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At least 325 records · Page 18Linked to original sources
PubMed2000

Reconstitution of conformationally dependent epitopes on the N-terminal extracellular domain of the human muscle acetylcholine receptor alpha subunit expressed in Escherichia coli: implications for myasthenia gravis therapeutic approaches.

Myasthenia gravis (MG) is an autoimmune disease, caused by autoantibodies against the muscle acetylcholine receptor (AChR), an oligomeric transmembrane glycoprotein composed of alpha(2)beta gamma delta subunits. The alpha subunit carries in its N-terminal extracellular domain the main immunogenic region (MIR), a group of conformationally dependent epitopes that seems to be a major target for the anti-AChR antibodies in MG patients. Detailed epitope studies on pathogenic anti-AChR antibodies have been hindered because the binding of most of these antibodies is conformationally dependent, which precludes the use of denatured AChR fragments. The N-terminal extracellular fragment, residues 1-207, of the human AChR alpha subunit was expressed in Escherichia coli in a denatured form, solubilized in a guanidinium hydrochloride-containing buffer, purified, and renatured using a refolding approach which employs a detergent and a cyclodextrin as 'artificial chaperones'. Compared with the non-refolded protein, the refolded molecule exhibited a dramatic improvement in terms of the binding of all anti-MIR mAb tested. Anti-MIR mAb that normally bind weakly to the denatured alpha subunit bound approximately 30-100 times better to the refolded polypeptide and other anti-MIR mAb that bind exclusively to completely conformationally dependent epitopes also bound quite efficiently. These results, in addition to providing a means for the thorough investigation of the antigenic structure of the AChR, show that the conformationally dependent MIR epitopes do not require the participation of the oligosaccharide moiety of the alpha subunit nor the contribution of neighboring subunits for antibody binding. Such AChR fragments may be used in structural studies of the AChR autoantigen, and should prove valuable in the understanding and development of therapeutic approaches for MG.

Antibodies, Monoclonal↗
PubMed2000

Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice.

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-regulated, antibody-mediated autoimmune diseases. The major autoantigen in MG is the nicotinic acetylcholine receptor (AChR). Two peptides, representing sequences of the human AChR alpha-subunit, p195-212 and p259-271, were previously shown to be immunodominant T cell epitopes in MG patients as well as, respectively, in SJL and BALB/c mice. A dual analog (termed Lys-262-Ala-207) composed of the tandemly arranged two single amino acid analogs of p195-212 and p259-271 was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual analog could down-regulate myasthenogenic manifestations in mice with EAMG that was induced by inoculation of a pathogenic T cell line. In the present study, the ability of the dual analog to treat EAMG induced in susceptible C57BL/6 mice by native Torpedo AChR was evaluated. Mice that were diagnosed to have clinical symptoms of EAMG were treated with the dual analog by oral administration, 500 microg per mouse three times a week for 5-8 weeks. Treatment with the dual analog down-regulated the clinical manifestations of the ongoing disease as assessed by the clinical score, grip strength (measured by a grip strength meter), and electromyography. The effects on the clinical EAMG correlated with a reduced production of anti-AChR antibody as well as a decrease in the secretion of interleukin-2 and, more dramatically, interferon-gamma, in response to AChR triggering. Thus, the dual analog is an efficient immunomodulator of EAMG in mice and might be of specific therapeutic potential for MG.

Administration, Oral↗
PubMed1998

The Th2 cytokine IL-4 is not required for the progression of antibody-dependent autoimmune myasthenia gravis.

Experimental autoimmune myasthenia gravis (EAMG), a disorder of the neuromuscular junction, is mediated by autoantibodies against muscle nicotinic acetylcholine receptor (AChR). The roles of IFN-gamma (Th1) and IL-4 (Th2) cytokines in the initiation and progression of this disease are not fully understood. Recently, we have demonstrated that IFN-gamma is necessary for the initiation of tAChR-induced EAMG in mice. However, the role of IL-4 in the progression of clinical EAMG remained undetermined. In this study we have addressed the contribution of IL-4 in the disease progression in IL-4(-/-) C57BL/6j mice whose IL-4 gene has been disrupted. Following immunization with Torpedo (t) AChR, the IL-4(-/-) mice readily developed signs of muscle weakness and succumbed to clinical EAMG with kinetics similar to the susceptibility of IL-4(+/+) mice. The tAChR-primed lymph node cells from IL-4(-/-) mice vigorously proliferated to tAChR and to its dominant alpha146-162 sequence associated with disease pathogenesis. However, these T cells secreted higher levels of IFN-gamma and IL-2, suggesting the development of a Th1 default pathway in these mice. Nevertheless, the IL-4 mutation had no effect on the recruitment of CD4+ Vbeta6+ T cells specific to the dominant tAChR alpha146-162 sequence in vivo. Immune sera from IL-4(-/-) mice showed a dramatic increase in mouse AChR-specific IgG2a levels followed by a concomitant decrease in IgG1 levels, but these mice did not exhibit an accelerated disease. In conclusion, we have demonstrated for the first time that IL-4 is not required either for the generation of a pathogenic anti-AChR humoral immune response or for progression of clinical EAMG in mice.

Amino Acid Sequence↗
PubMed1998

TCR-Vbeta usage in the thymus and blood of myasthenia gravis patients.

In myasthenia gravis (MG) the muscle acetylcholine receptor (AChR) is the target of an autoimmune response. The anti-AChR response may originate in the thymus, which is abnormal in most MG patients and contains anti-AChR T and B cells. Microbial superantigens (sAg) may trigger autoimmune responses and in this study we sought clues as to whether sAg play a role in the pathogenesis of MG. We investigated the frequency of use of the different TCR Vbeta families by the thymus and blood T cells in MG patients and in control subjects, using a multi-primer PCR assay. Identical TCR-Vbeta usage was found in the thymi of MG patients and controls, except Vbeta2, which showed a small increase in MG patients' thymi. Blood T cells of MG patients used Vbeta4, Vbeta6, Vbeta15, Vbeta16 and Vbeta24 significantly more than those of the controls. Vbeta4 and Vbeta6 are the gene families most frequently used by anti-AChR CD4(+) cells in MG patients. Blood T cells from MG patients used Vbeta12, Vbeta14, Vbeta17 and Vbeta18 significantly less than controls. MG patients used Vbeta4 and Vbeta6 significantly more in the blood than in the thymus, while the opposite occurred for Vbeta7, Vbeta12 and Vbeta14. Controls used Vbeta17 more and Vbeta24 less in the blood than in the thymus. The preferential expansion of Vbeta4 and Vbeta6 in MG patients might reflect the immunodominance of certain AChR epitopes, or the action of a sAg outside the thymus. The minimal differences in the TCR-Vbeta usage in the blood and thymus of control subjects might be due to expansion of T cell clones specific for common antigens. Identical Vbeta usage in the thymi of MG patients and controls does not support an important role of the thymus as the location of anti-AChR sensitization when MG is clinically evident. The differences observed in the Vbeta usage in blood and thymi of MG patients are likely to be due to preferential Vbeta usage by the anti-AChR T cells in the blood.

Adolescent↗
PubMed2004

[Seronegative myasthenia gravis].

Six to 20 p.cent of patients with generalized myasthenia gravis and 30 to 50 p.cent of those with ocular myasthenia gravis do not have anti AchR antibodies. Strict clinical, pharmacological and electrophysiological criteria are needed for the diagnosis of sero-negative myasthenia gravis. Sero-negative myasthenia gravis is an autoimmune disorder. But thymic hyperplasia is generally absent. Antibodies directed against the muscle receptor of tyrosine kinase (anti MuSK antibodies) were recently demonstrated in 40 to 70 p.cent of patients with sero-negative myasthenia gravis. Sero-negative and sero-positive myasthenia gravis may be clinically very similar. But sero-negative myasthenia gravis may express predominantly severe oculobulbar weakness or mainly neck, shoulder and respiratory muscle weakness. Sero-negative myasthenia gravis is never associated with thymoma. Sero-negative myasthenia gravis responds to immunodulation but perhaps less well than sero-positive myasthenia gravis.

Age of Onset↗
PubMed1990

Interferon system and natural killer cell activity in myasthenia gravis.

The autoimmune response in myasthenia gravis is well characterized, but little is known about the mechanisms initiating it. We have studied the interferon system and natural killer cell activity in 25 patients with myasthenia gravis and compared them to 68 healthy subjects and 96 patients with acute viral infections. Forty-four per cent of patients had circulating interferon (greater than 16 mu/ml), and in a similar proportion their peripheral blood mononuclear cells were in an antiviral state, i.e., showed low levels of viral replication when infected by vesicular stomatitis virus. Spontaneous in vitro interferon production by patients' peripheral blood mononuclear cells was also common (greater than 10 mu/ml, 32 per cent), while the response to the alpha-interferon inducer poly I:C was lower than expected, possibly reflecting the already high state of activation of the interferon system. These results were essentially similar to those obtained in patients with viral illnesses and differed significantly from healthy controls. In many myasthenia gravis patients (16 of 22, 73 per cent), a markedly deficient natural killer cell activity was found, with a median cytotoxicity of 6.5 per cent compared to 29 per cent in healthy subjects (p less than 0.005). Thus, many patients with myasthenia gravis have evidence of an activated interferon system and defective natural killer cell activity, suggesting an occult viral infection or reflecting nonspecific stimulation which may nevertheless contribute to the pathogenesis of the autoimmune response.

Acute Disease↗
PubMed1997

Ocular myasthenia gravis: response to long-term immunosuppressive treatment.

OBJECTIVE: Ocular myasthenia gravis is a subtype of myasthenia gravis that causes relatively mild disability, but may convert into severe generalised muscle weakness. A universal management plan for ocular myasthenia gravis has not been established. This study was performed to determine the outcome of ocular myasthenia gravis with the currently available therapeutic options. METHODS: Retrospective analysis of 78 patients with ocular myasthenia gravis with a mean disease duration of 8.3 (range 0.5-58.3) years. RESULTS: In 54 patients (69%) symptoms and signs remained confined to the extraocular muscles during the observation period. The remaining 24 patients (31%) developed symptoms of generalised myasthenia gravis; 50% of them within two years, 75% within four years after onset. A somewhat reduced risk of generalisation was found in those with mild symptoms, normal repetitive nerve stimulation test, and low or absent antiacetylcholine receptor (AChR) antibodies at the time of diagnosis. Patients receiving immunosuppressive treatment (corticosteroids and/or azathioprine) rarely developed generalised myasthenia gravis (six of 50, 12%). Those without such treatment, usually due to uncertain diagnosis and late referral, converted into generalised myasthenia gravis significantly more often (18 of 28, 64%). CONCLUSIONS: The prognosis of ocular myasthenia gravis is good. A conventional scheme with short-term corticosteroids and long-term azathioprine seems adequate to achieve remission in most patients. The proportion of patients developing generalised myasthenia gravis was smaller in this population compared with previously published groups (usually 50%-70%). Early immunosuppressive treatment is at least partially responsible for this finding. Thymectomy (performed here in 12 patients with an abnormal chest CT) also correlated with a good outcome, but had no apparent advantage over medical treatment alone.

Adolescent↗
PubMed1979

Preeclampsia and the patient with myasthenia gravis.

Three cases of myasthenia gravis in pregnancy are presented. In 2 cases there were moderately severe hypertension or preeclampsia and difficulty in controlling the myasthenia symptoms. The other case was uncomplicated. The possible relationship between myasthenia gravis and preeclampsia is discussed.

Adult↗
PubMed1991

[Familial infantile myasthenia gravis].

The several forms of myasthenia gravis that occur in infancy include transient neonatal myasthenia, congenital myasthenia, and familial infantile myasthenia gravis. The latter is inherited in an autosomal recessive pattern. Severe episodes of respiratory distress are frequent in infancy, and are often provoked by mild respiratory infections. 2 sisters with congenital myasthenia gravis are described. Probably 2 other sisters died of the same disease, but no definite diagnosis was made in their cases.

Female↗
PubMed2000

Myasthenia gravis and associated autoimmune diseases in children.

Myasthenia gravis has been associated with other autoimmune disorders. We report two children with myasthenia gravis and another autoimmune disease: an 18-month-old boy with ocular myasthenia gravis and Hashimoto's disease and a 14-year-old girl presenting with autoimmune polymyositis, then generalized myasthenia gravis 2 years later. The rare combinations of myasthenia gravis and Hashimoto's disease or polymyositis in children are discussed, and we also briefly review myasthenia gravis and other associated autoimmune diseases in children.

Adolescent↗
PubMed1990

[Heart disease in myasthenia gravis].

The symptoms in myasthenia gravis are mainly due to reduced function of skeletal muscle. But some patients, especially those with a thymoma, have symptoms or signs of myasthenia-related heart disease. Some of our patients with histological myocarditis have died suddenly and unexpectedly. The frequency of electrocardiographic abnormalities among myasthenic patients has increased. Patients with myasthenia gravis should be subjected to cardiac monitoring after thymic surgery and during myasthenic crisis and other severe illnesses. If clinical examination leads to suspicion of myocarditis, the patient should receive immunosuppressive therapy.

Adult↗
PubMed1977

Malabsorption of pyridostigmine in patients with myasthenia gravis.

Four patients with myasthenia gravis were under unsatisfactory control while receiving oral pyridostigmine. In each of these patients, the serum levels of this drug were below those observed in patients with myasthenia gravis who are well controlled. The strength of each of these patients improved when the serum pyridostigmine level was increased by intravenous administration of this agent. Furthermore, the rate of disappearance of pyridostigmine from the serum following intravenous administration was the same as that for control subjects and patients under good control. This demonstrates that failure to achieve adequate serum pyridostigmine levels following oral administration is due to malabsorption rather than to increased rates of tissue uptake, degradation, or excretion of the drug.

Administration, Oral↗
PubMed1981

Antibodies to polyadenylic acid in patients with myasthenia gravis.

Sera from 100 patients with myasthenia gravis and 45 patients with non-myasthenia gravis neuromuscular diseases were studied for antibodies to poly rA, poly rA-rU, native and denatured DNA. All patients with myasthenia gravis had significant anti-acetylcholine receptor antibodies with a mean titre of 1.2 X 10(-7)M. Forty-eight per cent of the myasthenia gravis patients had anti-poly rA antibody levels which were greater than 3 standard deviations from the mean of 65 control patients by Millipore filter radioimmunoassay. The antibody was specific for poly rA and present in a much higher frequency than antibodies to the other nucleic acids tested. Sucrose-gradient ultracentrifugation demonstrated that the antibody was limited to the IgM class alone. Mechanisms relating these findings to a more generalized immunological dysfunction are discussed.

Antibodies↗
PubMed1986

Myasthenia gravis: a nursing perspective.

Myasthenia gravis, a chronic neuromuscular disease, results in weakness of striated voluntary muscles. The muscles involved and the degree of weakness vary from patient to patient. Nursing care of the patient with muscle weakness from myasthenia gravis presents a challenge for the neuroscience nurse. Drug therapy and thymectomy treatments are discussed, along with their complications. Nursing interventions for other problems for the myasthenic patient, including impaired breathing patterns, inability to clear the airway, impaired communication, altered nutrition, self-care deficits, and impaired vision are described.

Activities of Daily Living↗
PubMed1986

Histiocytosis X of the thymus in association with myasthenia gravis.

A patient with myasthenia gravis underwent thymectomy following the failure of medical treatment. The thymus was normal except for four nodules, which, on histologic and electron microscopic examination, were found to consist of proliferative clusters of Langerhans' cells characteristic of histiocytosis X. This patient therefore had two disease processes in which thymic abnormalities are frequently encountered, but their simultaneous occurrence in the same patient has not hitherto been documented. The case is briefly discussed in the context of current concepts of the pathogenesis of histiocytosis X and myasthenia gravis.

Adult↗
PubMed1986

Psychological correlates of myasthenia gravis: a brief report.

Myasthenia gravis patients and matched normal controls were assessed on a range of psychological indices; myasthenic patients had higher scores on trait anxiety and suppression of anger. There were no other significant differences between the groups on psychological symptom measures (anxiety, depression or anger) or other trait measures (anger, suppression of anxiety and suppression of depression). It is concluded that trait anxiety and suppression of anger may predispose to myasthenia gravis.

Adolescent↗
PubMed1982

[Myasthenia gravis and pemphigus foliaceus].

Myasthenia gravis associated with thymoma affecting a 76-year-old white woman is reported. Two years later, after an immunosuppressive treatment with prednisone and irradiation of the tumor, bullous lesions appeared on the skin sparing the mucosae. The histopathologic features and the direct and indirect immunofluorescence tests indicated the existence of pemphigus foliaceus. The association of Myasthenia Gravis with pemphigus foliaceus is very rare, and the present case is actually the third reported in the literature.

Aged↗
PubMed2005

[Our strategy in the therapy of myasthenia gravis].

Surgical treatment of myasthenia gravis has at the 3 (rd) Department of Surgery, 1 (st) Medicine Faculty of Charles University in Prague a multiyear tradition which has originated in the 60's of the 20 (th) century. Since that time we carried out over 1 000 operations on the thymus, especially thymectomy for myasthenia gravis (MG) and with lesser frequency for thymomas. Thymectomy combined with exenteration of fatty tissue from the front mediastinum belongs to basic MG surgery. According to our experience an optimal approach to the thymus is given by partial sternotomy. A jugular approach is not regarded as enough radical. Videothoracoscopic approach and operation are possible but take more time, however they are the method of choice at some workplaces. The combined conservative and surgical treatment brings in 80 % of the cases an obvious improvement or deletion of the symptoms of the disease.

Adult↗