An acetylcholine receptor alpha subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis.
Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor (AChR). Although the autoantigen is present in the thymus, it is not tolerated in MG patients. In addition, the nature of the cell bearing the autoantigen is controversial. To approach these questions, we used two lineages of transgenic mice in which the beta-galactosidase (beta-gal) gene is under the control of a 842-bp (Tg1) or a 3300-bp promoter fragment (Tg2) of the chick muscle alpha subunit AChR gene. In addition to expression in muscle cells, thymic expression was observed in both mouse lines (mainly in myoid cells in Tg1 and myoid cells and epithelial cells in Tg2). After challenge with beta-gal, Tg1 mice produced Th2-dependent anti-beta-gal antibodies, while Tg2 mice were almost unresponsive. By contrast, in a proliferation assay both Tg lines were unresponsive to beta-gal. Cells from Tg1 mice produce Th2-dependent cytokine whereas cells from Tg2 mice were nonproducing in response to beta-gal. These data indicate that the level of expression in Tg1 mice could be sufficient to induce tolerance of Th1 cells but not of Th2 cells, while both populations are tolerated in Tg2 mice. These findings are compatible with the hypothesis that AChR expression is not sufficiently abundant in MG thymus to induce a full tolerance.
Salmon
A M
AM
Unité de Neurobiologie Moléculaire, CNRS URA-1284, Institut Pasteur, 75015 Paris, France.
Bruand
C
C
Cardona
A
A
Changeux
J P
JP
Berrih-Aknin
S
S
D000818:Animals; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000494:pharmacology; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009157:Myasthenia Gravis / Q000276:immunology*; D011401:Promoter Regions, Genetic; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000502:physiology; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology; D013950:Thymus Gland / Q000378:metabolism*; D001616:beta-Galactosidase / Q000276:immunology / Q000378:metabolism
D007376:Interleukin-2; D011950:Receptors, Cholinergic; D001616:beta-Galactosidase