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 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 CXCR5-negative natural killer cells ameliorate experimental autoimmune myasthenia gravis by suppressing follicular helper T cells

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Chun-Lin Yang ◽  
Peng Zhang ◽  
Ru-Tao Liu ◽  
Na Zhang ◽  
Min Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Myasthenia Gravis ◽  
Nk Cells ◽  
Ex Vivo ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune ◽  
Cell Zone

Abstract Background Recent studies have demonstrated that natural killer (NK) cells can modulate other immune components and are involved in the development or progression of several autoimmune diseases. However, the roles and mechanisms of NK cells in regulating experimental autoimmune myasthenia gravis (EAMG) remained to be illustrated. Methods To address the function of NK cells in experimental autoimmune myasthenia gravis in vivo, EAMG rats were adoptively transferred with splenic NK cells. The serum antibodies, and splenic follicular helper T (Tfh) cells and germinal center B cells were determined by ELISA and flow cytometry. The roles of NK cells in regulating Tfh cells were further verified in vitro by co-culturing splenocytes or isolated T cells with NK cells. Moreover, the phenotype, localization, and function differences between different NK cell subtypes were determined by flow cytometry, immunofluorescence, and ex vivo co-culturation. Results In this study, we found that adoptive transfer of NK cells ameliorated EAMG symptoms by suppressing Tfh cells and germinal center B cells. Ex vivo studies indicated NK cells inhibited CD4+ T cells and Tfh cells by inducing the apoptosis of T cells. More importantly, NK cells could be divided into CXCR5- and CXCR5+ NK subtypes according to the expression of CXCR5 molecular. Compared with CXCR5- NK cells, which were mainly localized outside B cell zone, CXCR5+ NK were concentrated in the B cell zone and exhibited higher expression levels of IL-17 and ICOS, and lower expression level of CD27. Ex vivo studies indicated it was CXCR5- NK cells not CXCR5+ NK cells that suppressed CD4+ T cells and Tfh cells. Further analysis revealed that, compared with CXCR5- NK cells, CXCR5+ NK cells enhanced the ICOS expression of Tfh cells. Conclusions These findings highlight the different roles of CXCR5- NK cells and CXCR5+ NK cells. It was CXCR5- NK cells but not CXCR5+ NK cells that suppressed Tfh cells and inhibited the autoimmune response in EAMG models.

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

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.

scholarly journals Both CD4+ and CD8+ T cells are essential to induce experimental autoimmune myasthenia gravis.

1996 ◽  
Vol 184 (2) ◽  
pp. 349-356 ◽  
Author(s):  
G X Zhang ◽  
B G Xiao ◽  
M Bakhiet ◽  
P van der Meide ◽  
H Wigzell ◽  
...  
Keyword(s):  
T Cells ◽  
Myasthenia Gravis ◽  
Cd8 T Cells ◽  
Cell Types ◽  
Interleukin 4 ◽  
Wild Type ◽  
Ifn Gamma ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune

CD4+ T cells have been shown to be crucial in the development of experimental autoimmune myasthenia gravis (EAMG). The role of CD8+ T cells in EAMG is less well established. We previously showed that antibody depletion of CD8+ T cells in rats effectively suppresses EAMG. To further study the role and relationship of CD4+ versus CD8+ T cells in induction of EAMG, CD4-/-, CD8-/-, and CD4-8- mutant C57BL/6 mice and the parent CD4+8- wild-type mice were immunized with Torpedo acetylcholine receptor (AChR) plus complete Freund's adjuvant. Clinical EAMG was nearly completely prevented in CD4-8-, CD4-/-, and CD8-/- mice. This was associated with strongly reduced AChR-specific T and B cell responses, and with reduced levels of AChR-reactive interferon gamma (IFN-gamma) and interleukin 4 (IL-4) mRNA-expressing cells in lymphoid organs when compared with CD4+8+ wild-type mice. We conclude that (a) both CD4+ and CD8+ T cells are essential for development of EAMG, and a collaboration between these cell types may be necessary; (b) CD4+ as well as CD8+ T cells secrete IFN-gamma and IL-4, and both cytokines are involved in the development of EAMG; and (c), besides T cells, other immune cells might also be responsible for help of anti-AChR antibody production.

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 IL-17-producing CD4+T cells contribute to the loss of B-cell tolerance in experimental autoimmune myasthenia gravis

2015 ◽  
Vol 45 (5) ◽  
pp. 1339-1347 ◽  
Author(s):  
Hanne Schaffert ◽  
Andreas Pelz ◽  
Abhishek Saxena ◽  
Mario Losen ◽  
Andreas Meisel ◽  
...  
Keyword(s):  
T Cells ◽  
Myasthenia Gravis ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Experimental Autoimmune Myasthenia Gravis ◽  
Autoimmune Myasthenia ◽  
Experimental Autoimmune
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