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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(a) Proliferative response of lymph node cells MOG+/+ (n = 6) and MOG–/–...
(a) Proliferative response of lymph node cells MOG+/+ (n = 6) and MOG–/– (n = 6) mice 10 days after immunization with 31 overlapping mouse MOG peptides. The in vitro recall response was induced using individual MOG peptides (200 μg/ml). SI, stimulation index. (b) The proliferative response of lymph node cells of MOG+/+ (n = 3) and MOG–/– (n = 3) mice 10 days after immunization with mouse rMOG. The recall response was elicited with different doses of rMOG. (c) The MOG 35–55–specific T cell population was enumerated by IFN-γ ELISPOT in splenocyte cultures of individual MOG+/+ (n = 4) and MOG–/– (n = 3) mice 14 days after MOG 35–55 immunization. Unfractionated or CD8-depleted spleen cultures were stimulated with purified protein derivative (PPD) (50 μg/ml), or MOG 35–55 (50 μg/ml). (d) MOG-specific antibody response in MOG+/+ (n = 4) and MOG–/– (n = 4) mice at days 0, 20, and 60 after immunization with rat rMOG. MOG-specific IgG levels were assessed by ELISA on serum diluted 1:60; quantitatively similar results were obtained with 1:360 and 1:2,160 dilutions (data not shown). (e) Analysis of the fine specificity of anti-MOG IgG in MOG+/+ and MOG–/– mice 40 days after immunization with rat rMOG. Peptide-specific IgGs were assessed by ELISA with a panel of 13 overlapping rat MOG peptides. Comparable results were obtained at days 20 and 60 after immunization.