Ocular myasthenia gravis induced by human acetylcholine receptor ϵ subunit immunization in HLA DR3 transgenic mice.
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.
Department of Ophthalmology, First Affiliated Hospital, Nanchang University, Nanchang 330006, PR China.
Xiaorong
X
Wu
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
Erdem
E
Tuzun
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
Shamsher S
SS
Saini
Second Department of Respiratory Disease, Jiangxi Provincial People's Hospital, Nanchang, PR China.
Jun
J
Wang
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
Jing
J
Li
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
Leopoldo
L
Aguilera-Aguirre
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
Ruksana
R
Huda
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA. Electronic address: pchrista@utmb.edu.
Premkumar
P
Christadoss
D000818:Animals; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005620:Freund's Adjuvant / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000379:methods; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D009801:Oculomotor Muscles / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology
D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015803:HLA-DR3 Antigen; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D005620:Freund's Adjuvant
Acetylcholine receptor; Autoimmunity; Epsilon subunit; Myasthenia gravis; Ocular myasthenia