scholarly journals Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies.

1976 ◽  
Vol 144 (3) ◽  
pp. 739-753 ◽  
Author(s):  
J M Lindstrom ◽  
A G Engel ◽  
M E Seybold ◽  
V A Lennon ◽  
E H Lambert
Keyword(s):  
Myasthenia Gravis ◽  
Nerve Stimulation ◽  
Neuromuscular Transmission ◽  
Postsynaptic Membrane ◽  
Passive Transfer ◽  
Autoimmune Response ◽  
End Plate ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune

Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.

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

1978 ◽  
Vol 147 (4) ◽  
pp. 973-983 ◽  
Author(s):  
V A Lennon ◽  
M E Seybold ◽  
J M Lindstrom ◽  
C Cochrane ◽  
R Ulevitch
Keyword(s):  
Myasthenia Gravis ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuromuscular Transmission ◽  
Passive Transfer ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune

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.

scholarly journals Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis.

1976 ◽  
Vol 144 (3) ◽  
pp. 726-738 ◽  
Author(s):  
J M Lindstrom ◽  
B L Einarson ◽  
V A Lennon ◽  
M E Seybold
Keyword(s):  
Myasthenia Gravis ◽  
Acetylcholine Receptor ◽  
Neuromuscular Transmission ◽  
Clinical Signs ◽  
Autoimmune Response ◽  
Receptor Complexes ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Alpha Bungarotoxin ◽  
Experimental Autoimmune

Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.

scholarly journals Deficits in Endogenous Adenosine Formation by Ecto-5′-Nucleotidase/CD73 Impair Neuromuscular Transmission and Immune Competence in Experimental Autoimmune Myasthenia Gravis

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Laura Oliveira ◽  
Alexandra Correia ◽  
Ana Cristina Costa ◽  
Sónia Guerra-Gomes ◽  
Fátima Ferreirinha ◽  
...  
Keyword(s):  
T Cells ◽  
Myasthenia Gravis ◽  
Adenosine Deaminase ◽  
Immune Suppression ◽  
Neuromuscular Transmission ◽  
Therapeutic Potential ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Adenosine Deaminase Activity ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune

AMP dephosphorylation via ecto-5′-nucleotidase/CD73 is the rate limiting step to generate extracellular adenosine (ADO) from released adenine nucleotides. ADO, viaA2Areceptors (A2ARs), is a potent modulator of neuromuscular and immunological responses. The pivotal role of ecto-5′-nucleotidase/CD73, in controlling extracellular ADO formation, prompted us to investigate its role in a rat model of experimental autoimmune myasthenia gravis (EAMG). Results show that CD4+CD25+FoxP3+regulatory T cells express lower amounts of ecto-5′-nucleotidase/CD73 as compared to controls. Reduction of endogenous ADO formation might explain why proliferation of CD4+T cells failed upon blockingA2Areceptors activation with ZM241385 or adenosine deaminase in EAMG animals. Deficits in ADO also contribute to neuromuscular transmission failure in EAMG rats. Rehabilitation ofA2AR-mediated immune suppression and facilitation of transmitter release were observed by incubating the cells with the nucleoside precursor, AMP. These findings, together with the characteristic increase in serum adenosine deaminase activity of MG patients, strengthen our hypothesis that the adenosinergic pathway may be dysfunctional in EAMG. Given that endogenous ADO formation is balanced by ecto-5′-nucleotidase/CD73 activity and thatA2ARs exert a dual role to restore use-dependent neurocompetence and immune suppression in myasthenics, we hypothesize that stimulation of the two mechanisms may have therapeutic potential in MG.

scholarly journals Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs.

1975 ◽  
Vol 141 (6) ◽  
pp. 1365-1375 ◽  
Author(s):  
V A Lennon ◽  
J M Lindstrom ◽  
M E Seybold
Keyword(s):  
Myasthenia Gravis ◽  
Guinea Pigs ◽  
Autoimmune Response ◽  
Mammalian Skeletal Muscle ◽  
Electrophorus Electricus ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Electric Organs ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune ◽  
Experimental Disease

Immunization of animals with acetylcholine receptor (AChR) protein from the electric organs of Electrophorus electricus and Torpedo californica induces an autoimmune response to the AChR of mammalian skeletal muscle. Rats and guinea pigs develop experimental autoimmune myasthenia gravis (EAMG) after a single inoculation with small quantities of AChR and adjuvant. The indicence and severity of disease appears to depend on the dose of AChR and stability of the emulsion. EAMG is strikingly similar to myasthenia gravis (MG) of man in its clinical picture and its electrophysiological abnormalities. The presence of antibodies to syngeneic rat muscle AChR in the serum of rats with EAMG documents the existence of autoimmunity in the experimental disease. A common immunopathogenesis is suggested for both EAMG and mg.

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