RESUMO
OBJECTIVES: Myasthenia gravis (MG) represents a spectrum of clinical subtypes with differences in disease mechanisms and treatment response. MG with muscle-specific tyrosine kinase (MuSK) antibodies accounts for 1%-10% of all MG patients. We conducted a meta-analysis to evaluate the association between HLA genes and MuSK-MG susceptibility. SUBJECTS AND METHODS: Studies were searched in Pubmed, EMBASE database and other sources between 2001 and 2018. Genotype, allele and haplotype frequencies of HLA loci in MuSK-MG patients and healthy controls were extracted from each included study. RESULTS: The meta-analysis showed that HLA DQB1*05, DRB1*14 and DRB1*16 were strongly associated with an increased risk of MuSK-MG (P < .0001), whereas HLA DQB*03 was less frequent in MuSK patients compared with healthy controls (P < .05). Haplotype analysis showed that these DQB1 and DRB1 alleles were closely linked, forming both risk (DQ5-DR14, DQ5-DR16, P < .0001) and protective (DQ3-DR4, DQ3-DR11, P < .05) haplotypes. CONCLUSION: The distinct genetic patterns of MuSK-MG indicate that variation in HLA class II genes plays an important role in the pathogenesis of MuSK-MG patients.
Assuntos
Predisposição Genética para Doença/genética , Antígenos de Histocompatibilidade Classe II/genética , Miastenia Gravis/genética , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Alelos , Feminino , Frequência do Gene , Genótipo , Haplótipos , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Miastenia Gravis/imunologiaRESUMO
BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disease caused by antibody mediated impairment in the neuromuscular junction. Seronegative MG (SNMG) without antibodies against acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) by routine assays accounts for about 20% of all MG patients. METHODS: Plasma from 81 Chinese MG patients previously found to be seronegative was tested by routine assays for AChR and MuSK antibodies. These samples were screened by (i) a novel, highly sensitive radioimmunoassay for AChR antibodies; (ii) cell-based assays for clustered AChR, MuSK and lipoprotein receptor-related protein 4 (LRP4) antibodies; (iii) a radioimmunoassay for titin antibodies. RESULTS: Antibodies to AChR, MuSK, LRP4 and titin were found in 25% (20/81), 4% (3/81), 7% (6/81) and 6% (5/78) of SNMG patients, respectively. In total, 37% of SNMG patients were found to be positive for at least one of the tested antibodies. AChR antibody positive patients had more severe disease (P = 0.008) and a trend towards fewer remissions/minimal manifestations than AChR antibody negative patients. The four patients with coexistence of antibodies had more severe disease, whilst the seronegative patients had milder MG (P = 0.015). CONCLUSIONS: Detection of multiple muscle antibodies by more sensitive assays provides additional information in diagnosing and subgrouping of MG and may guide MG treatment.
Assuntos
Autoanticorpos/sangue , Conectina/imunologia , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Radioimunoensaio , Adulto JovemRESUMO
Both environmental and genetic factors contribute to the development of Parkinson's disease (PD). We have examined environmental risk factors in a Norwegian population of incident PD patients and controls, the Norwegian ParkWest study. All five neurological wards in the study area of Western Norway participated in the study. A 4-step diagnostic procedure was used to establish a representative cohort of patients with incident PD at a high level of diagnostic accuracy. 212 incident PD patients and 175 age- and gender-matched controls were included. PD patients and controls were asked for information on occupation, education, exposure to pesticides, tobacco, alcohol, and caffeine. Agricultural work was associated with a higher risk of PD (OR 1.75 (1.03-3.0) P = 0.009). There were no differences as to other occupations. Smoking (OR 0.63 (0.42-0.95) P = 0.016) and alcohol use (OR 0.55 P = 0.008) were associated with a lower risk for PD. Interestingly, this inverse association was only seen in postural instability gait difficulties (PIGD) PD (P = 0.046 for smoking, P = 0.07 for alcohol consumption), and not in tremor dominant (TD) PD which was similar to controls. Consumption of coffee was lower in PD patients (3.3 ± 1.8 cups per day vs. 3.8 ± 2.0 in controls P = 0.02). In the regression model including intake of alcohol, coffee, and smoke, only coffee (P = 0.007) and alcohol intake (P = 0.021) remained significant whereas smoking was no longer significant. Thus, it seems as though only coffee intake reduces the risk of PD in general while associations to alcohol and smoking differ between PIGD and TD-PD patients.
Assuntos
Marcha , Doença de Parkinson/etiologia , Equilíbrio Postural , Consumo de Bebidas Alcoólicas/efeitos adversos , Café/efeitos adversos , Comportamento de Ingestão de Líquido , Humanos , Doença de Parkinson/fisiopatologia , Análise de Regressão , Fatores de Risco , Índice de Gravidade de Doença , Fumar/efeitos adversos , Estatísticas não ParamétricasRESUMO
BACKGROUND: Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs' syndrome). METHODS: To prepare consensus guidelines for the treatment of the autoimmune NMT disorders, references retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts. CONCLUSIONS: Anticholinesterase drugs should be given first in the management of MG, but with some caution in patients with MuSK antibodies (good practice point). Plasma exchange is recommended in severe cases to induce remission and in preparation for surgery (recommendation level B). IvIg and plasma exchange are effective for the treatment of MG exacerbations (recommendation level A). For patients with non-thymomatous MG, thymectomy is recommended as an option to increase the probability of remission or improvement (recommendation level B). Once thymoma is diagnosed, thymectomy is indicated irrespective of MG severity (recommendation level A). Oral corticosteroids are first choice drugs when immunosuppressive drugs are necessary (good practice point). When long-term immunosuppression is necessary, azathioprine is recommended to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (recommendation level A). 3,4-Diaminopyridine is recommended as symptomatic treatment and IvIG has a positive short-term effect in LEMS (good practice point). Neuromyotonia patients should be treated with an antiepileptic drug that reduces peripheral nerve hyperexcitability (good practice point). For paraneoplastic LEMS and neuromyotonia optimal treatment of the underlying tumour is essential (good practice point). Immunosuppressive treatment of LEMS and neuromyotonia should be similar to MG (good practice point).
Assuntos
Doenças Autoimunes/terapia , Protocolos Clínicos/normas , Doenças da Junção Neuromuscular/terapia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/tendências , Humanos , Síndrome de Isaacs/tratamento farmacológico , Síndrome de Isaacs/imunologia , Síndrome de Isaacs/terapia , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Síndrome Miastênica de Lambert-Eaton/imunologia , Síndrome Miastênica de Lambert-Eaton/terapia , MEDLINE , Metanálise como Assunto , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Doenças da Junção Neuromuscular/tratamento farmacológico , Doenças da Junção Neuromuscular/imunologia , Literatura de Revisão como AssuntoRESUMO
OBJECTIVE: Resection of meningiomas involving the cavernous sinus often is incomplete and associated with considerable morbidity. As a result, an increasing number of patients with such tumors have been treated with gamma knife surgery (GKS). However, few studies have investigated the long-term outcome for this group of patients. METHODS: 100 patients (23 male/77 female) with meningiomas involving the cavernous sinus received GKS at the Department of Neurosurgery at Haukeland University Hospital, Bergen, Norway, between November 1988 and July 2006. They were followed for a mean of 82.0 (range, 0-243) months. Only 2 patients were lost to long-term follow-up. Sixty patients underwent craniotomy before radiosurgery, whereas radiosurgery was the primary treatment for 40 patients. RESULTS: Tumor growth control was achieved in 84.0% of patients. Twelve patients required re-treatment: craniotomy (7), radiosurgery (1), or both (4). Three out of 5 patients with repeated radiosurgery demonstrated secondary tumor growth control. Excluding atypical meningiomas, the growth control rate was 90.4%. The 1-, 5-, and 10-year actuarial tumor growth control rates are 98.9%, 94.2%, and 91.6%, respectively. Treatment failure was preceded by clinical symptoms in 14 of 15 patients. Most tumor growths appeared within 2.5 years. Only one third grew later (range, 6-20 yr). The complication rate was 6.0%: optic neuropathy (2), pituitary dysfunction (3), worsening of diplopia (1), and radiation edema (1). Mortality was 0. At last follow-up, 88.0% were able to live independent lives. CONCLUSION: GKS gives long-term growth control and has a low complication rate. Most tumor growths manifest within 3 years following treatment. However, some appear late, emphasizing the need for long-term follow-up.
Assuntos
Seio Cavernoso/cirurgia , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Radiocirurgia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos Longitudinais , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Paraneoplastic myasthenia gravis (MG) is accompanied by a neoplasm, usually thymoma. In patients with thymoma and a specific genetic make-up, the paraneoplastic immune response develops further in thymic remnant or peripheral lymphatic tissue. Paraneoplastic MG and late-onset MG (age >or= 50 years) share a similar immunological profile with high titin and ryanodine receptor (RyR) antibody prevalence. This profile is the most important predictor of clinical outcome in paraneoplastic MG. The presence of a thymoma per se does not cause more severe MG. MG severity is linked to the patient's immunological profile. Paraneoplastic MG causes a distinctive non-limb symptom profile at MG onset, characterized by bulbar, ocular, neck, and respiratory symptoms. When the diagnosis of paraneoplastic MG is established, the neoplasm should be removed surgically. Pre-thymectomy plasmapheresis or iv-IgG should be considered in these patients to minimize post-thymectomy MG exacerbation risk. Paraneoplastic MG usually continues after thymectomy. The pharmacological treatment of paraneoplastic MG does not differ from non-paraneoplastic MG, except for tacrolimus that should be considered in difficult cases. Tacrolimus is an immunosuppressant acting specifically in RyR antibody positive patients through enhancing RyR-related sarcoplasmic calcium release that in theory might be blocked by RyR antibodies, causing symptomatic relief in paraneoplastic MG.
Assuntos
Miastenia Gravis/etiologia , Polineuropatia Paraneoplásica/etiologia , Timoma/complicações , Neoplasias do Timo/complicações , Idade de Início , Atrofia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Terapia Combinada , Conectina , Humanos , Hiperplasia , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Proteínas Musculares/imunologia , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/epidemiologia , Miastenia Gravis/imunologia , Proteínas do Tecido Nervoso/imunologia , Polineuropatia Paraneoplásica/tratamento farmacológico , Polineuropatia Paraneoplásica/imunologia , Plasmaferese , Prognóstico , Proteínas Quinases/imunologia , Receptores Colinérgicos/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Timectomia , Timoma/imunologia , Timoma/cirurgia , Timo/patologia , Neoplasias do Timo/imunologia , Neoplasias do Timo/cirurgiaAssuntos
Neuroborreliose de Lyme/complicações , Síndrome de Opsoclonia-Mioclonia/diagnóstico , Síndrome de Opsoclonia-Mioclonia/microbiologia , Adulto , Antibacterianos/administração & dosagem , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Ataxia/microbiologia , Ataxia/fisiopatologia , Borrelia burgdorferi/imunologia , Encéfalo/microbiologia , Encéfalo/fisiopatologia , Ceftriaxona/administração & dosagem , Feminino , Humanos , Neuroborreliose de Lyme/diagnóstico , Neuroborreliose de Lyme/fisiopatologia , Imageamento por Ressonância Magnética , Náusea/etiologia , Cervicalgia/microbiologia , Noruega , Síndrome de Opsoclonia-Mioclonia/fisiopatologia , Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Important progress has been made in our understanding of the cellular and molecular processes underlying the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia (peripheral nerve hyperexcitability; Isaacs syndrome). To prepare consensus guidelines for the treatment of the autoimmune NMT disorders. References retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts and a patient representative. The proposed practical treatment guidelines are agreed upon by the Task Force: (i) Anticholinesterase drugs should be the first drug to be given in the management of MG (good practice point). (ii) Plasma exchange is recommended as a short-term treatment in MG, especially in severe cases to induce remission and in preparation for surgery (level B recommendation). (iii) Intravenous immunoglobulin (IvIg) and plasma exchange are equally effective for the treatment of MG exacerbations (level A Recommendation). (iv) For patients with non-thymomatous autoimmune MG, thymectomy (TE) is recommended as an option to increase the probability of remission or improvement (level B recommendation). (v) Once thymoma is diagnosed TE is indicated irrespective of the severity of MG (level A recommendation). (vi) Oral corticosteroids is a first choice drug when immunosuppressive drugs are necessary in MG (good practice point). (vii) In patients where long-term immunosuppression is necessary, azathioprine is recommended together with steroids to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (level A recommendation). (viii) 3,4-diaminopyridine is recommended as symptomatic treatment and IvIg has a positive short-term effect in LEMS (good practice point). (ix) All neuromyotonia patients should be treated symptomatically with an anti-epileptic drug that reduces peripheral nerve hyperexcitability (good practice point). (x) Definitive management of paraneoplastic neuromyotonia and LEMS is treatment of the underlying tumour (good practice point). (xi) For immunosuppressive treatment of LEMS and NMT it is reasonable to adopt treatment procedures by analogy with MG (good practice point).
Assuntos
Doenças Autoimunes do Sistema Nervoso/terapia , Doenças da Junção Neuromuscular/terapia , Corticosteroides/uso terapêutico , Azatioprina/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Síndrome Miastênica de Lambert-Eaton/terapia , MEDLINE/estatística & dados numéricos , Miastenia Gravis/terapia , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Troca Plasmática/métodos , Timectomia/métodosRESUMO
Some myasthenia gravis (MG) patients have antibodies against skeletal muscle antigens in addition to the acetylcholine receptor (AChR). Two major antigens for non-AchR antibodies in MG are the Ca(2+) release channel of the sarcoplasmic reticulum, the ryanodine receptor (RyR) and titin, a gigantic filamentous muscle protein essential for muscle structure, function and development. RyR and titin antibodies are found mainly in thymoma MG patients and in a few late-onset MG patients and correlate with a severe MG disease. The presence of titin antibodies, which bind to key regions near the A/I junction and in the central I-band, correlates with myopathy. The immunosuppressant (FK506), which enhances Ca(2+) release from the RyR, seems to have a symptomatic effect on MG patients with RyR antibodies. The RyR antibodies recognize a region near the N-terminus important for channel regulation and inhibit Ca(2+) release in vitro. However, evidence that antibodies against the intracellular antigens RyR and titin are pathogenic in vivo is still missing.
Assuntos
Anticorpos/fisiologia , Proteínas Musculares/imunologia , Miastenia Gravis/imunologia , Proteínas Quinases/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Conectina , Humanos , Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To investigate the role of acetylcholine receptor (AChR) and other anti-muscle autoantibodies in myasthenia gravis (MG). Since many of these autoantibodies target proteins with structural or signalling functions, we examined the effect of MG sera on muscle cell morphology. MATERIALS AND METHODS: Primary human myoblast cultures were exposed to MG sera and morphological changes observed by light and fluorescence microscopy. RESULTS: MG patient sera caused changes in cell shape (cell retraction) and led to the formation of inclusion bodies and intracellular vesicles. A disordered arrangement of actin microfilaments was also observed. The effects were not complement-mediated, were both dose- and time-dependent, and appeared to correlate with disease severity of the MG donor. CONCLUSION: The factors responsible for these effects in vitro may also play a role in the pathogenesis of MG in vivo. Further study of these factors may improve our understanding of MG pathogenesis.
Assuntos
Autoanticorpos/fisiologia , Proteínas Musculares/imunologia , Miastenia Gravis/patologia , Mioblastos/patologia , Receptores Colinérgicos/imunologia , Soro/fisiologia , Apoptose/fisiologia , Técnicas de Cultura de Células , Núcleo Celular/patologia , Citoesqueleto/patologia , Humanos , Miastenia Gravis/imunologiaRESUMO
Thymectomy is still widely carried out in myasthenia gravis (MG) patients, but its role, especially in late-onset MG patients, is not established. These patients are immunologically heterogeneous, some with thymoma-like and others with early onset-like features. We evaluated whether any therapeutic effects of thymectomy correlate with the presence of non-acetylcholine receptor (AChR) muscle antibodies. The severity of MG, and titin and ryanodine receptor (RyR) antibodies, were assessed yearly starting from MG onset in 21 thymectomized and 22 non-thymectomized AChR antibody positive late-onset MG patients, who were followed for 2, 3 and 5 years. Clinical or pharmacological remission were seen in six of 11 titin antibody negative but none of the 10 titin antibody positive thymectomized patients, however, the non-thymectomized cases showed an opposite trend. The three MG-related deaths were all in patients with titin antibodies. There was no significant difference in MG severity between thymectomized and non-thymectomized patients; 2 years after MG onset, both groups were significantly improved. This study showed no dramatic benefit from thymectomy in late-onset MG in general. Any limited improvement appeared less likely in cases with titin and/or RyR antibodies.
Assuntos
Autoanticorpos/imunologia , Músculo Esquelético/imunologia , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Timectomia , Idade de Início , Idoso , Atrofia , Estudos de Coortes , Conectina , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/imunologia , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Miastenia Gravis/patologia , Proteínas Quinases/imunologia , Receptores Colinérgicos/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Timo/patologiaRESUMO
Some myasthenia gravis (MG) patients have antibodies against skeletal muscle antigens in addition to the acetylcholine receptor (AChR). A major antigen for these antibodies is the Ca2+ release channel of the sarcoplasmic reticulum the ryanodine receptor (RyR). These antibodies are found mainly in MG patients with a thymoma MG and correlate with severe MG symptoms. The antibodies recognize a region near the N-terminus on the RyR, which seems to be of importance for RyR regulation. The antibodies cause allosteric inhibition of RyR function in vitro, inhibiting Ca2+ release from sarcoplasmic reticulum.
Assuntos
Autoimunidade , Miastenia Gravis/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Animais , Humanos , Imunossupressores/uso terapêutico , Técnicas In Vitro , Miastenia Gravis/complicações , Miastenia Gravis/tratamento farmacológico , Timoma/complicações , Timoma/imunologia , Neoplasias do Timo/complicações , Neoplasias do Timo/imunologiaRESUMO
Similar to human autoimmune myasthenia gravis (MG), canine MG occurs spontaneously and is associated with autoantibodies against the nicotinic acetylcholine receptor (AChR). In addition to AChR, human MG patients with thymoma or late-onset MG have antibodies against titin and ryanodine receptor (RyR). The objective of this study was to establish if dogs with confirmed MG (AChR antibody titer >0.6 nmol/l) also developed titin and RyR antibodies and identify possible associations with thymoma, late age of onset, or severity of clinical signs. Sera from dogs (n=430) with previously diagnosed autoimmune MG (N=415), other immune-mediated neuromuscular disorders including polymyositis (PM) and masticatory muscle myositis (N=5), and control dogs (N=10) were evaluated for the presence of titin antibodies in ELISA using MGT-30 as antigen, a peptide representing the main immunogenic region (MIR) for human titin antibodies. Titin antibody positive sera were further examined for RyR antibodies in Western blots using a RyR fusion protein (pc2-RyR) as antigen, which covers the MIR for human MG sera. Titin antibodies were found in sera of 80/430 dogs. Thymoma was present in 11/80 and age of onset was after 4 years in 66/80 titin positive dogs. Two of the titin positive dogs had PM. RyR antibodies were found in 13/80 sera (8/13 thymoma, 12/13 age of onset after 4 years, and 1/13 PM). Neither titin nor RyR antibodies were found in sera of healthy control dogs. Acute fulminating MG was described in five dogs with both titin and RyR antibodies. From these studies we conclude that titin and RyR antibodies in canine and human MG have a similar association with thymoma, late-onset MG, and possibly with more severe forms of MG.
Assuntos
Autoanticorpos/sangue , Doenças do Cão/imunologia , Proteínas Musculares/imunologia , Miastenia Gravis/veterinária , Proteínas Quinases/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Timoma/imunologia , Timoma/veterinária , Neoplasias do Timo/veterinária , Idade de Início , Animais , Autoanticorpos/imunologia , Western Blotting/veterinária , Conectina , Cães , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Miastenia Gravis/imunologia , Radioimunoensaio/veterinária , Neoplasias do Timo/imunologiaRESUMO
BACKGROUND: Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR). Non-AChR muscle autoantibodies are present in many MG serum samples, mainly from patients with thymoma or late-onset MG. The exact relationship between MG severity and several non-AChR muscle antibodies is unknown. OBJECTIVE: To study the correlation between the severity of MG and the concentration of antibodies against striated muscle tissue sections, titin, citric acid antigen, ryanodine receptor, and AChR. SETTING: The severity of MG was graded in 146 consecutive patients with MG, and their serum samples were tested for the presence of autoantibodies. Ten patients who were titin antibody positive were observed in longitudinal follow-up. RESULTS: No significant difference was found in MG severity between late-onset and thymoma MG. Titin, citric acid antigen, and ryanodine receptor antibodies occurred significantly more often among patients with severe MG than among patients with less severe disease. Changes in MG severity correlated with changes in titin antibody titer in the individual patient. Titin antibodies showed a better longitudinal correlation with disease severity than the AChR antibodies. CONCLUSIONS: Non-AChR muscle autoantibodies occurred more frequently in severe MG regardless of MG subgroup. Thymoma per se does not generate a more severe MG. It may well be the presence of a humoral immune response to non-AChR muscle antigens such as titin, citric acid antigen, and ryanodine receptor that leads to a severe disease, not the presence of thymoma or a late age of onset. These antibodies can serve as important prognostic markers in MG regardless of the presence of thymoma.
Assuntos
Autoanticorpos/sangue , Ácido Cítrico/imunologia , Proteínas Musculares/imunologia , Músculo Esquelético/imunologia , Miastenia Gravis/imunologia , Proteínas Quinases/imunologia , Receptores Colinérgicos/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Adulto , Idade de Início , Conectina , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Timoma/complicações , Neoplasias do Timo/complicaçõesRESUMO
Titins are a family of gigantic filamentous muscle proteins essential for muscle structure, function and development. Most of their sequence consists of repetitive modules of two superfamily motifs, immunoglobulin and fibronectin, interspersed with unique sequences. A special feature is that many regions are differentially expressed in different muscle types, providing unique characteristics. Titin is evolutionarily old, and many regions are highly conserved. Most mutations that alter titin's characteristics seem to be incompatible with life, since very few associated genetic diseases have been described. The autoimmune response against titin in the paraneoplastic form of myasthenia gravis is discussed.
Assuntos
Proteínas Musculares/fisiologia , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Proteínas Quinases/fisiologia , Animais , Autoanticorpos/imunologia , Cromossomos/metabolismo , Conectina , Elasticidade , Humanos , Proteínas Musculares/química , Proteínas Musculares/genética , Proteínas Musculares/imunologia , Músculo Esquelético/citologia , Miastenia Gravis/imunologia , Miastenia Gravis/fisiopatologia , Síndromes Paraneoplásicas/imunologia , Síndromes Paraneoplásicas/fisiopatologia , Proteínas Quinases/química , Proteínas Quinases/genética , Proteínas Quinases/imunologiaRESUMO
To elucidate the mechanism of immune damage caused by titin and ryanodine receptor (RyR) autoantibodies in myasthenia gravis (MG), we studied the complement-activating capacity and the IgG subclass distribution of these autoantibodies in sera from 49 MG patients. Complement activation occurred in 38 out of 49 titin antibody positive sera, and in 14 out of 21 RyR antibody positive sera. The titin antibodies occurred only in the IgG 1 and IgG 4 subclasses, whereas the RyR antibodies occurred in all four IgG subclasses but with IgG 1 predominance. Complement-activating RyR antibodies occurred with higher frequency in sera of thymoma MG than of late-onset MG. RyR IgG 1 antibodies occurred more often in severe MG than in mild and moderate disease groups. Mean total IgG and IgG 1 titin and RyR antibody titers fell during long-time patient observation together with an improvement of the MG symptoms.
Assuntos
Autoanticorpos/imunologia , Ativação do Complemento/imunologia , Imunoglobulina G/imunologia , Proteínas Musculares/imunologia , Miastenia Gravis/imunologia , Proteínas Quinases/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Adulto , Idade de Início , Idoso , Autoanticorpos/sangue , Conectina , Feminino , Humanos , Imunoglobulina G/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Receptores Colinérgicos/imunologia , Timoma/imunologiaRESUMO
Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR), but several other muscle autoantibodies have also been identified in patient sera. We studied muscle autoantibodies against AChR, striated muscle tissue sections (SH), titin, citric acid antigen (CA), and ryanodine receptor (RyR) in sera from 146 consecutive MG patients to evaluate whether a single test or several tests together can predict a thymoma. The MG patients were divided into five subgroups; ocular MG, early-onset MG (< 50 years), late-onset MG (> 50 years), MG with thymoma, and AChR antibody negative MG. AChR, SH, titin, CA, and RyR antibodies were detected in 85%, 34%, 34%, 25%, and 14% of the MG patients, respectively. For thymoma MG, AChR, SH, titin, CA, and RyR antibodies were detected in 100%, 75%, 95%, 70%, and 70% respectively. SH, titin, CA, RyR antibodies, and computed tomography of the anterior mediastinum have similar sensitivity for thymoma MG. The specificity of RyR, titin, CA, and SH antibodies for thymoma was 70%, 39%, 38%, and 31%, respectively, which is significantly higher for RyR antibodies than for the others. No single muscle antibody assay can predict a thymoma, and a combination of several antibody assays is preferred, although RyR antibody testing alone showed 70% sensitivity and specificity for thymoma MG. SH and CA antibodies provided only little additional information.
Assuntos
Autoanticorpos/análise , Músculo Esquelético/imunologia , Miastenia Gravis/imunologia , Adulto , Idoso , Ácido Cítrico/imunologia , Conectina , Feminino , Previsões , Humanos , Masculino , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/etiologia , Neoplasias do Mediastino/cirurgia , Pessoa de Meia-Idade , Proteínas Musculares/imunologia , Miastenia Gravis/complicações , Proteínas Quinases/imunologia , Receptores Colinérgicos/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/imunologia , Timectomia , Timoma/diagnóstico por imagem , Timoma/etiologia , Timoma/cirurgia , Tomografia Computadorizada por Raios XRESUMO
We studied 65 patients with myasthenia gravis (MG). Clinical, neurophysiological, immunological, and histological findings suggested the coexistence of a presumed autoimmune myopathy. The clinical features were persistent pyridostigmine-resistant weakness and atrophy of striated muscles. The myopathy was found more often in patients with late-onset MG than in those with early-onset (37% vs 13%). Patients with myopathy were also prone to have other immune disorders (47% vs 13%). Elevated titres of antibodies against titin were detected more often in patients with electromyography (EMG) evidence of myopathy than in the sera of those without, and only in late-onset MG cases.
Assuntos
Autoanticorpos/imunologia , Proteínas de Ligação a Calmodulina/imunologia , Proteínas Musculares/imunologia , Miastenia Gravis/imunologia , Miastenia Gravis/fisiopatologia , Proteínas Quinases/imunologia , Adolescente , Adulto , Idade de Início , Conectina , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Músculo Esquelético/patologia , Miastenia Gravis/patologiaRESUMO
BACKGROUND: Tumor necrosis factor (TNF) alpha and TNF-beta are proinflammatory cytokines thought to be involved in the pathogenesis of myasthenia gravis (MG). OBJECTIVE: To examine whether TNF polymorphisms are associated with MG, MG subgroups, and the presence of titin and ryanodine-receptor antibodies. PATIENTS AND METHODS: We did genotyping on 30 patients with MG and 92 healthy blood donors for 2 biallelic TNFA polymorphisms (G to A at positions -238 and -308) and 1 TNFB polymorphism (NcoI digestive site) using methods based on the polymerase chain reaction. RESULTS: Patients with thymoma were typically homozygous for both the TNFA*T1 and the TNFB*2 alleles, but patients having an early onset of MG without thymoma were carriers of the TNFA*T2 and TNFB*1 alleles. Patients without thymoma who had the titin antibody had the same high frequency of TNFA*T1 and TNFB*2 as patients with thymoma, whereas patients without the titin antibody carried the same allele, TNFA*T2 and TNFB*1, regardless of age and thymic disease. No association was found with acetylcholine-receptor levels or disease severity for any of the TNFA or TNFB polymorphisms. CONCLUSION: Patients having MG, including those with thymoma, who have the titin antibody are most often homozygous for the TNFA*T1 and TNFB*2 alleles, whereas the presence of the TNFA*T2 and TNFB*1 alleles correlates with early-onset MG and the absence of titin antibodies.