Targeting complement system to treat myasthenia gravis


HUDA R., Tuzun E. , CHRISTADOSS P.

REVIEWS IN THE NEUROSCIENCES, cilt.25, ss.575-583, 2014 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 25 Konu: 4
  • Basım Tarihi: 2014
  • Doi Numarası: 10.1515/revneuro-2014-0021
  • Dergi Adı: REVIEWS IN THE NEUROSCIENCES
  • Sayfa Sayıları: ss.575-583

Özet

While the complement system is desired for protective immunity, antibody-and complement-mediated neuromuscular junction (NMJ) destruction, a hallmark of myasthenia gravis (MG) or experimental autoimmune MG (EAMG), is a significant concern. Evidence suggests that the binding of complement factors to the pathogenic anti-acetylcholine receptor (AChR) autoantibody induces the formation of membrane attack complexes (MAC), which ultimately lead to NMJ destruction and muscle weakness. Studies corroborating the evidence show that the complement (C3-C6)-deficient or complement inhibitor (anti-C1q, soluble CR1, anti-C6, and C5 inhibiting peptide)-treated animals are highly resistant to EAMG induction, whereas the deficiency of the naturally occurring complement inhibitors, such as the decay-accelerating factor (DAF), increases EAMG susceptibility. Notably, the complement-inhibited animals do not exhibit significant immunosuppression but only a marginal reduction in the production of certain cytokines and immunoglobulin isotypes. A preliminary clinical trial using antibody-based C5 inhibitor eculizumab has been shown to be of potential use for MG treatment. The inhibition of the classic complement pathway (CCP) alone appears to be enough to suppress EAMG, suggesting that the complement inhibitors targeting specifically the classic pathway could effectively treat MG without causing immunosuppressive and other side effects. For instance, a recent non-antibody-based therapeutic approach selectively targeting the CCP component C2 by small interfering RNA (siRNA) has proven useful in EAMG treatment. The treatment strategies developed for MG might also be beneficial for other complement-mediated autoimmune diseases.