Mice with IFN-gamma receptor deficiency are less susceptible to experimental autoimmune myasthenia gravis.
IFN-gamma can either adversely or beneficially affect certain experimental autoimmune diseases. To study the role of IFN-gamma in the autoantibody-mediated experimental autoimmune myasthenia gravis (EAMG), an animal model of myasthenia gravis in humans, IFN-gammaR-deficient (IFN-gammaR-/-) mutant C57BL/6 mice and congenic wild-type mice were immunized with Torpedo acetylcholine receptor (AChR) plus CFA. IFN-gammaR-/- mice exhibited significantly lower incidence and severity of muscle weakness, lower anti-AChR IgG Ab levels, and lower Ab affinity to AChR compared with wild-type mice. Passive transfer of serum from IFN-gammaR-/- mice induced less muscular weakness compared with serum from wild-type mice. In contrast, numbers of lymph node cells secreting IFN-gamma and of those expressing IFN-gamma mRNA were strongly augmented in the IFN-gammaR-/- mice, reflecting a failure of negative feedback circuits. Cytokine studies by in situ hybridization revealed lower levels of lymphoid cells expressing AChR-reactive IL-1beta and TNF-alpha mRNA in AChR + CFA-immunized IFN-gammaR-/- mice compared with wild-type mice. No differences were found for AChR-reactive cells expressing IL-4, IL-10, or TGF-beta mRNA. These results indicate that IFN-gamma promotes systemic humoral responses in EAMG by up-regulating the production and the affinity of anti-AChR autoantibodies, thereby contributing to susceptibility to EAMG in C57BL/6-type mice.
Zhang
G X
GX
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden. gxzhang@mail.med.upenn.edu
Xiao
B G
BG
Bai
X F
XF
van der Meide
P H
PH
Orn
A
A
Link
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H
D000818:Animals; D000915:Antibody Affinity / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000276:immunology*; D007106:Immune Sera / Q000008:administration & dosage; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000097:blood; D007132:Immunoglobulin Isotypes / Q000097:blood; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018908:Muscle Weakness / Q000235:genetics / Q000276:immunology; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011950:Receptors, Cholinergic / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics* / Q000502:physiology; D000096743:Interferon gamma Receptor
D016207:Cytokines; D007106:Immune Sera; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007371:Interferon-gamma; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor