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 pre sent in the thymus, it is not tolerated in MG patients. In addition, t he nature of the cell bearing the autoantigen is controversial. To app roach these questions, we used two lineages of transgenic mice in whic h 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 cw subunit AChR gene. In addition to expression in muscle cells, thymic e xpression was observed in both mouse lines (mainly in myoid cells in T g1 and myoid cells and epithelial cells in Tg2). After challenge with beta-gar, Tg1 mice produced Th2-dependent anti-beta-gal antibodies, wh ile Tg2 mice were almost unresponsive. By contrast, in a proliferation assay both Tg lines were unresponsive to beta-gal. Cells from Tg1 mic e produce Th2-dependent cytokine whereas cells from Tg2 mice were nonp roducing in response to beta-gal. These data indicate that the level o f expression in Tg1 mice could be sufficient to induce tolerance of Th 1 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.