Monoclonal autoantibodies to acetylcholine receptors: Evidence for a dominant idiotype and requirement of complement for pathogenicity

Vanda A Lennon, E. H. Lambert

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Abstract

An antigenic determinant of mammalian muscle acetylcholine receptors (AChR) remote from the ACh-binding site and exposed extracellularly at the neuromuscular junction has been defined by monoclonal autoantibodies (McAb's). The determinant is a dominant antigen in the rat's autoimmune response to AChR. It was defined by four IgG McAb's (from two individual donor rats) which shared a common idiotype (Id) complementary to the AchR determinant. These four McAb's bound to AChR in vivo and induced experimental autoimmune myasthenia graivs (EAMG). They also bound to nonjunctional AChR on living myotubes in culture at 37° and caused loss of α-bungarotoxin (α-BT) binding sites. The McAb's did not inhibit binding of α-BT to solubilized AChR or to nonjunctional AChR in membranes of muscle cells held at 4° C. Impairment of neuromuscular transmission by the McAb's required activation of complement via the classical pathway. In the absence of C3 → C9, or in silated deficiency of C4, binding of McAb's to at least 62% of AChR for 72 hours in vivo did not alter miniature endplate potentials (MEPPs) or EPPs or reduce the muscle's content of AChR. The common Id was detectable in sera of rats immunized with AChR of either Torpedo, eel or syngeneic muscle. Anti-Id antibodies raised against 3 of the McAb's inhibited in vitro binding of each of the 4 McAb's to AChR; absorption of one anti-Id by a second McAb removed inhibitory activity for all McAb's. However, when rats with high titers of anti-Id were challenged by immunization with Torpedo AchR, the severity of EAMG was undiminished despite a continuing excess of anti-Id antibodies. Success of the anti-Id approach to therapy of myasthenia gravis may require definition of the several antigenic determinants of human muscle AChR with which patients' auto-antibodies interact in vivo.

Original languageEnglish (US)
Pages (from-to)77-96
Number of pages20
JournalAnnals of the New York Academy of Sciences
VolumeVol. 377
StatePublished - 1981

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Cholinergic Receptors
Autoantibodies
Virulence
Muscle
Rats
Autoimmune Experimental Myasthenia Gravis
Torpedo
Muscles
Epitopes
Anti-Idiotypic Antibodies
Binding Sites
Classical Complement Pathway
Immunization
Bungarotoxins
Rat
Eels
Neuromuscular Junction
Myasthenia Gravis
Skeletal Muscle Fibers
Autoimmunity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "Monoclonal autoantibodies to acetylcholine receptors: Evidence for a dominant idiotype and requirement of complement for pathogenicity",
abstract = "An antigenic determinant of mammalian muscle acetylcholine receptors (AChR) remote from the ACh-binding site and exposed extracellularly at the neuromuscular junction has been defined by monoclonal autoantibodies (McAb's). The determinant is a dominant antigen in the rat's autoimmune response to AChR. It was defined by four IgG McAb's (from two individual donor rats) which shared a common idiotype (Id) complementary to the AchR determinant. These four McAb's bound to AChR in vivo and induced experimental autoimmune myasthenia graivs (EAMG). They also bound to nonjunctional AChR on living myotubes in culture at 37° and caused loss of α-bungarotoxin (α-BT) binding sites. The McAb's did not inhibit binding of α-BT to solubilized AChR or to nonjunctional AChR in membranes of muscle cells held at 4° C. Impairment of neuromuscular transmission by the McAb's required activation of complement via the classical pathway. In the absence of C3 → C9, or in silated deficiency of C4, binding of McAb's to at least 62{\%} of AChR for 72 hours in vivo did not alter miniature endplate potentials (MEPPs) or EPPs or reduce the muscle's content of AChR. The common Id was detectable in sera of rats immunized with AChR of either Torpedo, eel or syngeneic muscle. Anti-Id antibodies raised against 3 of the McAb's inhibited in vitro binding of each of the 4 McAb's to AChR; absorption of one anti-Id by a second McAb removed inhibitory activity for all McAb's. However, when rats with high titers of anti-Id were challenged by immunization with Torpedo AchR, the severity of EAMG was undiminished despite a continuing excess of anti-Id antibodies. Success of the anti-Id approach to therapy of myasthenia gravis may require definition of the several antigenic determinants of human muscle AChR with which patients' auto-antibodies interact in vivo.",
author = "Lennon, {Vanda A} and Lambert, {E. H.}",
year = "1981",
language = "English (US)",
volume = "Vol. 377",
pages = "77--96",
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AU - Lennon, Vanda A

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N2 - An antigenic determinant of mammalian muscle acetylcholine receptors (AChR) remote from the ACh-binding site and exposed extracellularly at the neuromuscular junction has been defined by monoclonal autoantibodies (McAb's). The determinant is a dominant antigen in the rat's autoimmune response to AChR. It was defined by four IgG McAb's (from two individual donor rats) which shared a common idiotype (Id) complementary to the AchR determinant. These four McAb's bound to AChR in vivo and induced experimental autoimmune myasthenia graivs (EAMG). They also bound to nonjunctional AChR on living myotubes in culture at 37° and caused loss of α-bungarotoxin (α-BT) binding sites. The McAb's did not inhibit binding of α-BT to solubilized AChR or to nonjunctional AChR in membranes of muscle cells held at 4° C. Impairment of neuromuscular transmission by the McAb's required activation of complement via the classical pathway. In the absence of C3 → C9, or in silated deficiency of C4, binding of McAb's to at least 62% of AChR for 72 hours in vivo did not alter miniature endplate potentials (MEPPs) or EPPs or reduce the muscle's content of AChR. The common Id was detectable in sera of rats immunized with AChR of either Torpedo, eel or syngeneic muscle. Anti-Id antibodies raised against 3 of the McAb's inhibited in vitro binding of each of the 4 McAb's to AChR; absorption of one anti-Id by a second McAb removed inhibitory activity for all McAb's. However, when rats with high titers of anti-Id were challenged by immunization with Torpedo AchR, the severity of EAMG was undiminished despite a continuing excess of anti-Id antibodies. Success of the anti-Id approach to therapy of myasthenia gravis may require definition of the several antigenic determinants of human muscle AChR with which patients' auto-antibodies interact in vivo.

AB - An antigenic determinant of mammalian muscle acetylcholine receptors (AChR) remote from the ACh-binding site and exposed extracellularly at the neuromuscular junction has been defined by monoclonal autoantibodies (McAb's). The determinant is a dominant antigen in the rat's autoimmune response to AChR. It was defined by four IgG McAb's (from two individual donor rats) which shared a common idiotype (Id) complementary to the AchR determinant. These four McAb's bound to AChR in vivo and induced experimental autoimmune myasthenia graivs (EAMG). They also bound to nonjunctional AChR on living myotubes in culture at 37° and caused loss of α-bungarotoxin (α-BT) binding sites. The McAb's did not inhibit binding of α-BT to solubilized AChR or to nonjunctional AChR in membranes of muscle cells held at 4° C. Impairment of neuromuscular transmission by the McAb's required activation of complement via the classical pathway. In the absence of C3 → C9, or in silated deficiency of C4, binding of McAb's to at least 62% of AChR for 72 hours in vivo did not alter miniature endplate potentials (MEPPs) or EPPs or reduce the muscle's content of AChR. The common Id was detectable in sera of rats immunized with AChR of either Torpedo, eel or syngeneic muscle. Anti-Id antibodies raised against 3 of the McAb's inhibited in vitro binding of each of the 4 McAb's to AChR; absorption of one anti-Id by a second McAb removed inhibitory activity for all McAb's. However, when rats with high titers of anti-Id were challenged by immunization with Torpedo AchR, the severity of EAMG was undiminished despite a continuing excess of anti-Id antibodies. Success of the anti-Id approach to therapy of myasthenia gravis may require definition of the several antigenic determinants of human muscle AChR with which patients' auto-antibodies interact in vivo.

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