Rapid and reversible responses to IVIG in autoimmune neuromuscular diseases suggest mechanisms of action involving competition with functionally important autoantibodies

Abstract

Intravenous immunoglobulin (IVIG) is widely used in autoimmune neuromuscular diseases whose pathogenesis is undefined. Many different effects of IVIG have been demonstrated in vitro, but few studies actually identify the mechanism(s) most important in vivo. Doses and treatment intervals are generally chosen empirically. Recent studies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy show that some effects of IVIG are readily reversible and highly dependent on the serum IgG level. This suggests that in some autoantibody-mediated neuromuscular diseases, IVIG directly competes with autoantibodies that reversibly interfere with nerve conduction. Mechanisms of action of IVIG which most likely involve direct competition with autoantibodies include: neutralization of autoantibodies by anti-idiotypes, inhibition of complement deposition, and increasing catabolism of pathologic antibodies by saturating FcRn. Indirect immunomodulatory effects are not as likely to involve competition and may not have the same reversibility and dose-dependency. Pharmacodynamic analyses should be informative regarding most relevant mechanism(s) of action of IVIG as well as the role of autoantibodies in the immunopathogenesis of each disease. Better understanding of the role of autoantibodies and of the target(s) of IVIG could lead to more efficient use of this therapy and better patient outcomes.

Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica

“…A major effect of hIgG is inhibition of complement activation (Berger et al, 2013). hIgG has been reported to decrease binding/activation of C1q, C3a, C3b and C4 and thus prevent the formation of the membrane attack complex (Gelfand, 2012; Piepers et al, 2010).…”

“…hIgG has since been used for the treatment of a broad range of immune-mediated demyelinating diseases of the nervous system including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, diabetic polyneuropathy, multifocal motor neuropathy, relapsing-remitting multiple sclerosis and myasthenia gravis (Gelfand, 2012). hIgG has been reported to have pleiotropic actions on the immune system, including accelerated clearance of autoantibodies, inhibition of complement deposition, interference with antigen recognition, and block of Fcγ receptors (Berger et al, 2013; Jacob and Rajabally, 2009). Other possible immunomodulatory actions of hIgG have been reported as well, including cytokine neutralization, inhibition of leukocyte migration, expansion of regulatory T cell populations, and dendritic cell activation (Jacob and Rajabally, 2009).…”

Role of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease duration and effects of IVIG

“…The three main mechanisms that are likely to involve direct competition with pathologic autoantibodies are anti-idiotypic binding, FcRn saturation, and complement scavenging (3,23). Our findings that F(ab=) 2 fragments of the IVIG have the same effect as IVIG in vitro (ELISA binding studies to the M 3 -RL2 peptide and whole M 3 -R in LSMMP) suggest the presence of anti-idiotypic antibodies in IVIG that block the activity of pathogenic SScIgGs (3).…”

Rescue effects of intravenous immunoglobulin on optic nerve degeneration in a rat model of neuromyelitis optica

“…Thus, other modalities with fewer systemic side effects are needed, among which intravenous immunoglobulin (IVIG) is a candidate for the treatment of NMO [1]. It has been shown that IVIG has pleiotropic actions on the immune system, including accelerated clearance of autoantibodies, inhibition of complement deposition, and interference with antigen recognition [2,3]. Other possible actions of IVIG regarding immunoreactivity are reported, including cytokine neutralization, inhibition of leukocyte migration, and neutralization of B cell activating factor [4].…”