A new mouse model of autoimmune ocular myasthenia gravis

Huan Yang, Bo Wu, Erdem Tüzün, Shamsher S. Saini, Jing Li, Windy Allman, Stephen Higgs, Tian Lin Xiao, Premkumar Christadoss

Research output: Contribution to journalArticle

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Abstract

PURPOSE. To establish a novel model of autoimmune ocular myasthenia gravis (oMG) in mice and study the pathogenic mechanisms of oMG. METHODS. oMG was induced in HLA-DQ8 transgenic, HLA-DR3 transgenic, major histocompatibility complex (MHC) class II-deficient, C57BL/6, and C57BL/10 mice by immunization with an Escherichia coli plasmid expressing the recombinant human acetylcholine receptor (AChR) alpha subunit. RESULTS. All strains of immunized mice developed ocular myasthenia gravis with varying disease incidence and severity. HLA-DQ8 transgenic mice were highly susceptible to oMG. Mice with oMG had serum autoantibodies to the mouse extraocular AChR, pathologic deposits of IgG, C3, and C5b-C9 in their extraocular and limb neuromuscular junctions, and droopiness of eyelids. HLA-DR3 transgenic and MHC class II-deficient mice were relatively resistant to oMG induced by AChR alpha subunit immunization and had minimal ocular abnormalities. CONCLUSIONS. These findings suggest that oMG pathogenesis could be triggered by immunity to the human AChR alpha subunit and that MHC class II molecule is required for human AChR alpha subunit presentation and CD4 cell-mediated anti-AChR antibody class switching. Differential oMG susceptibility observed in DQ8 and DR3 transgenic mice correlated with the intensity of lymphocytes to respond to the human AChR alpha subunit. This new model of oMG will be a valuable tool for studying the mechanism of oMG and gMG pathogenesis in humans and for preclinical therapeutic analysis.

Original languageEnglish
Pages (from-to)5101-5111
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number11
DOIs
StatePublished - Nov 2007

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Myasthenia Gravis
Cholinergic Receptors
Major Histocompatibility Complex
HLA-DR3 Antigen
Transgenic Mice
Immunization
Eye Abnormalities
Immunoglobulin Class Switching
Immunoglobulin Isotypes
Neuromuscular Junction
Eyelids
Inbred C57BL Mouse
Autoantibodies
Immunity
Plasmids
Extremities
Immunoglobulin G
Lymphocytes
Escherichia coli

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Yang, H., Wu, B., Tüzün, E., Saini, S. S., Li, J., Allman, W., ... Christadoss, P. (2007). A new mouse model of autoimmune ocular myasthenia gravis. Investigative Ophthalmology and Visual Science, 48(11), 5101-5111. https://doi.org/10.1167/iovs.07-0271

A new mouse model of autoimmune ocular myasthenia gravis. / Yang, Huan; Wu, Bo; Tüzün, Erdem; Saini, Shamsher S.; Li, Jing; Allman, Windy; Higgs, Stephen; Xiao, Tian Lin; Christadoss, Premkumar.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 11, 11.2007, p. 5101-5111.

Research output: Contribution to journalArticle

Yang, H, Wu, B, Tüzün, E, Saini, SS, Li, J, Allman, W, Higgs, S, Xiao, TL & Christadoss, P 2007, 'A new mouse model of autoimmune ocular myasthenia gravis', Investigative Ophthalmology and Visual Science, vol. 48, no. 11, pp. 5101-5111. https://doi.org/10.1167/iovs.07-0271
Yang, Huan ; Wu, Bo ; Tüzün, Erdem ; Saini, Shamsher S. ; Li, Jing ; Allman, Windy ; Higgs, Stephen ; Xiao, Tian Lin ; Christadoss, Premkumar. / A new mouse model of autoimmune ocular myasthenia gravis. In: Investigative Ophthalmology and Visual Science. 2007 ; Vol. 48, No. 11. pp. 5101-5111.
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N2 - PURPOSE. To establish a novel model of autoimmune ocular myasthenia gravis (oMG) in mice and study the pathogenic mechanisms of oMG. METHODS. oMG was induced in HLA-DQ8 transgenic, HLA-DR3 transgenic, major histocompatibility complex (MHC) class II-deficient, C57BL/6, and C57BL/10 mice by immunization with an Escherichia coli plasmid expressing the recombinant human acetylcholine receptor (AChR) alpha subunit. RESULTS. All strains of immunized mice developed ocular myasthenia gravis with varying disease incidence and severity. HLA-DQ8 transgenic mice were highly susceptible to oMG. Mice with oMG had serum autoantibodies to the mouse extraocular AChR, pathologic deposits of IgG, C3, and C5b-C9 in their extraocular and limb neuromuscular junctions, and droopiness of eyelids. HLA-DR3 transgenic and MHC class II-deficient mice were relatively resistant to oMG induced by AChR alpha subunit immunization and had minimal ocular abnormalities. CONCLUSIONS. These findings suggest that oMG pathogenesis could be triggered by immunity to the human AChR alpha subunit and that MHC class II molecule is required for human AChR alpha subunit presentation and CD4 cell-mediated anti-AChR antibody class switching. Differential oMG susceptibility observed in DQ8 and DR3 transgenic mice correlated with the intensity of lymphocytes to respond to the human AChR alpha subunit. This new model of oMG will be a valuable tool for studying the mechanism of oMG and gMG pathogenesis in humans and for preclinical therapeutic analysis.

AB - PURPOSE. To establish a novel model of autoimmune ocular myasthenia gravis (oMG) in mice and study the pathogenic mechanisms of oMG. METHODS. oMG was induced in HLA-DQ8 transgenic, HLA-DR3 transgenic, major histocompatibility complex (MHC) class II-deficient, C57BL/6, and C57BL/10 mice by immunization with an Escherichia coli plasmid expressing the recombinant human acetylcholine receptor (AChR) alpha subunit. RESULTS. All strains of immunized mice developed ocular myasthenia gravis with varying disease incidence and severity. HLA-DQ8 transgenic mice were highly susceptible to oMG. Mice with oMG had serum autoantibodies to the mouse extraocular AChR, pathologic deposits of IgG, C3, and C5b-C9 in their extraocular and limb neuromuscular junctions, and droopiness of eyelids. HLA-DR3 transgenic and MHC class II-deficient mice were relatively resistant to oMG induced by AChR alpha subunit immunization and had minimal ocular abnormalities. CONCLUSIONS. These findings suggest that oMG pathogenesis could be triggered by immunity to the human AChR alpha subunit and that MHC class II molecule is required for human AChR alpha subunit presentation and CD4 cell-mediated anti-AChR antibody class switching. Differential oMG susceptibility observed in DQ8 and DR3 transgenic mice correlated with the intensity of lymphocytes to respond to the human AChR alpha subunit. This new model of oMG will be a valuable tool for studying the mechanism of oMG and gMG pathogenesis in humans and for preclinical therapeutic analysis.

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