Costimulatory molecule CD40 is essential for myelin protein 0 peptide 106-125-induced experimental autoimmune neuritis in mice
Autor(es): Brunn Anna,Utermöhlen Olaf,Mihelcic Mirna,Saupe Lisa,Fiocco Zeno,Schmidt Annika,Carstov Mariana,Montesinos-Rongen Manuel,Deckert Martina
Resumo: Myelin protein 0 peptide 106-125-induced murine experimental autoimmune neuritis (EAN) is a CD4-positive T cell-mediated monophasic axonal inflammatory neuropathy; interferon-? is the key proinflammatory mediator. Experimental autoimmune neuritis is well suited for elucidating pathogenetic mechanisms underlying human acute axonal Guillain-Barré syndrome. Here, the functional role of the costimulatory molecule CD40 was defined by characterization of EAN in CD40-deficient mice. In contrast to immunized C57BL/6 mice, CD40-deficient mice were resistant to EAN owing to impaired priming of CD4-positive T-effector cells. To determine whether CD40 is a suitable candidate for the treatment of EAN, we administered monoclonal anti-CD40 antibody either before immunization or upon onset of neurologic signs. Prophylactic anti-CD40 treatment completely abolished CD4-positive T-cell priming. Therapeutic application of anti-CD40 prevented full activation of CD4-positive T cells that were in the process of priming and suppressed production of interferon-? in peripheral lymph nodes, spleen, and serum, and of interleukin-6, interleukin-12p40, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, which are associated with activation of the nuclear factor-?B signaling pathway. This resulted in enhanced recovery by early generation of CD25-positive, Foxp3-positive, CD4-positive regulatory T cells. Thus, these experiments highlight the crucial role of CD40 as an important costimulatory molecule in EAN and suggest that it has potential as a therapeutic target in human neuritis.
Palavras-Chave: CD4 T cells; CD40; Costimulatory molecule; Experimental autoimmune neuritis; Guillain-Barre syndrome; Interferon-(delta)
Imprenta: Journal of Neuropathology and Experimental Neurology, v. 73, n. 5, p. 454-466, 2014
Identificador do objeto digital: 10.1097/NEN.0000000000000069
Descritores: Guillain-Barre Syndrome - Biosynthesis ; Guillain-Barre Syndrome - Cell ; Guillain-Barre Syndrome - Cytopathology ; Guillain-Barre Syndrome - Molecular Structure ; Guillain-Barre Syndrome - Pathogenesis ; Guillain-Barre Syndrome - Proteins ; Guillain-Barre Syndrome - Inflammation ; Guillain-Barre Syndrome - Molecular screening ; Guillain-Barre Syndrome - Immunology
Data de publicação: 2014
