Modulation of IgG–FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration

Excerpt

There is mounting evidence that IgG autoantibodies are involved in many autoimmune neurologic diseases including Guillain–Barré syndrome (GBS), chronic immune neuropathies, myasthenia gravis, immune myositis, and neuromyelitis optica variant of multiple sclerosis [2, 6]. Despite availability of current immunotherapies, a significant proportion of patients with neuroimmunological disorders are left with severe and permanent neurologic sequelae. Lowering the levels of pathogenic autoantibodies could be critical to treat these disorders and has been postulated to be one of the mechanisms account for IVIg’s beneficial effects [4]. Neonatal Fc receptor (FcRn) is pivotal in IgG hemostasis/catabolism. The blockage of FcRn can reduce in vivo IgG levels and had been demonstrated to be effective in animal model of humoral autoimmune disorder [5]. However, it remains untested whether a reduction of pathogenic antibody via inhibiting FcRn can ameliorate autoantibody-mediated peripheral neuropathies in animal models. Anti-glycan/ganglioside antibodies (AGAs) are strongly associated with axonal GBS [7]. We previously showed that AGA inhibits axon regeneration in a murine model of AGA-mediated nerve injury [3], which echoes the clinical observations correlating AGA and poor prognosis in GBS. Besides FcRn-mediated IgG catabolism, recent studies suggest that AGA uptake at nerve terminal might also contribute to AGA clearance [1]. However, in the current study, we mainly focus on examining whether modulation of FcRn expression or IgG–FcRn interactions can alter Ab-mediated pathological effects in this model. …