T cell receptor transgenic mice recognizing the immunodominant epitope of the Torpedo californica acetylcholine receptor.
Myasthenia gravis (MG) is an autoimmune disease caused by T cell-dependent antibody-mediated reduction of acetylcholine receptors (AChR) at the neuromuscular junction. Immunization of animals with Torpedo californica AChR (TAChR) results in an experimental model of MG. We used the variable regions of alpha and beta T cell receptor (TCR) genes recognizing an immunodominant peptide containing amino acids 146-162 from the alpha subunit of TAChR presented in the context of I-A(b) to generate TCR-transgenic mice. We found that the transgenic TCR was strongly positively selected and that transgenic T cells proliferated robustly to the immunodominant peptide and TAChR. Unexpectedly, there was a variable paucity of B cells in the blood and spleen from transgenic mice, which averaged about 16% of peripheral blood lymphocytes, compared to 55% in wild-type B6 mice. Unselected transgenic mice immunized with TAChR exhibited weak anti-TAChR antibody responses. However, transgenic mice selected to have relatively higher B cell numbers produced anti-TAChR titers equal to B6 mice and a predominance of Th1-induced antibody isotypes were observed in certain experiments. The incidence and severity of clinical disease was variable following immunizations. These mice should be useful for studying the pathogenesis and treatment of MG.
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Adrian A
AA
Lobito
Bingzhi
B
Yang
Marcela F
MF
Lopes
Alexei
A
Miagkov
Robert N
RN
Adams
Gregory R
GR
Palardy
Michele M
MM
Johnson
Hugh I
HI
McFarland
Michael
M
Recher
Daniel B
DB
Drachman
Michael J
MJ
Lenardo
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002455:Cell Division; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015870:Gene Expression; D016056:Immunodominant Epitopes / Q000276:immunology*; D018655:Lymphocyte Count; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D014101:Torpedo; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011950:Receptors, Cholinergic