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J M Lindstrom

Publications and source records attributed to J M Lindstrom.

At least 91 records · Page 5Linked to original sources
PubMed1982

Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies.

The pattern of antibody specificities in sera from patients with myasthenia gravis (MG) was determined by the ability of monoclonal antibodies against defined determinants on the acetylcholine receptor molecule to inhibit binding of the serum antibodies to receptor from human muscle. We found that MG patients produce fundamentally the same pattern of specificities as that produced by animals immunized with receptor purified from fish electric organs or mammalian muscle. Most of the antibodies are directed at the "main immunogenic region' which is located on the extracellular surface of the alpha subunit and is distinct from the acetylcholine binding site. Regions on the beta and gamma subunits near the main immunogenic region are also significantly immunogenic. In one patient the proportions of antibodies to various regions are constant over time despite changes in total antibody amount and clinical state. Between patients there is no obvious correlation between antibody specificities and clinical state. These data suggest that the autoimmune response in MG is stimulated by human receptor rather than a crossreacting (e.g., viral) antigen and that in both MG and experimental autoimmune MG the pattern of specificities produced is determined by the inherently immunogenic structural features of the receptor molecule. They also suggest that the wide differences in clinical state sometimes observed between patients with the same total concentration of antireceptor antibody are due primarily to differences in endogenous factors which affect the safety factor for neuromuscular transmission rather than to the presence of especially pathogenic antireceptor specificities.

Antibodies, Monoclonal↗
PubMed1982

Subunit structure of the acetylcholine receptor from Electrophorus electricus.

The amino-terminal amino acid sequences of the four major peptides (Mr 41,000, 50,000, 55,000, and 62,000) present in purified preparations of Electrophorus electricus nicotinic acetylcholine receptor (AcChoR) have been determined for 24 cycles by automated sequence analysis procedures yielding four unique polypeptide sequences. The sequences showed a high degree of similarity, having identical residues in a number of positions ranging between 37% and 50% for specific pairs of subunits. Comparison of the sequences obtained with those of the subunits of similar molecular weight from Torpedo californica AcChoR revealed an even higher degree of homology (from 46% to 71%) for these two highly diverged species. Simultaneous sequence analysis of the amino termini present in native, purified Electrophorus AcChoR showed that these four related sequences were the only ones present and that they occur in a ratio of 2:1:1:1, with the smallest subunit ("alpha 1") being present in two copies. Genealogical analysis suggests that the subunits of both Torpedo and Electrophorus AcChoRs derive from a common ancestral gene, the divergence having occurred early in the evolution of the receptor. This shared ancestry and the very early divergence of the four subunits, as well as the highly conserved structure of the AcChoR complex along animal evolution, suggest that each of the subunits evolved to perform discrete crucial roles in the physiological function of the AcChoR.

Amino Acid Sequence↗
PubMed1981

Mapping of surface structures of electrophorus acetylcholine receptor using monoclonal antibodies.

Forty monoclonal antibodies to acetylcholine receptor from the electric organs of Electrophorus electricus have been characterized by immunoglobulin isotype, affinity for receptor, and specificity for species, subunit, and determinants within subunits. Using these antibodies, nine immunogenic regions on the receptor molecule were distinguished. Most of these are species specific, and are located on various subunits of the acetylcholine receptor. The least species-specific region forms the "main immunogenic region" (MIR). Most monoclonal antibodies and most antibodies in conventional antisera are directed at this region. The MIR is located on the extracellular surface of the alpha subunits and is homologous to the MIR which we previously described on Torpedo californica receptor. An homologous MIR is also a characteristic feature of receptor from mammalian muscle. The possible immunological and structural significance of the MIR is discussed.

Animals↗
PubMed1981

Patterns of acetylcholine receptor antibody fluctuation in myasthenia gravis.

Serial acetylcholine receptor antibody (AChR-ab) titers have been followed in 32 patients with myasthenia gravis (MG) for an average of 43 months (range 12-81 months). Seventeen patients became asymptomatic or markedly improved during the study, 12 of whom showed AChR-ab decreases of greater than 50% sustained for 12 months. Only three of 15 patients showing no substantial clinical improvement had AChR-ab decreases greater than 50%. Steroids were more often associated with AChR-ab suppression than was thymectomy. The differences in AChR-ab suppressibility among identically treated patients were not predictable by any clinical characteristics studied. The study indicates a strong relationship between clinical course and AChR-ab in the individual patient when sustained improvement over 12 months and AChR-ab decreases greater than 50% are examined.

Adolescent↗
PubMed1981

Myasthenia gravis in infancy.

Symptoms of myasthenia gravis in infancy may occur from passive transfer of maternal disease, acquired autoimmune disease, or nonautoimmune hereditary disease. Of nine patients with infantile-onset myasthenia who were not born to mothers with the disease, two had detectable antibody to acetylcholine receptor. Patients with or without antibodies were clinically indistinguishable, except for the occurrence of similar disease in siblings of patients without antibody. Differentiation of autoimmune and hereditary, myasthenia in infancy is necessary for appropriate therapeutic measures and genetic counseling. Antibody determinations provide a useful aid in this differentiation.

Antibodies↗
PubMed1981

Antiacetylcholine receptor antibody and its relationship to HLA type in asymptomatic siblings of a patient with myasthenia gravis.

Antibodies to acetylcholine receptors (AChR-ab) were detected in a patient with myasthenia gravis (MG) and at much lower levels in her asymptomatic fraternal twin and one other asymptomatic sibling. These three carried the HLA-B8 allele, as did four other family members. In a previous study, we observed no AChR-ab in 175 non-MG patients. The occurrence of AChR-ab in 3 of 12 siblings suggests that all were affected by an unidentified pathologic factor acting on a favorable genetic background.

Autoantibodies↗
PubMed1980

Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits.

Seventeen cell lines producing monoclonal antibodies against Torpedo californica (torpedo) acetylcholine receptor (AcChoR) and its subunits were established. By using these antibodies as probes, we identified: (i) a similar antigenic determinant on alpha and beta torpedo subunits, (ii) a similar antigenic determinant on gamma and delta subunits, (iii) antigenic determinants unique for alpha or beta torpedo AcChoR subunits, (iv) a small region on the alpha subunit that dominates the immunogenicity of native torpedo AcChoR in rats (a monoclonal antibody directed at this region could bind to rat AcChoR in vivo and cause passive experimental autoimmune myasthenia gravis), and (v) antigenic determinants on torpedo subunits recognized in AcChoR from other species. The unexpected similarities between alpha and beta and between gamma and delta subunits raise the possibility that the complex four-subunit structure of AcChoR was derived from a simpler precursor and suggests that these antigenic similarities might reflect some structural and functional homologies.

Animals↗
PubMed1979

Acetylcholine receptor degradation in adult rat diaphragms in organ culture and the effect of anti-acetylcholine receptor antibodies.

Acetylcholine receptor located at the neuromuscular synapse of normal innervated adult muscle fibers is extremely stable metabolically. We have studied the kinetics of receptor degradation in both normal innervated and denervated rat diaphragms in organ culture. These studies show that degradation of receptor-bound 125I-alpha-bungarotoxin is a valid measure of junctional receptor degradation. Degradation of junctional receptor is similar or identical to degradation of extrajunctional receptor in many ways: 1) both require energy, 2) both are inhibited by specific lysosomal protease inhibitors, 3) both are inhibited by treatment with colchicine, and 4) both are stimulated by treatment with anti-acetylcholine receptor antibodies. The one important distinction between degradation of junctional and extrajunctional receptor is a 10-fold difference in rate constant for the process.

Acetylcholine↗
PubMed1979

Degradation of acetylcholine receptor in diaphragms of rats with experimental autoimmune myasthenia gravis.

The degradation of acetylcholine receptor observed in denervated and innervated normal rat diaphragms in organ culture is stimulated by exogenous antireceptor serum. In this paper we demonstrate that diaphragms from rats with experimental autoimmune myasthenia gravis contain reduced amounts of acetylcholine receptor. Acetylcholine receptor from myasthenic, but not from normal, rats has antibody bound to it and is degraded at an accelerated rate. We conclude that in the chronic phase of experimental autoimmune myasthenia gravis increased acetylcholine receptor degradation can be accounted for by a mechanism involving antigenic modulation, and that such a process can contribute to the clinical symptoms of impaired neuromuscular transmission.

Acetylcholine↗
PubMed1979

Passively transferred experimental autoimmune myasthenia gravis. Sequential and quantitative study of the motor end-plate fine structure and ultrastructural localization of immune complexes (IgG and C3), and of the acetylcholine receptor.

Experimental autoimmune myasthenia gravis (EAMG) was passively transferred with immunoglobulin from rats with chronic EAMG to normal recipients. IgG and C3 were localized on terminal expansions of junctional folds of end-plates by 6 hours. Segments of folds rich in acetylcholine receptor (AChR) and coated with IgG and C3 were shed into the synaptic space by 24 hours, resulting in AChR deficiency of the postsynaptic membrane. Many sensitized postsynaptic regions were destroyed by macrophages by day 2, but effective nerve-muscle contacts were reestablished by day 5. On day 10, end-plates were still structurally abnormal and showed AChR deficiency, but the animals were clinically recovered. On day 54, postsynaptic regions were still reduced in size, with slight reduction of postsynaptic AChR. Throughout the study, the miniature end-plate potential amplitude tended to vary directly with morphometric estimates of the abundance of the postsynaptic membrane reacting for AChR. Complement-mediated injury to the junctional folds and opsonization of the postsynaptic region can explain the morphologic changes. It is not yet known why phagocytic invasion of the end-plate occurs in acute EAMG and in passively transferred EAMG induced by chronic EAMG immuglobulin, but not in chronic EAMG and only rarely in the human disease.

Animals↗
PubMed1978

Anti-acetylcholine-receptor antibody concentrations after thymectomy in patients with myasthenia gravis.

Serum concentrations of anti-acetylcholine-receptor (anti-AChR) antibody were measured in patients with myasthenia gravis. In those patients undergoing thymectomy concentrations were measured before and after the operation to see whether there might be a connection between the thymus and antibody production. We found no correlation between antibody concentration and either thymectomy or duration and severity of the disease before the operation. Our results suggest that if anti-AChR antibodies are the principal pathogenic factor in myasthenia gravis then immunological and neurophysical variables other than the total serum anti-AChR antibody concentration contribute to the severity of the disease.

Acetylcholine↗
PubMed1978

Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis.

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.

Animals↗
PubMed1978

Penicillamine-induced myasthenia gravis associated with antibodies to acetylcholine receptor.

A woman with rheumatoid arthritis was treated with penicillamine and developed myasthenia gravis. This drug-induced disease was associated with characteristic autoantibodies to acetycholine receptor. After discontinuing the drug, her symptoms improved and the antibody titers fell. Penicillamine is now being used much more frequently in the treatment of rheumatoid arthritis and it is likely that this complication will become more prevalent.

Adult↗
PubMed1977

Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis.

Plasmapheresis combined with prednisone and azathioprine therapy produced striking clinical improvement in five patients with myasthenia gravis who still had moderate to severe disability despite thymectomy, high-dose prednisone therapy and optimal doses of cholinesterase inhibitors. Serial determinations of titers of serum antibody toward the acetylcholine receptor demonstrated a fall to 21 +/- 5 per cent (mean +/- S.D.) of the original levels concurrently with the patients' increasing strength. Clinically improved patients maintained lowered titers, whereas clinical relapses were associated with a rebound in titer. Our results suggest that plasmapheresis will find a place in the management of patients with myasthenia gravis, and they implicate antibodies to acetylcholine receptor as a pathogenic factor in this disease.

Acetylcholine↗