© The Rockefeller University Press, 0022-1007/1997/8/385/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 3, August 4, 1997 385-391
Interferon
(IFN-
) Is Necessary for the Genesis of Acetylcholine Receptor–induced Clinical Experimental Autoimmune Myasthenia gravis in Mice
Balaji Balasa*,
Caishu Deng
,
Jae Lee*,
Linda M. Bradley*,
Dyana K. Dalton
,
Premkumar Christadoss
, and
Nora Sarvetnick*
From * The Department of Immunology, The Scripps Research Institute, La Jolla, California 92037;
The Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019;
Trudeau Institute, Saranac Lake, New York 12983
Experimental autoimmune myasthenia gravis (EAMG) is an animal model of human myasthenia gravis (MG). In mice, EAMG is induced by immunization with Torpedo californica acetylcholine receptor (AChR) in complete Freund's adjuvant (CFA). However, the role of cytokines in the pathogenesis of EAMG is not clear. Because EAMG is an antibody-mediated disease, it is of the prevailing notion that Th2 but not Th1 cytokines play a role in the pathogenesis of this disease. To test the hypothesis that the Th1 cytokine, interferon (IFN)-
, plays a role in the development of EAMG, we immunized IFN-
knockout (IFN-gko) (–/–) mice and wild-type (WT) (+/+) mice of H-2b haplotype with AChR in CFA. We observed that AChR-primed lymph node cells from IFN-gko mice proliferated normally to AChR and to its dominant pathogenic
146–162 sequence when compared with these cells from the WT mice. However, the IFN-gko mice had no signs of muscle weakness and remained resistant to clinical EAMG at a time when the WT mice exhibited severe muscle weakness and some died. The resistance of IFN-gko mice was associated with greatly reduced levels of circulating anti-AChR antibody levels compared with those in the WT mice. Comparatively, immune sera from IFN-gko mice showed a dramatic reduction in mouse AChR-specific IgG1 and IgG2a antibodies. However, keyhole limpet hemocyanin (KLH)–priming of IFN-gko mice readily elicited both T cell and antibody responses, suggesting that IFN-
regulates the humoral immune response distinctly to self (AChR) versus foreign (KLH) antigens. We conclude that IFN-
is required for the generation of a pathogenic anti-AChR humoral immune response and for conferring susceptibility of mice to clinical EAMG.
Address correspondence to Dr. Nora Sarvetnick, Ph.D., Department of Immunology, The Scripss Research Institute, 10555 North Torrey Pines Road, La Jolla, CA 92037. Phone: 619-784-9066; FAX: 619-784-9383; E-mail: noras{at}scripps.edu
B. Balasa (DVM., Ph.D) has been supported successively by postdoctoral fellowships from the Myasthenia Gravis Foundation of America, Inc., and the Juvenile Diabetes Foundation International. C. Deng is a Myasthenia Gravis Foundation Osserman postdoctoral fellow. This work was supported by the Diabetes Interdisciplinary Research Program grant from Juvenile Diabetes Foundation International (N. Sarvetnick), and the Muscular Dystrophy Association (P. Christadoss). This is manuscript No. 10815-IMM.
1 Abbreviations used in this paper: AAbs, autoantibodies; AChR, acetylcholine receptor; EAMG, experimental autoimmune myasthenia gravis; HRPO, horseradish peroxidase; IFN-gko, IFN-
knockout; LNC, lymph node cells; M-AChR, mouse AChR; MG, myasthenia gravis; NMS, normal mouse serum.

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