Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myeloma immunoglobulins, once thought to be without any immunological function, are now known to be reactive with many antigens, including self components. We have screened 149 monoclonal immunoglobulin samples and found 14 (9%) to react with the human acetylcholine receptor (AChR). Such anti-AChR antibodies are often associated with the autoimmune disease myasthenia gravis (MG). The anti-AChR binding of the myeloma components was restricted to the F(ab')2 fragment and the affinities were similar to anti-AChR antibodies isolated from MG patients. Despite the presence of anti-AChR antibodies none of the patients exhibited any symptoms of MG.
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PMID:Human monoclonal immunoglobulins that bind the human acetylcholine receptor. 369 28

Monoclonal anti-human IgG subclass antibodies have been used in an immunoprecipitation assay for the determination of anti-acetylcholine receptor IgG subclasses in plasma from patients with myasthenia gravis. Solubilized acetylcholine receptors labelled with 125I-alpha-bungarotoxin were incubated with patient plasma. Monoclonal mouse antibodies to human IgG subclasses 1-4 were added to the incubation and finally precipitated with anti-mouse IgG antibody. A maximal IgG subclass precipitation of 62-76% was determined with 125I-labelled myeloma IgG subclasses 1-4 added to normal human plasma. The anti-IgG subclass antibodies were added in excess which ensured that the precipitation of IgG2, IgG3 or IgG4 were unchanged, and that of IgG1 was only reduced by 17%, when the plasma IgG concentration was increased by a factor of two. The anti-IgG subclass antibodies were highly specific for their complementary subclasses. Determination of the IgG subclass of the anti-acetylcholine receptor antibodies from 8 patients with myasthenia gravis showed that IgG1 and IgG3 antibodies are predominant. This may support the hypothesis that complement mediated lysis of the neuromuscular end-plate plays a pathogenetic role in myasthenia gravis.
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PMID:A triple antibody assay for the quantitation of plasma IgG subclass antibodies to acetylcholine receptors in patients with myasthenia gravis. 390 78

To investigate individual components of the humoral immune response directed against the acetylcholine receptor in experimental myasthenia, we injected monoclonal antireceptor antibody into normal rats. These antibodies were produced by cloned hybridoma lines formed by fusion of immune spleen cells with the myeloma cell line P3-X63-Ag8. Antibodies from two of seven clones induced acute experimental myasthenia, manifested by clinical weakness, decremental electromyographic response to repetitive nerve stimulation, and diminished mean amplitudes of miniature end-plate potentials (mepps): 0.55 +/- 0.02 mv (SEM) versus 0.71 mv for controls (p less than 0.001). In clinically affected animals, mepp amplitudes from the diaphragm correlated with decremental responses in the gastronemius muscle (r = -0.91, p less than 0.01). The results suggest that binding of a single antibody species to a single determinant on the acetylcholine receptor molecule is sufficient to induce acute experimental myasthenia gravis.
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PMID:Myasthenia induced by monoclonal anti-acetylcholine receptor antibodies: clinical and electrophysiological aspects. 616 99

Recently we described a procedure for preparing antibodies to the acetylcholine receptor (AChR) based on immunoglobulin idiotypes and on the hypothesis that, regardless of functional differences, macromolecules of the same specificity will show structural homologies in their binding sites. Antibodies were prepared in rabbits to a structurally constrained agonist of AChR, trans-3,3'-bis[alpha-(trimethylammonio)methyl]azobenzene bromide (BisQ). These antibodies mimicked the binding specificity of AChR in its activated state--agonists were bound with affinities that were in accord with their biological activities and antagonists were bound poorly. Rabbits were then immunized with a specifically purified preparation of anti-BisQ to elicit a population of antibodies specific for the binding sites of anti-BisQ. A portion of the anti-idiotypic antibodies produced in the second set of rabbits cross-reacted with determinants on AChR preparations from Torpedo californica, Electrophorus electricus and rat muscle. Moreover, several of the rabbits showed signs of experimental myasthenia gravis, in which circulating AChR antibodies are typically found. To devise a more direct route to monoclonal anti-receptor antibodies we based our strategy on acceptance of the concept of the anti-idiotypic network theory of Jerne. According to this theory, injection of an antigen elicits, in addition to antibodies to the antigen, other populations that include anti-idiotypic antibodies directed at the combining sites of the antigen-specific antibodies. If the antigen-specific antibodies recognize a ligand of a receptor, then the anti-idiotypic antibodies should bind receptor. Thus, when a mouse is immunized with a bovine serum albumin conjugate of BisQ (BisQ-BSA), it should be possible to expand populations of spleen cells that secrete antibodies which bind anti-BisQ and AChR, in addition to populations specific for BisQ. Fusion of the spleen cells with an appropriate myeloma line should yield monoclonal anti-AChR antibodies. Here we report the success of this approach and its implications.
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PMID:Monoclonal antibodies to the acetylcholine receptor by a normally functioning auto-anti-idiotypic mechanism. 660 26

Myasthenia gravis (MG) is a disease which occurs as a consequence of an autoimmune response directed against the nicotinic acetylcholine receptor (AChR) of the myoneural junction. Antisera raised against complex antigens such as AChR comprise a mixture of antibodies reactive with various determinants on the antigen molecule. The antibodies against any single determinant may be of several immunoglobulin classes and idiotypes. Antibodies produced by cloned lymphocyte-myeloma hybridoma cell lines have provided a way of analysing the diverse components making up a polyclonal antiserum and assessing the relative contribution made by each to the overall immune reaction in vivo. We have applied this technique to the investigation of the autoimmune response in MG. We demonstrate here that certain monoclonal anti-Torpedo AChR antibodies, when injected intravenously into normal rats, induce an acute myasthenic syndrome. Thus binding of a single molecular species of antibody reactive with a single antigenic determinant can result in all of the manifestations of an autoimmune disease.
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PMID:Monoclonal anti-acetylcholine receptor antibodies can cause experimental myasthenia. 741 61

We have developed idiotype-anti-idiotype monoclonal antibodies that provide evidence for rabies virus binding to the acetylcholine receptor (AChR). Hybridoma cell lines 7.12 and 7.25 resulted after fusion of NS-1 myeloma cells with spleen cells from a BALB/c mouse immunized with rabies virus strain CVS. Antibody 7.12 reacted with viral glycoprotein and neutralized virus infectivity in vivo. It also neutralized infectivity in vitro when PC12 cells, which express neuronal AChR, but not CER cells or neuroblastoma cells (clone N18), which have no AChR, were used. Antibody 7.25 reacted with nucleocapsid protein. Anti-idiotypic monoclonal antibody B9 was produced from fusion of NS-1 cells with spleen cells from a mouse immunized with 7.12 Fab. In an enzyme-linked immunosorbent assay and immunoprecipitation, B9 reacted with 7.12, polyclonal rabies virus immune dog serum, and purified AChR. The binding of B9 to 7.12 and immune dog serum was inhibited by AChR. B9 also inhibited the binding of 7.12 to rabies virus both in vitro and in vivo. Indirect immunofluorescence revealed that B9 reacted at neuromuscular junctions of mouse tissue. B9 also reacted in indirect immunofluorescence with distinct neurons in mouse and monkey brain tissue as well as with PC12 cells. B9 staining of neuronal elements in brain tissue of rabies virus-infected mice was greatly reduced. Rabies virus inhibited the binding of B9 to PC12 cells. Mice immunized with B9 developed low-titer rabies virus-neutralizing antibody. These mice were protected from lethal intramuscular rabies virus challenge. In contrast, anti-idiotypic antibody raised against nucleocapsid antibody 7.25 did not react with AChR.
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PMID:Evidence from the anti-idiotypic network that the acetylcholine receptor is a rabies virus receptor. 767 60

Univalent antibody fragments directed against the main immunogenic region (MIR) of the human acetylcholine receptor (AChR) are capable of protecting the AChR against loss induced by antibodies from myasthenia gravis (MG) patients. Our aim was to construct single-chain Fv (scFv) antibody fragments as a first step towards the production of therapeutic protecting molecules, from two high-affinity anti-MIR monoclonal antibodies (mAb 192 and mAb 195). During the construction of scFv192 fragment, two light chains co-secreted from the hybridoma mAb192 were identified. N-terminal amino acid and cDNA sequence analysis showed that one of the two light chains corresponded to the antigen binding molecule while the other originated from the non-secreting myeloma S194/5.XXO.BU.1 which was used in the production of the hybridoma. Functional scFv 192 and 195 fragments were constructed, expressed in Escherichia coli and affinity purified. The binding affinities of scFv192 and scFv195 (K(D) = 0.6 and 0.8 nM for human AChR) were two orders of magnitude higher than that of the earlier constructed scFv198. The scFv192 almost completely protected human AChR against binding of intact anti-MIR mAbs. Human AChR was also very efficiently protected (74-85%) by the scFv192 against binding of autoantibodies from MG sera with high anti-alpha subunit antibody fractions. These scFvs are good candidates for protection of MG patients after appropriate genetic modifications.
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PMID:High affinity single-chain Fv antibody fragments protecting the human nicotinic acetylcholine receptor. 1037 32

Bortezomib is a potent inhibitor of proteasomes currently used to eliminate malignant plasma cells in multiple myeloma patients. It is also effective in depleting both alloreactive plasma cells in acute Ab-mediated transplant rejection and their autoreactive counterparts in animal models of lupus and myasthenia gravis (MG). In this study, we demonstrate that bortezomib at 10 nM or higher concentrations killed long-lived plasma cells in cultured thymus cells from nine early-onset MG patients and consistently halted their spontaneous production not only of autoantibodies against the acetylcholine receptor but also of total IgG. Surprisingly, lenalidomide and dexamethasone had little effect on plasma cells. After bortezomib treatment, they showed ultrastructural changes characteristic of endoplasmic reticulum stress after 8 h and were no longer detectable at 24 h. Bortezomib therefore appears promising for treating MG and possibly other Ab-mediated autoimmune or allergic disorders, especially when given in short courses at modest doses before the standard immunosuppressive drugs have taken effect.
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PMID:Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients. 2497 45