title: Deficits in endogenous adenosine formation by ecto-5'-nucleotidase/CD73 impair neuromuscular transmission and immune competence in experimental autoimmune myasthenia gravis.
abstract: AMP dephosphorylation via ecto-5'-nucleotidase/CD73 is the rate limiting step to generate extracellular adenosine (ADO) from released adenine nucleotides. ADO, via A2A receptors (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 blocking A2A receptors activation with ZM241385 or adenosine deaminase in EAMG animals. Deficits in ADO also contribute to neuromuscular transmission failure in EAMG rats. Rehabilitation of A2AR-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 that A2ARs 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.
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal.
authors.forename: Laura
authors.identifier: 0000-0002-8620-077X
authors.initials: L
authors.lastname: Oliveira
authors.affiliation: Laboratório de Imunologia, Departamento de Imunofisiologia e Farmacologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal ; IBMC-Instituto de Biologia Celular e Molecular, Universidade do Porto, Rua do Campo Alegre No. 823, 4150-180 Porto, Portugal.
authors.forename: Alexandra
authors.identifier: 0000-0003-0408-6262
authors.initials: A
authors.lastname: Correia
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Cristina Costa
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal.
authors.forename: Sónia
authors.initials: S
authors.lastname: Guerra-Gomes
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Ferreirinha
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Magalhães-Cardoso
authors.affiliation: Laboratório de Imunologia, Departamento de Imunofisiologia e Farmacologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal ; IBMC-Instituto de Biologia Celular e Molecular, Universidade do Porto, Rua do Campo Alegre No. 823, 4150-180 Porto, Portugal.
authors.forename: Manuel
authors.identifier: 0000-0001-7007-306X
authors.initials: M
authors.lastname: Vilanova
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira No. 228, Edificio 2 Piso 4, 4050-313 Porto, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Correia-de-Sá
mesh_terms: D015720:5'-Nucleotidase / Q000172:deficiency / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000097:blood* / Q000172:deficiency; D000818:Animals; D005260:Female; D009119:Muscle Contraction / Q000235:genetics / Q000276:immunology / Q000502:physiology; D009157:Myasthenia Gravis / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; D000241:Adenosine