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Interferon gamma (IFN-gamma) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice.

Balasa B, Deng C, Lee J, Bradley LM, Dalton DK, Christadoss P, Sarvetnick N - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
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)-gamma, plays a role in the development of EAMG, we immunized IFN-gamma knockout (IFN-gko) (-/-) mice and wild-type (WT) (+/+) mice of H-2(b) 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 alpha146-162 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-gamma regulates the humoral immune response distinctly to self (AChR) versus foreign (KLH) antigens. We conclude that IFN-gamma is required for the generation of a pathogenic anti-AChR humoral immune response and for conferring susceptibility of mice to clinical EAMG.

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RIA of serum anti-AChR Ab to mouse muscle AChR. Serum samples were collected on day 89 after immunization. The difference  in anti-AChR antibody levels between WT and IFN-gko mice (P =  0.002) and between C57BL/6 and IFN-gko mice (P = 0.003) was statistically significant. The difference in anti-AChR antibody levels between  WT and C57BL/6 mice (P = 0.222) is not statistically significant. —*,  the mean value.
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Figure 2: RIA of serum anti-AChR Ab to mouse muscle AChR. Serum samples were collected on day 89 after immunization. The difference in anti-AChR antibody levels between WT and IFN-gko mice (P = 0.002) and between C57BL/6 and IFN-gko mice (P = 0.003) was statistically significant. The difference in anti-AChR antibody levels between WT and C57BL/6 mice (P = 0.222) is not statistically significant. —*, the mean value.

Mentions: The primary pathology of EAMG, the end plate AChR loss, stems from the deleterious effect of pathogenic AAbs to the AChR (2). Therefore, to learn whether a reduced anti–AChR Ab response underlies the resistance of IFN-gko (−/−) mice to EAMG, we used RIA to compare their levels of serum anti–M-AChR Ab to those in C57BL/6 (+/+), and WT (+/+) mice on day 89 after immunization with AChR in CFA. The results appear in Fig. 2. The results indicate that the resistance of the mutants (−/−) to EAMG correlated with their dramatic decrease in the level of AAbs to AChR compared with significantly higher levels in the C57BL/6 (+/+) and WT (+/+) mice. The individual AChR-immunized C57BL/6 (+/+) and WT (+/+) mice responded heterogeneously. A wide heterogeneity in anti-AChR response has earlier been documented in inbred C57BL/6 mice (13). However, we did not find a correlation between the anti-AChR antibody response magnitude of individual mice (C57BL/6 and WT) and severity of EAMG. Our findings further support the earlier findings that no correlation exists between the magnitude of the anti-AChR antibody response and severity of EAMG (8, 13–15).


Interferon gamma (IFN-gamma) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice.

Balasa B, Deng C, Lee J, Bradley LM, Dalton DK, Christadoss P, Sarvetnick N - J. Exp. Med. (1997)

RIA of serum anti-AChR Ab to mouse muscle AChR. Serum samples were collected on day 89 after immunization. The difference  in anti-AChR antibody levels between WT and IFN-gko mice (P =  0.002) and between C57BL/6 and IFN-gko mice (P = 0.003) was statistically significant. The difference in anti-AChR antibody levels between  WT and C57BL/6 mice (P = 0.222) is not statistically significant. —*,  the mean value.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198999&req=5

Figure 2: RIA of serum anti-AChR Ab to mouse muscle AChR. Serum samples were collected on day 89 after immunization. The difference in anti-AChR antibody levels between WT and IFN-gko mice (P = 0.002) and between C57BL/6 and IFN-gko mice (P = 0.003) was statistically significant. The difference in anti-AChR antibody levels between WT and C57BL/6 mice (P = 0.222) is not statistically significant. —*, the mean value.
Mentions: The primary pathology of EAMG, the end plate AChR loss, stems from the deleterious effect of pathogenic AAbs to the AChR (2). Therefore, to learn whether a reduced anti–AChR Ab response underlies the resistance of IFN-gko (−/−) mice to EAMG, we used RIA to compare their levels of serum anti–M-AChR Ab to those in C57BL/6 (+/+), and WT (+/+) mice on day 89 after immunization with AChR in CFA. The results appear in Fig. 2. The results indicate that the resistance of the mutants (−/−) to EAMG correlated with their dramatic decrease in the level of AAbs to AChR compared with significantly higher levels in the C57BL/6 (+/+) and WT (+/+) mice. The individual AChR-immunized C57BL/6 (+/+) and WT (+/+) mice responded heterogeneously. A wide heterogeneity in anti-AChR response has earlier been documented in inbred C57BL/6 mice (13). However, we did not find a correlation between the anti-AChR antibody response magnitude of individual mice (C57BL/6 and WT) and severity of EAMG. Our findings further support the earlier findings that no correlation exists between the magnitude of the anti-AChR antibody response and severity of EAMG (8, 13–15).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
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)-gamma, plays a role in the development of EAMG, we immunized IFN-gamma knockout (IFN-gko) (-/-) mice and wild-type (WT) (+/+) mice of H-2(b) 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 alpha146-162 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-gamma regulates the humoral immune response distinctly to self (AChR) versus foreign (KLH) antigens. We conclude that IFN-gamma is required for the generation of a pathogenic anti-AChR humoral immune response and for conferring susceptibility of mice to clinical EAMG.

Show MeSH
Related in: MedlinePlus