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.

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

Journal of Experimental Medicine ◽

10.1084/jem.144.3.739 ◽

1976 ◽

Vol 144 (3) ◽

pp. 739-753 ◽

Cited By ~ 161

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.

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Exosomes derived from statin-modified bone marrow dendritic cells increase thymus-derived natural regulatory T cells in experimental autoimmune myasthenia gravis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1587-0 ◽

2019 ◽

Vol 16 (1) ◽

Author(s):

Peng Zhang ◽

Ru-Tao Liu ◽

Tong Du ◽

Chun-Lin Yang ◽

Yu-Dong Liu ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Myasthenia Gravis ◽

Stromal Cells ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Thymic Stromal Cells ◽

Experimental Autoimmune

Abstract Background The thymus plays an essential role in the pathogenesis of myasthenia gravis (MG). In patients with MG, natural regulatory T cells (nTreg), a subpopulation of T cells that maintain tolerance to self-antigens, are severely impaired in the thymuses. In our previous study, upregulated nTreg cells were observed in the thymuses of rats in experimental autoimmune myasthenia gravis after treatment with exosomes derived from statin-modified dendritic cells (statin-Dex). Methods We evaluated the effects of exosomes on surface co-stimulation markers and Aire expression of different kinds of thymic stromal cells, including cTEC, mTEC, and tDCs, in EAMG rats. The isolated exosomes were examined by western blot and DLS. Immunofluorescence was used to track the exosomes in the thymus. Flow cytometry and western blot were used to analyze the expression of co-stimulatory molecules and Aire in vivo and in vitro. Results We confirmed the effects of statin-Dex in inducing Foxp3+ nTreg cells and found that both statin-Dex and DMSO-Dex could upregulate CD40 but only statin-Dex increased Aire expression in thymic stromal cells in vivo. Furthermore, we found that the role of statin-Dex and DMSO-Dex in the induction of Foxp3+ nTreg cells was dependent on epithelial cells in vitro. Conclusions We demonstrated that statin-Dex increased expression of Aire in the thymus, which may further promote the Foxp3 expression in the thymus. These findings may provide a new strategy for the treatment of myasthenia gravis.

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In Vitro and In Vivo studies of daunomycin-acetylcholine receptor conjugates in the treatment of experimental autoimmune myasthenia gravis

Journal of Neuroimmunology ◽

10.1016/0165-5728(87)90376-6 ◽

1987 ◽

Vol 16 (1) ◽

pp. 159-160

Author(s):

Diane Shelton ◽

Yoshitaka Fujii ◽

Jon Lindstrom

Keyword(s):

Myasthenia Gravis ◽

Acetylcholine Receptor ◽

In Vivo Studies ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Experimental Autoimmune

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Standardization of the experimental autoimmune myasthenia gravis (EAMG) model by immunization of rats with Torpedo californica acetylcholine receptors — Recommendations for methods and experimental designs

Experimental Neurology ◽

10.1016/j.expneurol.2015.03.010 ◽

2015 ◽

Vol 270 ◽

pp. 18-28 ◽

Cited By ~ 22

Author(s):

Mario Losen ◽

Pilar Martinez-Martinez ◽

Peter C. Molenaar ◽

Konstantinos Lazaridis ◽

Socrates Tzartos ◽

...

Keyword(s):

Myasthenia Gravis ◽

Acetylcholine Receptors ◽

Experimental Designs ◽

Torpedo Californica ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Experimental Autoimmune

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

Mediators of Inflammation ◽

10.1155/2015/460610 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 13

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.

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