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International Immunology, Vol. 12, No. 10, 1381-1388, October 2000
© 2000 Japanese Society for Immunology

Tumor necrosis factor receptor-1 is critically involved in the development of experimental autoimmune myasthenia gravis

Hua-Bing Wang1, Hulun Li1, Fu-Dong Shi2,3, Benedict J. Chambers2, Hans Link1 and Hans-Gustaf Ljunggren2

1 Experimental Neurology Unit, Division of Neurology, Karolinska Institutet, Huddinge University Hospital, 14186 Stockholm, Sweden
2 Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 17177 Stockholm, Sweden

Correspondence to: H.-B. Wang

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 Th1 (IFN-{gamma}, IL-2 and IL-12)-type cytokines, but elevated levels of Th2 (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.

Keywords: autoantibody, experimental autoimmune myasthenia gravis, IL-12, Th cell, tumor necrosis factor receptor-1

3 Present address: The Scripps Research Institute, IMM-23, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

Transmitting editor: L. Steinman


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