RESUMO
Striational autoantibodies (StrAb), which react with elements of skeletal muscle cross-striations, occur frequently in patients with thymoma associated with myasthenia gravis (MG). Dissociated thymic lymphocytes from 22 of 72 MG patients secreted StrAb when cultured with PWM. A high yield of EBV-transformed B cell lines was established from thymus, thymoma, and peripheral blood of seven patients with MG, but clones secreting StrAb arose only from the three patients who had StrAb in their sera. The monoclonal StrAb bound to A bands or I bands in skeletal muscle of human, rat, and frog. One bound to mitochondria in addition to myofibrillar I bands. None bound to nuclei, smooth muscle, or gastric mucosal cells. In immunoblot analyses and ELISAs the monoclonal StrAb bound to muscle and nonmuscle isotypes of myosin, alpha actinin, and/or actin. All bound to contractile proteins common to thymus and muscle, and one selectively immunostained epithelial cells of the thymic medulla. From these antigenic specificities we suggest that StrAb might arise as an immune response directed against the cytoskeletal anchoring proteins associated with nicotinic acetylcholine receptors in thymic epithelial cells undergoing neoplastic transformation to thymoma.
Assuntos
Actinina/imunologia , Actinas/imunologia , Autoanticorpos/biossíntese , Músculos/imunologia , Miastenia Gravis/imunologia , Miosinas/imunologia , Adulto , Idoso , Animais , Anticorpos Monoclonais/biossíntese , Linfócitos B/imunologia , Células Clonais , Feminino , Herpesvirus Humano 4 , Humanos , Imunoglobulina M/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Ratos , Receptores Colinérgicos/imunologia , Timoma/imunologia , Timo/imunologiaRESUMO
Immunization of animals with acetylcholine receptor (AChR) protein from the electric organs of Electrophorus electricus and Torpedo californica induces an autoimmune response to the AChR of mammalian skeletal muscle. Rats and guinea pigs develop experimental autoimmune myasthenia gravis (EAMG) after a single inoculation with small quantities of AChR and adjuvant. The indicence and severity of disease appears to depend on the dose of AChR and stability of the emulsion. EAMG is strikingly similar to myasthenia gravis (MG) of man in its clinical picture and its electrophysiological abnormalities. The presence of antibodies to syngeneic rat muscle AChR in the serum of rats with EAMG documents the existence of autoimmunity in the experimental disease. A common immunopathogenesis is suggested for both EAMG and mg.
Assuntos
Doenças Autoimunes , Modelos Animais de Doenças , Miastenia Gravis/imunologia , Acetilcolina , Animais , Autoanticorpos/análise , Peso Corporal , Órgão Elétrico/imunologia , Eletromiografia , Electrophorus , Feminino , Cobaias , Miastenia Gravis/etiologia , Miastenia Gravis/fisiopatologia , Neostigmina/farmacologia , Postura , Ratos , Células Receptoras Sensoriais/imunologia , Venenos de Serpentes/farmacologiaRESUMO
Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.
Assuntos
Autoanticorpos , Miastenia Gravis/imunologia , Receptores Colinérgicos , Animais , Complexo Antígeno-Anticorpo , Autoanticorpos/análise , Sítios de Ligação , Bungarotoxinas/metabolismo , Electrophorus/imunologia , Feminino , Músculos , Miastenia Gravis/fisiopatologia , Junção Neuromuscular/fisiopatologia , Ratos , Ratos Endogâmicos Lew , Transmissão SinápticaRESUMO
Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.
Assuntos
Autoanticorpos , Miastenia Gravis/imunologia , Receptores Colinérgicos , Animais , Complexo Antígeno-Anticorpo , Autoanticorpos/análise , Proteínas do Sistema Complemento/metabolismo , Feminino , Imunização Passiva , Potenciais da Membrana , Miastenia Gravis/fisiopatologia , Junção Neuromuscular/fisiopatologia , Fagocitose , Ratos , Transmissão Sináptica , Fatores de TempoRESUMO
An acute phase of experimental autoimmune myasthenia gravis (EAMG) occurs transiently early in the immune response of Lewis rats to nicotinic acetylcholine receptors (AChR) when Bordetella pertussis is used as adjuvant. It is characterized by a destructive cellular attack directed at the postsynaptic membranes of muscle. Acute EAMG can be passively transferred to normal rats by IgG from serum of rats with chronic EAMG. In the present study, acute EAMG, induced either by passive transfer of syngeneic antibodies or by active immmunization, was inhibited in rats depleted of complement by treatment with cobra venom factor (CoF). Furthermore, passive transfer of antibodies in excess of the muscle's content of AChR was without any measurable effect in rats treated with CoF. Although 60% of the muscle's AChR was complexed with antibody, there was no reduction in the muscle's content of AChR, and neuromuscular transmission was not compromised as judged electromyographically by curare sensitivity. These data imply that redistribution, accelerated degradation, and impairment of the ionophore function of AChR, effects of antibodies described in vitro on extrajunctional AChR, do not play a significant role in vivo in impairing neuromuscular transmission in an intact neuromuscular junction. Complement appears to be a critical mediator of anti-AChR antibodies' pathogenicity in vivo.
Assuntos
Doenças Autoimunes/etiologia , Proteínas do Sistema Complemento/fisiologia , Miastenia Gravis/etiologia , Animais , Anticorpos , Complemento C3/fisiologia , Venenos Elapídicos/farmacologia , Imunização Passiva , Miastenia Gravis/imunologia , Junção Neuromuscular/imunologia , Ratos , Receptores Nicotínicos/imunologia , Membranas Sinápticas/imunologia , Transmissão SinápticaRESUMO
The smaller form of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD65) is a major autoantigen in two human diseases that affect its principal sites of expression. Thus, destruction of pancreatic beta cells, which results in insulin-dependent diabetes mellitus (IDDM), and impairment of GABA-ergic synaptic transmission in Stiff-Man syndrome (SMS) are both characterized by circulating autoantibodies to GAD65. Anti-GAD65 autoantibodies in IDDM are predominantly directed to conformational epitopes. Here we report the characterization of humoral autoimmune responses to GAD65 in 35 SMS patients, of whom 13 (37%) also had IDDM. All SMS patients immunoprecipitated native GAD65 and the main titers were orders of magnitude higher than in IDDM patients. Furthermore, in contrast to the situation in IDDM, autoantibodies in 35 of 35 (100%) of SMS patients recognized denatured GAD65 on Western blots. Two major patterns of epitope specificity were identified on Western blots. The first pattern, detected in 25 of 35 SMS patients (71%), of whom 11 had IDDM (44%), was predominantly reactive with a linear NH2-terminal epitope residing in the first eight amino acids of GAD65. Nine of nine individuals who were HLA-haplotyped in this group carried an IDDM susceptibility haplotype and HLA-DR3, DQw2 was particularly abundant. The second pattern, detected in 10 of 35 patients (29%) of whom two had IDDM (20%), included reactivity with the NH2-terminal epitope plus strong reactivity with one or more additional epitope(s) residing COOH-terminal to amino acid 101. The second epitope pattern may represent epitope spreading in the GAD65 molecule, but may also include some cases of epitope recognition associated with IDDM resistant HLA-haplotypes. The principal NH2-terminal linear epitope in GAD65 distinguishes the reactivity of SMS and IDDM autoantibodies and may be a determinant of pathogenicity for GABA-ergic neurons. The greater magnitude and distinct specificity of the humoral response to GAD65 in SMS may reflect a biased involvement of the T helper cell type 2 (Th2) subset of CD4+ T cells and antibody responses, whereas IDDM is likely mediated by the Th1 subset of CD4+ T cells and cytotoxic T cell responses.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Epitopos/imunologia , Glutamato Descarboxilase/imunologia , Rigidez Muscular Espasmódica/imunologia , Adulto , Idoso , Especificidade de Anticorpos , Feminino , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Masculino , Pessoa de Meia-Idade , Testes de PrecipitinaRESUMO
The clinical course of immune mediated optic neuritis (ON) will depend on the specific underlying inflammatory disease. These disorders have traditionally been classified according to clinical and MRI findings. Aquaporin-4 (AQP4) autoantibodies (neuromyelitis optica-IgG (NMO-IgG)) may have diagnostic and prognostic value in patients who present with isolated ON. In this prospective study, NMO-IgG was evaluated in 114 patients with ON in the following contexts: neuromyelitis optica (NMO), multiple sclerosis (MSON), chronic relapsing inflammatory ON (CRION), relapsing isolated ON (RION) and single isolated ON (SION). The proportion seropositive was 56% for NMO (n = 9), 0% for MSON (n = 28) and 5% for the remaining diagnostic categories (CRION (n = 19), RION (n = 17) and SION (n = 41)). Testing for NMO-IgG in patients with recurrent or severe ON who lack convincing evidence of MS may identify patients who would benefit from immunosuppression rather than MS directed immunomodulatory therapies.
Assuntos
Aquaporina 4/imunologia , Autoanticorpos/sangue , Neuromielite Óptica/imunologia , Neurite Óptica/imunologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Mielite/imunologia , Neurite Óptica/diagnóstico , Prognóstico , Estudos Prospectivos , Síndrome , Adulto JovemRESUMO
The Lambert-Eaton myasthenic syndrome (LES) is an autoimmune presynaptic disorder of peripheral cholinergic neurotransmission in which there is often an associated small cell lung carcinoma (SCC). SCC lines established from patients with and without LES exhibit a Ca2+ influx response to depolarization by K+ that is consistent with the presence of voltage-gated Ca2+ channels. Autoantibodies antagonistic to SCC Ca2+ channel activity were found exclusively in patients with LES, independent of cancer status. Depolarization-induced uptake of 45Ca2+ by SCC lines was reduced maximally after 3-4 days of exposure to serum immunoglobulins from 14 of 19 LES patients, while 53 control immunoglobulins (including patients with SCC, other tumors, other paraneoplastic syndromes, and other neurological and autoimmune diseases) were without effect. The snail neurotoxin omega-conotoxin of subtype GVIA, which is a specific antagonist of presynaptic Ca2+ channels, inhibited K+-stimulated Ca2+ uptake in a dose-dependent manner that was essentially irreversible. Adenosine, reported to be a specific antagonist of neuronal Ca2+ channels, also impaired voltage-stimulated Ca2+ influx in SCC. Use of LES patients' IgG and omega-conotoxin in further studies of SCC may facilitate identification and purification of the LES antigen(s) and yield a quantitative serological test for diagnosing this autoimmune paraneoplastic syndrome.
Assuntos
Doenças Autoimunes/metabolismo , Cálcio/metabolismo , Carcinoma de Células Pequenas/metabolismo , Canais Iônicos/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Doenças Musculares/metabolismo , Síndromes Paraneoplásicas/metabolismo , Adenosina/farmacologia , Autoanticorpos/imunologia , Bloqueadores dos Canais de Cálcio/farmacologia , Humanos , Imunoglobulina G/imunologia , Venenos de Moluscos/farmacologia , Células Tumorais Cultivadas , ômega-Conotoxina GVIARESUMO
The new synthesis of myelin and the proliferation of oligodendrocytes was stimulated by serum from syngeneic mice immunized with homogenized spinal cord (SCH). Treatment with this antiserum produced a 10-fold increase in the area of remyelination in spinal cords that had become demyelinated previously as a result of infection by Theiler's murine encephalomyelitis virus. Inflammation was decreased in regions of white matter that showed remyelination. Oligodendrocytes exposed to anti-SCH in vitro incorporated three to five times more [3H]thymidine than resting cells did and expressed more myelin basic protein in their cytoplasm, suggesting stimulation of myelinogenesis. Thus, there is a factor present in anti-SCH antiserum that stimulates central nervous system-type remyelination. This finding may provide clues for the therapy of patients with demyelinating disorders such as multiple sclerosis.
Assuntos
Doenças Desmielinizantes/terapia , Imunização Passiva , Proteínas da Mielina/biossíntese , Bainha de Mielina/metabolismo , Neuroglia/patologia , Oligodendroglia/patologia , Medula Espinal/imunologia , Animais , Divisão Celular , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Feminino , Imunofluorescência , Vírus Elberfeld do Camundongo/imunologia , Camundongos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Proteína Básica da Mielina/biossíntese , Bainha de Mielina/patologia , Oligodendroglia/metabolismo , Medula Espinal/patologia , Medula Espinal/ultraestrutura , Timidina/metabolismoRESUMO
Neuromuscular junction ultrastructure in rat forelimb digit extensor muscle was sequentially and quantitatively investigated in experimental autoimmune myasthenia gravis (EAMG). Experimental animals were immunized with highly purified eel electroplax acetylcholine receptor protein plus complete Freund's adjuvant and B pertussis vaccine; control animals received only adjuvant and vaccine. During the first 7 days (latent period) after immunization end-plate structure and neuromuscular transmission remained normal in the experimental group. Between day 7 and 11 (acute phase) mononuclear cells infiltrated those regions of muscle where the end-plates were located and there was intense degeneration of the postsynaptic regions with splitting away of abnormal junctional folds from the underlying muscle fibers. Macrophages entered the gaps thus formed and removed the degenerating folds by phagocytosis. The nerve terminals were displaced from their usual location but maintained their structural integrity. Neuromuscular transmission was blocked in many muscle fibers. Miniature end-plate potentias (MEPPs), detectable in only a few fibers, were of abnormally low amplitude. After day 11 (chronic phase) the nerve terminals returned to the highly simplified postsynaptic folds became reconstituted and again degenerated. Immature junctions with poorly differentiated postsynaptic regions and nerve sprouts near end-plates were also observed. In two animals relapsing during the chronic phase degeneration of the postsynaptic folds was more intense than in the other chronic-phase animals. The posysynaptic membrane length and length per unit area and the MEPP amplitudes were significantly decreased in all chronic phase animals and the decreases were greater in the relapsing than in the non-lapsing animals. Minor morphometric alterations were also observed in the nerve terminals. These might have been secondary to the postsynaptic changes. The postsynaptic region is the primary target of the autoimmune reaction in EAMG. The ultrastructural, morphometric and electrophysiological abnormalities of the end-plate in chronic EAMG resemble those which have been observed in human myasthenia gravis.
Assuntos
Placa Motora/fisiopatologia , Placa Motora/ultraestrutura , Miastenia Gravis/patologia , Junção Neuromuscular/fisiopatologia , Junção Neuromuscular/ultraestrutura , Animais , Feminino , Mitocôndrias/ultraestrutura , Músculos/ultraestrutura , Miastenia Gravis/fisiopatologia , Ratos , Membranas Sinápticas/ultraestrutura , Vesículas Sinápticas/ultraestrutura , Fatores de TempoRESUMO
Rats immunized with purified torpedo acetylcholine receptor (AChR) plus adjuvants developed chronic experimental autoimmune myasthenia gravis (EAMG) after day 28. Forelimb muscles from EAMG rats 29 to 103 days after immunization and from control animals were used for the ultrastructural localization of IgG and C3. IgG was demonstrated with rabbit anti-rat IgG followed by treatment with peroxidase-labeled staphylococcal protein A; and C3 with peroxidase-labeled rabbit anti-rat C3, or with unlabeled rabbit anti-rat C3 followed by peroxidase-labeled protein A. In EAMG rats both IgG and C3 were localized on the terminal expansions of the junctional folds, where AChR is known to be located, and on detached, degenerated parts of the folds in the synaptic space. Background staining was negligible. The findings provide unambiguous evidence for a destructive autoimmune reaction involving the postsynaptic membrane in EAMG, implicate the complement system in this reaction and show that detachment of the tips of the junctional folds is one way by which immune complexes, and AChR, are eliminated from the postsynaptic membrane. The immuno-electron microscopic findings in chronic EAMG closely resemble those described in human myasthenia gravis.
Assuntos
Doenças Autoimunes/patologia , Complemento C3/análise , Doenças do Complexo Imune/patologia , Imunoglobulina G/análise , Placa Motora/ultraestrutura , Miastenia Gravis/patologia , Junção Neuromuscular/ultraestrutura , Animais , Doenças Autoimunes/imunologia , Feminino , Doenças do Complexo Imune/imunologia , Placa Motora/imunologia , Miastenia Gravis/imunologia , Ratos , Membranas Sinápticas/imunologia , Membranas Sinápticas/ultraestruturaRESUMO
Anti-acetylcholine receptor (AChR) autoantibodies are a marker of acquired myasthenia gravis (MG). Some of these antibodies cause muscle weakness. Striational autoantibodies (StrAb) also are a marker of MG. They are most prevalent in older patients and patients with thymoma. Here we describe a reproducible enzyme immunoassay (AChR-EIA) for detecting antibodies reactive with human muscle AChR, using antigens concentrated on plastic by prior sequential application of a biotinylated carrier, avidin, and biotinylated monoclonal IgG against AChR. There was significant correlation between values for antibodies assayed by AChR-EIA and by immunoprecipitation of AChR complexed with 125I-alpha-bungarotoxin. Unexpectedly, AChR-EIA and StrAb values also were significantly correlated. Further studies revealed a significant and unprecedented correlation for StrAb and AChR precipitating antibodies. A plausible explanation for these findings is that some StrAb may react with cytoskeletal proteins that associate and copurify with AChR. The AChR-EIA offers a nonradioactive method for detecting two autoantibodies that are relatively restricted to patients with acquired MG.
Assuntos
Autoanticorpos/análise , Técnicas Imunoenzimáticas , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Anticorpos Monoclonais , Avidina , Biotina , Humanos , PoliestirenosRESUMO
We tested thymus cells from 119 patients with acquired myasthenia gravis (MG) for in vitro production of acetylcholine receptor (AChR) binding antibodies (Ab); 109 were seropositive, of which 82 (75%) secreted AChRAb in vitro. As noted in earlier studies, thymus cell secretion of AChRAb paralleled serum Ab levels (rho s = 0.503; p < 0.0001; n = 119). Striational Ab secretion also correlated with the patients' serologic status. AChRAb secretion in vitro predicted the secretory activity of thymus cells implanted in severe combined immune deficiency (SCID) mice. Thymocytes from patients treated with corticosteroids made significantly less AChRAb than thymocytes from untreated patients (p < 0.005). Of particular note: (1) AChRAb was secreted by thymocytes from two of five nonimmunosuppressed patients who had generalized MG but who were seronegative for AChR binding autoantibodies; and (2) AChRAb secretion from both thymic and nonthymic sources was documented in a patient with noninvasive thymoma whose first signs of MG appeared 7 months after thymectomy. We conclude that the thymus in a majority of patients with acquired MG is the principal but not the sole reservoir of immunocytes that specifically react with muscle antigens.
Assuntos
Autoanticorpos/análise , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Timo/imunologia , Corticosteroides/uso terapêutico , Animais , Transplante de Células , Células Cultivadas , Feminino , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos SCID , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/fisiopatologia , Índice de Gravidade de Doença , Timo/patologia , Transplante HeterólogoRESUMO
We investigated specificities of acetylcholine receptor (AChR) antibodies in 100 seropositive patients with myasthenia gravis (MG). Antibodies in 74 of these sera were inhibited by more than 50% from binding to human muscle AChR by a rat monoclonal antibody (mAb) of "main immunogenic region" (MIR) specificity. The mAb inhibition was not explainable by epitope competition because (1) the mAb was reactive with both Torpedo and human AChR, but antibodies in 85 of the MG sera did not bind to Torpedo AChR, and (2) the mAb blocked binding of rat anti-peptide antibodies to an alpha subunit region of the human AChR unrelated antigenically to the designated MIR region. Individual patients' sera had evidence of extensive antibody heterogeneity and revealed interspecies polymorphisms in AChR antigenicity, near and remote from the neurotransmitter-binding region. The data challenge the concept that a MIR of the AChR is the principal stimulus for antibody production in MG and emphasize a potential pitfall in assuming seronegativity in MG on the basis of a single assay system.
Assuntos
Autoanticorpos/imunologia , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Adulto , Animais , Anticorpos Monoclonais/metabolismo , Especificidade de Anticorpos , Autoanticorpos/metabolismo , Sítios de Ligação de Anticorpos , Epitopos , Haplorrinos , Humanos , Camundongos , Músculos/metabolismo , Polimorfismo Genético , Ratos , TorpedoRESUMO
We tested the hypothesis that immunoglobulins directed against a CNS autoantigen, myelin basic protein, may promote remyelination in the course of a chronic, immune-mediated demyelinating disease. SJL/J mice infected chronically with Daniel's strain of Theiler's virus served as an experimental model of MS. The spinal cords of these mice exhibit extensive primary demyelination and inflammation with minimal spontaneous remyelination. Treatment with whole antiserum or affinity-purified mouse immunoglobulins directed against rat or rabbit myelin basic protein increased new myelin synthesis as measured by quantitative morphometry. Electron microscopy revealed numerous oligodendrocytes in remyelinated CNS lesions and a relative lack of inflammatory cells. Viral antigen persisted in the spinal cord despite enhanced CNS-type remyelination. These findings indicate that immunoglobulins reactive with myelin autoantigens have the potential to promote myelin repair.
Assuntos
Doenças Desmielinizantes/terapia , Imunoglobulinas/uso terapêutico , Proteína Básica da Mielina/imunologia , Bainha de Mielina/ultraestrutura , Poliomielite/terapia , Theilovirus , Animais , Western Blotting , Cerebelo/citologia , Cerebelo/patologia , Cerebelo/ultraestrutura , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Imunoglobulinas/farmacologia , Rim/imunologia , Camundongos , Camundongos Endogâmicos , Proteína Básica da Mielina/análise , Proteína Básica da Mielina/ultraestrutura , Bainha de Mielina/imunologia , Bainha de Mielina/patologia , Poliomielite/imunologia , Poliomielite/patologia , Coelhos , Ratos , Medula Espinal/imunologiaRESUMO
Autonomic dysfunction is a recognized feature of the Lambert-Eaton myasthenic syndrome (LES). However, the characteristic pattern of dysautonomia has not been clearly documented and its pathophysiologic basis is not known. We therefore abstracted autonomic symptomatology and results of quantitative tests for salivation, and vasomotor, cardiovagal, and sudomotor reflexes from records of 30 LES patients. Dry mouth (77%) and impotence (45% of men) were the most common symptoms. Composite Autonomic Scoring Scale results were abnormal in 93% of patients, and autonomic failure was severe in 20%. The frequency of specific test abnormalities were the following: sudomotor function, 83%; cardiovagal reflexes, 75%; salivation, 44%; and adrenergic function, 37%. Although voltage-gated N-type calcium (Ca2+) channels are implicated in autonomic transmission, the low frequency of serum antibodies to N-type Ca2+ channels found in the patients of this study (31% positive) argues against a pathogenic role in mediating LES-related dysautonomia. In contrast, 93% of the patients were seropositive for P/Q-type Ca2+ channel antibodies. A subset of these antibodies is thought to impair neuromuscular transmission. Autoantibodies of thyrogastric or glutamic acid decarboxylase specificity (markers of predisposition to type 1 diabetes mellitus) were found in 45% of patients, and type 1 antineuronal nuclear antibody (or anti-Hu, a marker of autoimmune neuropathy associated with small-cell lung carcinoma) was found in 3%. No autoantibody correlated with autonomic dysfunction severity. Sensorimotor neuropathy was documented in five patients, and was not significantly associated with autonomic neuropathy. Autonomic failure was most severe in older subjects with cancer (p = 0.02, age by cancer interaction).
Assuntos
Doenças do Sistema Nervoso Autônomo/imunologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Síndrome Miastênica de Lambert-Eaton/imunologia , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Adulto , Idoso , Autoanticorpos/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Neurônios/imunologia , Neurônios/fisiologia , Reflexo , Estudos RetrospectivosRESUMO
An infant with transient neonatal myasthenia gravis had a double-blood-volume exchange transfusion because of maternal-fetal blood group incompatibility. This seemed to accelerate both decline in antiacetylcholine antibody titer and clinical improvement.
Assuntos
Incompatibilidade de Grupos Sanguíneos/terapia , Transfusão Total , Doenças do Recém-Nascido/terapia , Miastenia Gravis/terapia , Sistema ABO de Grupos Sanguíneos , Anticorpos/análise , Incompatibilidade de Grupos Sanguíneos/complicações , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/complicações , Doenças do Recém-Nascido/imunologia , Miastenia Gravis/complicações , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologiaRESUMO
The diagnosis of acquired myasthenia gravis (MG) in apparently seronegative individuals is aided by finding immunoglobulin complexed to acetylcholine receptors (AChR) and a reduction in the number of binding sites for alpha-bungarotoxin (alpha-BTx) in nerve-muscle biopsies. In this study, we found that anti-AChR antibodies in extracellular fluids can complex with cytoplasmic epitopes of AChR in the process of muscle extraction. When normal muscle was briefly exposed to antibodies (greater than or equal to 0.3 nmol/l) in the initial step of tissue homogenization (before detergent extraction), membranous AChR became complexed with IgG. This was so even with a nonmyasthenogenic monoclonal antibody specific for the alpha-subunit's presumptive cytoplasmic segment 366-389. We also found that antibodies reactive with AChR's alpha-BTx binding region can significantly lower apparent yields of alpha-BTx binding sites extracted from muscle. Thus, the finding of IgG complexed to AChR extracted from biopsied muscle does not necessarily reflect in vivo binding but, nevertheless, is a sensitive indicator of AChR seropositivity in patients suspected to have MG.
Assuntos
Imunoglobulina G/metabolismo , Músculos/metabolismo , Receptores Colinérgicos/metabolismo , Animais , Anticorpos Monoclonais , Sítios de Ligação , Bungarotoxinas/metabolismo , Eletromiografia , Eletrofisiologia , Feminino , Placa Motora/fisiopatologia , Miastenia Gravis/diagnóstico , Miastenia Gravis/fisiopatologia , Ratos , Ratos Endogâmicos Lew , Testes SorológicosRESUMO
Type 1 antineuronal nuclear autoantibody (ANNA-1, also known as "anti-Hu") is a marker of neurologic autoimmunity that is highly associated with small-cell lung carcinoma (SCLC). To determine the spectrum of symptoms and signs as well as the frequency of cancer in adult patients who are seropositive for ANNA-1, we reviewed 162 sequential patients (67% female) identified as ANNA-1-positive in a comprehensive immunofluorescence screening test. In 21% of these patients, the antibody test requested by the physician was not ANNA-1. By the end of the follow-up period, cancer had been found in 142 patients (88%). Ten of these lacked evidence of SCLC (4 had prostate carcinoma, 3 breast carcinoma, 1 both prostate carcinoma and melanoma, 1 lymphoma, and 1 squamous-cell lung carcinoma). Of the 132 patients (81%) with proven SCLC, 17 had one or more coexisting malignant neoplasms (6 had renal carcinoma, 4 another lung primary carcinoma, 3 prostate carcinoma, 3 breast carcinoma, and 4 assorted neoplasms). The diagnosis of SCLC in 128 patients (97%) followed the onset of paraneoplastic symptoms. SCLC was identified in 10 patients by chest MRI after an equivocal chest radiograph or CT; in 28 by bronchoscopy, mediastinoscopy, or thoracotomy; and in 7 at autopsy. Neurologic signs in decreasing frequency were neuropathy (sensory > mixed somatic > autonomic > cranial [especially cranial nerve VIII] > motor), cerebellar ataxia, limbic encephalitis, polyradiculopathy, associated Lambert-Eaton myasthenic syndrome, myopathy, myelopathy, opsoclonus/myoclonus, motor neuronopathy, brachial plexopathy, and aphasia. Nineteen patients had a solely gastrointestinal initial presentation, including gastroparesis, pseudo-obstruction, esophageal achalasia, or other dysmotility. We conclude that seropositivity for ANNA-1 can expedite the diagnosis and treatment of otherwise occult cancer in patients, especially tobacco abusers, with varied neurologic and gastroenterologic presentations. The search for SCLC should not end on discovering a different neoplasm.
Assuntos
Autoanticorpos/análise , Neoplasias/epidemiologia , Proteínas do Tecido Nervoso , Síndromes Paraneoplásicas/imunologia , Proteínas de Ligação a RNA/imunologia , Adulto , Idoso , Carcinoma de Células Pequenas/epidemiologia , Proteínas do Líquido Cefalorraquidiano/análise , Proteínas ELAV , Feminino , Gastroenteropatias/imunologia , Motilidade Gastrointestinal , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/imunologiaRESUMO
We followed 21 patients with sensory neuronopathy without evidence of cancer for up to 23 years. All were seronegative for type 1 antineuronal nuclear antibodies (ANNA-1, also called "anti-Hu"). We additionally studied 67 seropositive patients with sensory neuropathy or a related neurologic syndrome. Ninety-one percent of the seropositive patients had a small-cell lung carcinoma. One, with a normal chest x-ray, had been followed for 7 years for sensory neuronopathy of indeterminate cause before serologic testing for ANNA-1 led to the discovery of the tumor by CT. We conclude that ANNA-1 seropositivity in a patient with sensory neuronopathy is strong evidence for an underlying small-cell lung cancer.