor. We have previously demonstrated a selection bias of CD4+ T cells expressing the Vbeta5.1 T-cell receptor gene in the thymus of HLA-DR3 patients with MG. To evaluate the pathogenicity of these cells, severe combined immunodeficiency mice engrafted with MG thymic lymphocytes were treated with anti-Vbeta5.1 antibody. Signs of pathogenicity (eg, acetylcholine receptor loss and complement deposits at the muscle end plates of chimeric mice) were prevented in anti-Vbeta5.1-treated severe combined immunodeficiency chimeras. Pathogenicity was mediated by autoantibodies against acetylcholine receptor. Thymic cells depleted of Vbeta5.1-positive cells in vitro before cell transfer were nonpathogenic, indicating that Vbeta5.1-positive cells are involved in the production of pathogenic autoantibodies. Acetylcholine receptor loss was prevented by Vbeta5.1 targeting in HLA-DR3 patients only, demonstrating specificity for HLA-DR3-peptide complexes. The action of the anti-Vbeta5.1 antibody involved both the in vivo depletion of Vbeta5.1-expressing cells and an increase in the interferon-gamma/interleukin-4 ratio, pointing to an immune deviation-based mechanism. This demonstration that a selective and specific T-helper cell population is involved in controlling pathogenic autoantibodies in MG holds promise for the treatment of MG.

Adolescent↗
PubMedDate not supplied

Genetic forms of myasthenia gravis.

Myasthenia in newborns and infants is usually genetic and not mediated by antibodies to the acetylcholine receptor. Several different pre- and postsynaptic defects are responsible for early-onset myasthenia. This review presents a classification of these syndromes based upon knowledge of their pathophysiologic bases and a plan for the evaluation of new patients.

Humans↗