Ocular myasthenia gravis induced by human acetylcholine receptor ε subunit immunization in HLA DR3 transgenic mice

Xiaorong Wu, Erdem Tuzun, Shamsher S. Saini, Jun Wang, Jing Li, Leopoldo Aguilera-Aguirre, Ruksana Huda, Premkumar Christadoss

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ε-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ε-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ε-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ε-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ε-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ε-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ε-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG.

Original languageEnglish (US)
Pages (from-to)306-312
Number of pages7
JournalImmunology Letters
Volume168
Issue number2
DOIs
StatePublished - Dec 1 2015

Fingerprint

Myasthenia Gravis
Cholinergic Receptors
HLA Antigens
Transgenic Mice
Immunization
Oculomotor Muscles
Autoimmune Experimental Myasthenia Gravis
Freund's Adjuvant
Immunoglobulin G
Muscle Weakness
Escherichia coli
Antibodies
Neuromuscular Junction
Hand Strength
Autoimmunity
Immunoglobulin M
Lymph Nodes
Alleles

Keywords

  • Acetylcholine receptor
  • Autoimmunity
  • Epsilon subunit
  • Myasthenia gravis
  • Ocular myasthenia

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Wu, X., Tuzun, E., Saini, S. S., Wang, J., Li, J., Aguilera-Aguirre, L., ... Christadoss, P. (2015). Ocular myasthenia gravis induced by human acetylcholine receptor ε subunit immunization in HLA DR3 transgenic mice. Immunology Letters, 168(2), 306-312. https://doi.org/10.1016/j.imlet.2015.10.009

Ocular myasthenia gravis induced by human acetylcholine receptor ε subunit immunization in HLA DR3 transgenic mice. / Wu, Xiaorong; Tuzun, Erdem; Saini, Shamsher S.; Wang, Jun; Li, Jing; Aguilera-Aguirre, Leopoldo; Huda, Ruksana; Christadoss, Premkumar.

In: Immunology Letters, Vol. 168, No. 2, 01.12.2015, p. 306-312.

Research output: Contribution to journalArticle

Wu, X, Tuzun, E, Saini, SS, Wang, J, Li, J, Aguilera-Aguirre, L, Huda, R & Christadoss, P 2015, 'Ocular myasthenia gravis induced by human acetylcholine receptor ε subunit immunization in HLA DR3 transgenic mice', Immunology Letters, vol. 168, no. 2, pp. 306-312. https://doi.org/10.1016/j.imlet.2015.10.009
Wu, Xiaorong ; Tuzun, Erdem ; Saini, Shamsher S. ; Wang, Jun ; Li, Jing ; Aguilera-Aguirre, Leopoldo ; Huda, Ruksana ; Christadoss, Premkumar. / Ocular myasthenia gravis induced by human acetylcholine receptor ε subunit immunization in HLA DR3 transgenic mice. In: Immunology Letters. 2015 ; Vol. 168, No. 2. pp. 306-312.
@article{f0af39fc4b2b4ee2987256df22900042,
title = "Ocular myasthenia gravis induced by human acetylcholine receptor ε subunit immunization in HLA DR3 transgenic mice",
abstract = "Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ε-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ε-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ε-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ε-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ε-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ε-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ε-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG.",
keywords = "Acetylcholine receptor, Autoimmunity, Epsilon subunit, Myasthenia gravis, Ocular myasthenia",
author = "Xiaorong Wu and Erdem Tuzun and Saini, {Shamsher S.} and Jun Wang and Jing Li and Leopoldo Aguilera-Aguirre and Ruksana Huda and Premkumar Christadoss",
year = "2015",
month = "12",
day = "1",
doi = "10.1016/j.imlet.2015.10.009",
language = "English (US)",
volume = "168",
pages = "306--312",
journal = "Immunology Letters",
issn = "0165-2478",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Ocular myasthenia gravis induced by human acetylcholine receptor ε subunit immunization in HLA DR3 transgenic mice

AU - Wu, Xiaorong

AU - Tuzun, Erdem

AU - Saini, Shamsher S.

AU - Wang, Jun

AU - Li, Jing

AU - Aguilera-Aguirre, Leopoldo

AU - Huda, Ruksana

AU - Christadoss, Premkumar

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ε-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ε-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ε-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ε-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ε-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ε-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ε-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG.

AB - Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ε-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ε-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ε-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ε-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ε-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ε-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ε-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG.

KW - Acetylcholine receptor

KW - Autoimmunity

KW - Epsilon subunit

KW - Myasthenia gravis

KW - Ocular myasthenia

UR - http://www.scopus.com/inward/record.url?scp=84949553980&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949553980&partnerID=8YFLogxK

U2 - 10.1016/j.imlet.2015.10.009

DO - 10.1016/j.imlet.2015.10.009

M3 - Article

VL - 168

SP - 306

EP - 312

JO - Immunology Letters

JF - Immunology Letters

SN - 0165-2478

IS - 2

ER -