Experimental autoimmune myasthenia gravis in B10.BV8S2 transgenic mice: preferential usage of TCRAV1 gene by lymphocytes responding to acetylcholine receptor.
Multiple TCRBV genes have been implicated in experimental autoimmune myasthenia gravis (EAMG) pathogenesis in susceptible H-2(b) strains of mice. We studied the contribution of specific TCRBV and AV genes in EAMG pathogenesis using B10.BV8S2 transgenic mice (H-2[b]). The TCR transgenic mice predominantly have TCRBV8S2 transgene, but can use any of the endogenous AV gene repertoire. The transgenic mice were immunized with acetylcholine receptor (AChR) in CFA and evaluated for EAMG pathogenesis. Although the lymphocyte responses to AChR in B10.BV8S2 transgenic and nontransgenic TCR wild-type mice were equivalent, a marked reduction in lymphocyte response to the dominant AChR alpha chain peptide 146-162 was observed in the TCR transgenic mice. After boosting with AChR in CFA, anti-AChR Abs were detected in the serum, and 14 of 42 (33%) of the TCR transgenic mice developed clinical EAMG. Furthermore, EAMG in TCR transgenic mice was prevented by treatment with mAb to TCRBV8, which depleted BV8-expressing T cells. Cloning and sequencing of TCRAV genes from AChR-reactive T cells from B10.BV8S2 transgenic mice revealed a pattern of restricted TCRAV gene usage. The majority (60%) of the clones sequenced showed a sequence identical with that of the TCRAV1S8 gene. In the normal spleen cells of TCR transgenic mice, AV gene usage was more random. Thus, despite the presence of a complete endogenous TCRAV repertoire in B10.BV8S2 transgenic mice, T cells responding to AChR preferentially used a single endogenous TCRAV gene, thus implicating the involvement of the TCRAV1S8 gene in EAMG pathogenesis.
Kaul
R
R
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston 77555, USA.
Wu
B
B
Goluszko
E
E
Deng
C
C
Dedhia
V
V
Nabozny
G H
GH
David
C S
CS
Rimm
I J
IJ
Shenoy
M
M
Haqqi
T M
TM
Christadoss
P
P
D000818:Animals; D002460:Cell Line; D005796:Genes; D007114:Immunization; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009157:Myasthenia Gravis / Q000276:immunology* / Q000517:prevention & control; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D016693:Receptors, Antigen, T-Cell, alpha-beta; D011950:Receptors, Cholinergic