Interferon gamma (IFN-gamma) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice.
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.
Balasa
B
B
The Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Deng
C
C
Lee
J
J
Bradley
L M
LM
Dalton
D K
DK
Christadoss
P
P
Sarvetnick
N
N
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D017353:Gene Deletion; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000502:physiology; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000097:blood; D007371:Interferon-gamma / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009157:Myasthenia Gravis / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology / Q000502:physiology*
D001323:Autoantibodies; D016056:Immunodominant Epitopes; D007132:Immunoglobulin Isotypes; D011950:Receptors, Cholinergic; D007371:Interferon-gamma