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C57BL/6 Mice Genetically Deficient in IL-12/IL-23 and IFN- Are Susceptible to Experimental Autoimmune Myasthenia Gravis, Suggesting a Pathogenic Role of Non-Th1 Cells¹

Wei Wang^2,*, Monica Milani^*, Norma Ostlie^*, David Okita^*, Rajeev K. Agarwal, Rachel Caspi and Bianca M. Conti-Fine^3,*

^* Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892

Immunization with Torpedo acetylcholine receptor (TAChR) induces experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 (B6) mice. EAMG development needs IL-12, which drives differentiation of Th1 cells. The role of IFN-, an important Th1 effector, is not clear and that of IL-17, a proinflammatory cytokine produced by Th17 cells, is unknown. In this study, we examined the effect of simultaneous absence of IL-12 and IFN- on EAMG susceptibility, using null mutant B6 mice for the genes of both the IL-12/IL-23 p40 subunit and IFN- (dKO mice). Wild-type (WT) B6 mice served as control for EAMG induction. All mice were immunized with TAChR in Freund’s adjuvant. dKO mice developed weaker anti-TAChR CD4⁺T cells and Ab responses than WT mice. Yet, they developed EAMG symptoms, anti-mouse acetylcholine receptor (AChR) Ab, and CD4⁺ T cell responses against mouse AChR sequences similar to those of WT mice. dKO and WT mice had similarly reduced AChR content in their muscles, and IgG and complement at the neuromuscular junction. Naive dKO mice had significantly fewer NK, NKT, and CD4⁺CD25⁺Foxp3⁺ T regulatory (Treg) cells than naive WT mice. Treg cells from TAChR-immunized dKO mice had significantly less suppressive activity in vitro than Treg cells from TAChR-immunized WT mice. In contrast, TAChR-specific CD4⁺ T cells from TAChR-immunized dKO and WT mice secreted comparable amounts of IL-17 after stimulation in vitro with TAChR. The susceptibility of dKO mice to EAMG may be due to reduced Treg function, in the presence of a normal function of pathogenic Th17 cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institute of Neurological and Communicative Disorders and Stroke Grant NS23919 (to B.M.C.-F.).

² Address correspondence and reprint requests to Dr. Wei Wang, Department of Biochemistry, Molecular Biology and Biophisic, University of Minnesota, 6/155 Jackson Hall, 321 Church Street, Minneapolis, MN 55455. E-mail address: wangx241{at}umn.edu

³ Bianca M. Conti-Fine was previously known as Bianca M. Conti-Tronconi.

⁴ Abbreviations used in this paper: Treg, T regulatory; AChR, acetylcholine receptor; MG, myasthenia gravis; EAMG, experimental autoimmune myasthenia gravis: EAMG; ¹²⁵I- BTX, ¹²⁵I- bungarotoxin; NMJ, neuromuscular junction; SI, stimulation index; TAChR, Torpedo AChR; WT, wild type; FoxP3, forkhead box P3.

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