Tumor necrosis factor receptor-1 (TNFR1, CD120a) has been implicated in the pathogenesis of several experimental models of T cell-mediated autoimmune disorders, but its role in antibodymediated autoimmune diseases has not been addressed. Experimental autoimmune myastheniagravis (EAMG), an autoantibody-mediated T cell-dependent neuromuscular disorder, representsan animal model for myasthenia gravis in human. To investigate the role of TNFR1 in thepathogenesis of EAMG, TNFR1-/- and wild-type mice were immunized with Torpedo acetylcholinereceptor (AChR) in complete Freund's adjuvant. TNFR1-/- mice failed to develop EAMG. Lymphoidcells from TNFR1-/- mice produced low amounts of Th1 (IFN-γ, IL-2 and IL-12)-type cytokines, butelevated levels of Th2 (IL-4 and IL-10)-type cytokines compared with lymphoid cells of wild-typemice. Accordingly, the levels of anti-AChR IgG2 antibodies were severely reduced and the level ofanti-AChR IgG1 antibodies were moderately reduced. Co-injection of recombinant mouse IL-12 withAChR in adjuvant restored T cell responses to AChR and promoted development of EAMG inTNFR1-/-mice. These results demonstrate that the TNF/TNFR1 system is required for thedevelopment of EAMG. The lack of a functional TNF/TNFR1 system can, at least in part, besubstituted by IL-12 at the stage of initial priming with AChR and adjuvant. Introduction.