Monoclonal anti-acetylcholine receptor antibodies can cause experimental myasthenia

Abstract

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.

Antibodies against low-density lipoprotein receptor–related protein 4 induce myasthenia gravis

“…Autoantibodies against AChRs can be detected in 80%-85% of MG patients (4,5). Evidence from classic experiments indicates the anti-AChR antibodies are pathogenic (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In rabbit, mouse, and rat models of experimental autoimmune MG (EAMG), antiAChR antibodies block AChR activity (8,11) and may accelerate AChR internalization and degradation (7).…”

Some properties and applications of monoclonal antibodies

“…Binding was detected by agglutination of sheep erythrocytes coated with purified receptor. Injection of rats with some but not all of the monoclonal antibodies caused typical experimental myasthenia gravis (Lennon & Lambert, 1980;Richman et al, 1980), showing that a single pure antibody species can produce the disease in these animals. It should now be possible to ask whether such antibodies have to be able to fix complement, or be directed to a particular part of the receptor.…”

“…At least four specificities of binding have been defined: binding that is (a) blocked by a-bungarotoxin, an 8000-mol.wt. peptide neurotoxin; (b) partially blocked by a-bungarotoxin and by all of a range of drugs that bind to the receptor; (c) enhanced by nicotinic drugs; (d) unaffected by the toxin or drugs (Richman et al, 1980). Binding was detected by agglutination of sheep erythrocytes coated with purified receptor.…”

Anti-acetylcholine receptor antibodies directed against the alpha-bungarotoxin binding site induce a unique form of experimental myasthenia.

“…In rats with EAMG, an acute phase of the disease also occurs in which, in addition to complement and IgG deposition, there is infiltration and phagocytosis of endplate membrane by macrophages (7). This acute phase, which can be reproduced by passive transfer into normal rats of polyclonal anti-AcChoR serum (12) or monoclonal antibody (mcAb) (13,14) has not been observed in MG (9). Studies from other laboratories demonstrated that immunoglobulin from MG (15) METHODS mcAb Production and Characterization.…”

“…§1734 solely to indicate this fact. (14), and the presence of bound rat Ig was demonstrated by using fluorescein-conjugated goat anti-rat Ig (36 (Fig. 1).…”