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

Figure 7

Participation of the adenosinergic system on neuroimmunological deficits present in EAMG rats. In healthy animals, R activation by ADO generated from the catabolism of released nucleotides via ecto-5′-nucleotidase/CD73 downmodulates T effector () cells proliferation in response to specific antigens by increasing the activity of T_reg () cells expressing FoxP3-dependent gene products, like ecto-5′-nucleotidase/CD73. At the neuromuscular junction, ecto-5′-nucleotidase/CD73 activity leads to the formation of ADO from released ATP (from both nerve and muscle), which facilitates acetylcholine release via prejunctional R activation that is necessary to resist tetanic depression. In EAMG rats, increases in serum adenosine deaminase (ADA) together with ecto-5′-nucleotidase/CD73 in T_reg () cells lead to insufficient amounts of extracellular ADO. The lack of the R immunosuppressive tonus contributes to the loss of peripheral tolerance to nAChR. Thus, increases in the proliferation of antigen-specific T effector cells triggers B cells differentiation into plasma cells and secretion of antibodies directed towards motor endplates nAChR clusters. This antibody attack leads to nAChR internalization/degradation and to complement-mediated morphological changes of the myasthenic postsynaptic membrane (e.g., fewer secondary synaptic folds, widening of the synaptic cleft). These changes contribute to neuromuscular transmission failure, which is further aggravated by deficits in the production of extracellular ADO, probably from released adenine nucleotides, namely, ATP. Impairment of tonic R-mediated facilitation of transmitter Impairment of tonic R-mediated facilitation of transmitter release turns myasthenic skeletal muscles unable to resist fatigue.