Tumor necrosis factor receptor-1 is critically involved in the development of experimental autoimmune myasthenia gravis.
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 antibody-mediated autoimmune diseases has not been addressed. Experimental autoimmune myasthenia gravis (EAMG), an autoantibody-mediated T cell-dependent neuromuscular disorder, represents an animal model for myasthenia gravis in human. To investigate the role of TNFR1 in the pathogenesis of EAMG, TNFR1(-/-) and wild-type mice were immunized with TORPEDO: acetylcholine receptor (AChR) in complete Freund's adjuvant. TNFR1(-/-) mice failed to develop EAMG. Lymphoid cells from TNFR1(-/-) mice produced low amounts of T(h)1 (IFN-gamma, IL-2 and IL-12)-type cytokines, but elevated levels of T(h)2 (IL-4 and IL-10)-type cytokines compared with lymphoid cells of wild-type mice. Accordingly, the levels of anti-AChR IgG2 antibodies were severely reduced and the level of anti-AChR IgG1 antibodies were moderately reduced. Co-injection of recombinant mouse IL-12 with AChR in adjuvant restored T cell responses to AChR and promoted development of EAMG in TNFR1(-/-) mice. These results demonstrate that the TNF/TNFR1 system is required for the development of EAMG. The lack of a functional TNF/TNFR1 system can, at least in part, be substituted by IL-12 at the stage of initial priming with AChR and adjuvant.
Wang
H B
HB
Experimental Neurology Unit, Division of Neurology, Karolinska Institutet, Huddinge University Hospital, 14186 Stockholm, Sweden.
Li
H
H
Shi
F D
FD
Chambers
B J
BJ
Link
H
H
Ljunggren
H G
HG
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D007074:Immunoglobulin G / Q000145:classification; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000209:etiology*; D011950:Receptors, Cholinergic / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D007074:Immunoglobulin G; D011950:Receptors, Cholinergic; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin