Activated natural killer cells enhance passive experimental autoimmune myasthenia gravis (44.35)

Abstract

Abstract Myasthenia gravis (MG) is characterized by autoantibody-mediated loss of nicotinic acetylcholine receptors (AChR). However, antibody titers alone do not determine the severity of disease. Interleukin-12 (IL-12), a major inducer of interferon-gamma (IFN-γ) production, enhances experimental autoimmune MG (EAMG) in mice independently of the level of antibody and complement bound to AChR. IFN-γ is produced by various cell types, including CD8+ T cells, natural killer (NK) cells, and NK1.1+ T (NKT) cells. To investigate the roles of these cell types in disease enhancement, NK and NKT cells were depleted using anti-NK1.1 antibody prior to administration of IL-12 and passive transfer of monoclonal anti-AChR antibody D6 in B6 mice. For comparison, IL-12 treatment and passive transfer of mAb D6 was performed using TCRβ/TCRδ dual knock-out mice, which possess B cells and NK cells but lack functional T cells and NKT cells. IL-12 treatment worsened passive disease in wild-type B6 and TCR dual knock-out mice, but not in NK depleted B6 mice. Serum IFN-γ correlated with disease. These findings suggest that innate NK cells are the main source of disease-enhancing IFN-γ upon administration of IL-12. This provides a mechanism by which the innate immune response can enhance MG even when antibody levels remain unchanged.