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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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Hypothetical model: how IFN-γ influences the humoral immune response to self (AChR) and foreign (AChR) antigens in vivo.
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Figure 4: Hypothetical model: how IFN-γ influences the humoral immune response to self (AChR) and foreign (AChR) antigens in vivo.

Mentions: The dichotomy observed in the humoral immune response to AChR versus KLH-immunized IFN-gko (−/−) mice is unexpected. Because a significant AChR-specific T cell proliferative response is observed in WT (+/+) and IFN-gko (−/−) mice, the loss of M-AChR–specific Ab responses in IFN-gko (−/−) mice probably results from defective T cell–B cell cognate interactions. What role could IFN-γ play in that process? It is known that T cells responding to self-antigen(s) are generally of low affinity compared with those responding to foreign antigens (23, 24). Additionally, the expression of AChR in the thymus (25) may enhance negative selection of higher affinity autoreactive T cells, resulting in a particularly low affinity AChR T cell repertoire. During cognate T cell–B cell interactions, these AChR-specific low affinity T cells may require a higher level of costimulation to achieve the threshold for contact-dependent signals to cause stimulation and differentiation of B cells and subsequent Ab production. Therefore, we speculate that mounting an effective humoral immune response to this (AChR) self-antigen is IFN-γ dependent, because the cytokine regulates the expression of costimulatory molecules (26, 27). On the other hand, the KLH-specific high affinity T cells do not require IFN-γ–dependent costimulation by B cells to effectively participate in humoral response. The hypothetical model is shown in Fig. 4. The data reported in our manuscript are suggestive of differential requirements for IFN-γ in the induction of humoral immune response to self (AChR) and foreign (KLH) antigens; however, the study of other self-antigens would substantiate this notion. The findings of humoral immune responses observed in KLH-immunized IFN-gko (−/−) mice are further supported by previous findings in which IFN-gko (−/−) mice produce antibodies to a wide variety of pathogens; influenza (17), Leishmania major (28), and Herpes simplex virus (29).


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)

Hypothetical model: how IFN-γ influences the humoral immune response to self (AChR) and foreign (AChR) antigens in vivo.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Hypothetical model: how IFN-γ influences the humoral immune response to self (AChR) and foreign (AChR) antigens in vivo.
Mentions: The dichotomy observed in the humoral immune response to AChR versus KLH-immunized IFN-gko (−/−) mice is unexpected. Because a significant AChR-specific T cell proliferative response is observed in WT (+/+) and IFN-gko (−/−) mice, the loss of M-AChR–specific Ab responses in IFN-gko (−/−) mice probably results from defective T cell–B cell cognate interactions. What role could IFN-γ play in that process? It is known that T cells responding to self-antigen(s) are generally of low affinity compared with those responding to foreign antigens (23, 24). Additionally, the expression of AChR in the thymus (25) may enhance negative selection of higher affinity autoreactive T cells, resulting in a particularly low affinity AChR T cell repertoire. During cognate T cell–B cell interactions, these AChR-specific low affinity T cells may require a higher level of costimulation to achieve the threshold for contact-dependent signals to cause stimulation and differentiation of B cells and subsequent Ab production. Therefore, we speculate that mounting an effective humoral immune response to this (AChR) self-antigen is IFN-γ dependent, because the cytokine regulates the expression of costimulatory molecules (26, 27). On the other hand, the KLH-specific high affinity T cells do not require IFN-γ–dependent costimulation by B cells to effectively participate in humoral response. The hypothetical model is shown in Fig. 4. The data reported in our manuscript are suggestive of differential requirements for IFN-γ in the induction of humoral immune response to self (AChR) and foreign (KLH) antigens; however, the study of other self-antigens would substantiate this notion. The findings of humoral immune responses observed in KLH-immunized IFN-gko (−/−) mice are further supported by previous findings in which IFN-gko (−/−) mice produce antibodies to a wide variety of pathogens; influenza (17), Leishmania major (28), and Herpes simplex virus (29).

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