Myelin/oligodendrocyte glycoprotein–deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice
Cécile Delarasse, … , Roland Liblau, Danielle Pham-Dinh
Cécile Delarasse, … , Roland Liblau, Danielle Pham-Dinh
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):544-553. https://doi.org/10.1172/JCI15861.
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Article Autoimmunity

Myelin/oligodendrocyte glycoprotein–deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice

Abstract

We studied the immunological basis for the very potent encephalitogenicity of myelin/oligodendrocyte glycoprotein (MOG), a minor component of myelin in the CNS that is widely used to induce experimental autoimmune encephalomyelitis (EAE). For this purpose, we generated a mutant mouse lacking a functional mog gene. This MOG-deficient mouse presents no clinical or histological abnormalities, permitting us to directly assess the role of MOG as a target autoantigen in EAE. In contrast to WT mice, which developed severe EAE following immunization with whole myelin, MOG-deficient mice had a mild phenotype, demonstrating that the anti-MOG response is a major pathogenic component of the autoimmune response directed against myelin. Moreover, while MOG transcripts are expressed in lymphoid organs in minute amounts, both MOG-deficient and WT mice show similar T and B cell responses against the extracellular domain of MOG, including the immunodominant MOG 35–55 T cell epitope. Furthermore, no differences in the fine specificity of the T cell responses to overlapping peptides covering the complete mouse MOG sequence were observed between MOG+/+ and MOG–/– mice. In addition, upon adoptive transfer, MOG-specific T cells from WT mice and those from MOG-deficient mice are equally pathogenic. This total lack of immune tolerance to MOG in WT C57BL/6 mice may be responsible for the high pathogenicity of the anti-MOG immune response as well as the high susceptibility of most animal strains to MOG-induced EAE.

Authors

Cécile Delarasse, Philippe Daubas, Lennart T. Mars, Csaba Vizler, Tobias Litzenburger, Antonio Iglesias, Jan Bauer, Bruno Della Gaspera, Anna Schubart, Laurence Decker, Dalia Dimitri, Guy Roussel, Andrée Dierich, Sandra Amor, André Dautigny, Roland Liblau, Danielle Pham-Dinh

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EAE is less severe in MOG–/– mice. (a) Mean clinical score of EAE induce...
EAE is less severe in MOG–/– mice. (a) Mean clinical score of EAE induced with rat rMOG in WT (n = 4) and MOG–/– (n = 4) mice. (b) Mean clinical score of two independent EAE experiments induced with whole myelin in WT (n = 8) and MOG–/– (n = 13) female mice. MOG+/+ females developed a more severe EAE than MOG–/– females (mean maximal clinical score ± SD, 4.4 ± 1.2 in MOG+/+ vs. 1.5 ± 1.5 in MOG–/–; P = 0.004, two-tailed Student t test), leading to higher mortality (75% in MOG+/+ vs. 15% in MOG–/–; P = 0.006, Fisher’s exact test). Disease onset was also delayed in MOG–/– mice (mean ± SD, 17.9 ± 6.6 days) as compared with WT mice (13.4 days ± 1.9; P = 0.008, log-rank test). (c) CNS histology of MOG–/– (left column) and WT mice (right column) at day 20 after induction of EAE with whole myelin. Upper panels (×11): H&E staining showing large infiltrates (arrowheads) in WT mice but no inflammation in MOG–/– mice. Middle panel (×70): Klüver-Barrera staining for myelin shows no loss of myelin in MOG–/– mice, but loss of subpial myelin in WT mice. Arrowheads indicate the presence of intramyelinic vacuoles. Lower panel (×70): Immunocytochemistry for CD3 shows the absence of T cell inflammation in MOG–/– mice, whereas WT mice have large numbers of T cells in inflammatory infiltrates.