The Th2 cytokine IL-4 is not required for the progression of antibody-dependent autoimmune myasthenia gravis.

Abstract

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.

• Authors: B Balasa, C Deng, J Lee, P Christadoss, N Sarvetnick
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 161 Issue 6 Pg. 2856-62 (Sep 15 1998) ISSN: 0022-1767 [Print] United States
• PMID: 9743346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Cytokines
• Immunodominant Epitopes
• Immunoglobulin G
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Nicotinic
• Interleukin-4

Topics

• Amino Acid Sequence
• Animals
• Autoantibodies (biosynthesis, blood, physiology)
• Cytokines (biosynthesis)
• Disease Progression
• Gene Deletion
• Immunization
• Immunodominant Epitopes (immunology)
• Immunoglobulin G (biosynthesis)
• Interleukin-4 (genetics, physiology)
• Lymphocyte Activation (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Sequence Data
• Myasthenia Gravis (etiology, genetics, immunology)
• Receptors, Antigen, T-Cell, alpha-beta (biosynthesis)
• Receptors, Nicotinic (immunology)
• T-Lymphocyte Subsets (immunology, metabolism)
• Th2 Cells (immunology, metabolism)
• Torpedo (immunology)