Antibodies from patients with myasthenia gravis recognize determinants unique to extrajunctional acetylcholine receptors.

Weinberg, Crispin B.; Hall, Zach W.

doi:10.1073/pnas.76.1.504

Cited by 122 publications

(51 citation statements)

References 33 publications

(30 reference statements)

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“…Although the main ACh-binding sites are on the ␣ subunits, they lie at the ␣/␦ and ␣/␥ interfaces: the distinctive ␣/␥ site of the fetal isoform seems to be the target for the inhibitory antibodies (Riemersma et al, 1997). Similar antibodies were found in one MG serum using rat fetal AChR in an early study (Weinberg and Hall, 1979), although they bound to both adult and fetal isoforms when human AChR was used (Burges et al, 1990). These inhibitory antibodies compete with 125 I-␣-BuTx for binding to one of its two sites, making their detection with 125 I-␣-BuTx-AChR more difficult, although we tried to overcome this difficulty by overlaying the filters with unlabeled AChR and adding 125 I-␣-BuTx subsequently.…”

Section: Fetal-specific Abs In Arthrogryposissupporting

confidence: 48%

Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Matthews

Sims

Ledwidge

et al. 2002

Laboratory Investigation

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SUMMARY:The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single V1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR. (Lab

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Section: Fetal-specific Abs In Arthrogryposissupporting

confidence: 48%

Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Matthews

Sims

Ledwidge

et al. 2002

Laboratory Investigation

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“…It should be noted that the AChR present on cultured muscle cells is of the extrajunctional type. The electrophysiological, metabolic, and biochemical, properties of extrajunctional AChR are known to differ from those of junctional AChR (26,27) and recent studies suggest that there is an immunological difference between the two receptor types (28 reported that mice immunized with T. californica AChR did develop EMG and that the response was strain dependent in that AKR mice seemed to be very susceptible to EMG, and other strains, particularly those possessing the H-2 q and H-2 s haplotypes, seemed to be resistant to EMG. Our studies are compatible with the results of Fulpius et al (29) in that BALB/c mice appear to be a low EMG-susceptibility strain and exhibit a high serum concentration of anti-AChR antibodies.…”

Section: Discussionmentioning

confidence: 99%

Experimental myasthenia gravis. A murine system.

Berman¹,

Patrick²

1980

The Journal of Experimental Medicine

139

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Mice from eight inbred strains were immunized with acetylcholine receptor (AChR) purified from Torpedo californica. All mice developed high concentrations of serum antibodies (10(-6) M) against the immunogen and approximately 80% possessed antibodies reactive with mouse nicotinic AChR. 33% of the mice immunized (n = 236) developed muscular weakness and flaccid paralysis. Behavioral, electrophysiological, and pharmacological similarities were found between the experimentally induced muscular weakness and the disease myasthenia gravis. Susceptibility to experimental myasthenia was found to be strain dependent in that the frequency of paralysis was much greater in some strains than others. The occurrence of muscular weakness and flaccid paralysis did not correlate with the concentration of antibodies reactive with T. californica or mouse AChR. Anti-receptor antibodies which increased the rate of AChR degradation on the mouse muscle cell line, BC3H-1, were found in the serum of both myasthenic and nonmyasthenic mice. 40% of the mice tested possessed antibodies reactive with antigenic determinants present on mouse receptor but not T. californica receptor. The occurrence of antibodies unique to mouse receptor did not correlate with myasthenia. Thus, myasthenia in the mouse does not occur simply as a consequence of the presence of antibodies directed against cell surface antigenic determinants of AChR. If anti-AChR antibodies are both necessary and sufficient for the induction of myasthenia, then these studies suggest that populations of a particular structure and/or specificity are required. It is anticipated that the mouse model of myasthenia gravis will permit the regulation of the anti-receptor immune response to be studied in detail.

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“…The loss of AChRs results from several different processes. Relatively few antibodies directly block the function of the ACh-induced ion channel, but these antibodies can be important in some patients [28,29] and some MG sera appear to have a transient inhibitory effect on AChR function in vitro. [30] A more important mechanism is a reduction in AChRs due to the crosslinking of AChRs by divalent antibodies.…”

Section: Mechanisms Of Diseasementioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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The neuromuscular junction (NMJ) is a prototypic synapse although its structure is rather different from those of the central nervous system (CNS). The unmyelinated motor nerve terminals are separated from the postsynaptic membrane by a cleft that contains a basal lamina. This includes many proteins such as collagens, laminins, fibronectin and perlecan which help anchor some of the key elements involved in NMJ The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-speciÞ c kinase antibodies which deÞ ne a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immunemediated disorders of the NMJ.Key words: Gravis, Lambert Eaton myasthenic syndrome, neuromyotonia, neuromuscular junction, autoimmunity, acetylcholine receptor, voltage-gated channel development and function; for instance acetylcholine esterase (AChE) is localized via ColQ, a collagen-like molecule, to the basal lamina. Agrin and neuregulins, secreted from the nerve terminal, are bound by the basal lamina and interact with their receptors, playing an important role in the location of postsynaptic membrane proteins, voltage-gated calcium channels and the dystroglycans. The postsynaptic membrane at the NMJ forms a series of deep folds. The acetylcholine receptors (AChRs) are found at the top one-third of these folds, whereas the voltage-gated sodium channels are anchored at the bottom of the folds. The development of the NMJ is a fascinating area of research [1] and many of the proteins involved are relevant to disease ([ Figure 1] for a simple representation).The nerve action potential opens voltage-gated calcium channels (VGCCs) that are located in the motor nerve terminal [ Figure 1]. The resulting influx of calcium leads to the release of about 30 (in human muscle) individual packets of acetylcholine (ACh). Some of the ACh is hydrolysed by AChE but about 65%...

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Antibodies from patients with myasthenia gravis recognize determinants unique to extrajunctional acetylcholine receptors.

Cited by 122 publications

References 33 publications

Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Experimental myasthenia gravis. A murine system.

Autoimmune disorders of the neuromuscular junction

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