The Th2 cytokine IL-4 is not required for the progression of antibody-dependent autoimmune myasthenia gravis.
Experimental autoimmune myasthenia gravis (EAMG), a disorder of the neuromuscular junction, is mediated by autoantibodies against muscle nicotinic acetylcholine receptor (AChR). The roles of IFN-gamma (Th1) and IL-4 (Th2) cytokines in the initiation and progression of this disease are not fully understood. Recently, we have demonstrated that IFN-gamma is necessary for the initiation of tAChR-induced EAMG in mice. However, the role of IL-4 in the progression of clinical EAMG remained undetermined. In this study we have addressed the contribution of IL-4 in the disease progression in IL-4(-/-) C57BL/6j mice whose IL-4 gene has been disrupted. Following immunization with Torpedo (t) AChR, the IL-4(-/-) mice readily developed signs of muscle weakness and succumbed to clinical EAMG with kinetics similar to the susceptibility of IL-4(+/+) mice. The tAChR-primed lymph node cells from IL-4(-/-) mice vigorously proliferated to tAChR and to its dominant alpha146-162 sequence associated with disease pathogenesis. However, these T cells secreted higher levels of IFN-gamma and IL-2, suggesting the development of a Th1 default pathway in these mice. Nevertheless, the IL-4 mutation had no effect on the recruitment of CD4+ Vbeta6+ T cells specific to the dominant tAChR alpha146-162 sequence in vivo. Immune sera from IL-4(-/-) mice showed a dramatic increase in mouse AChR-specific IgG2a levels followed by a concomitant decrease in IgG1 levels, but these mice did not exhibit an accelerated disease. In conclusion, we have demonstrated for the first time that IL-4 is not required either for the generation of a pathogenic anti-AChR humoral immune response or for progression of clinical EAMG in mice.
Balasa
B
B
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Deng
C
C
Lee
J
J
Christadoss
P
P
Sarvetnick
N
N
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D017353:Gene Deletion; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D015847:Interleukin-4 / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D011978:Receptors, Nicotinic / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D014101:Torpedo / Q000276:immunology
D001323:Autoantibodies; D016207:Cytokines; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011978:Receptors, Nicotinic; D015847:Interleukin-4