Targeting complement system to treat myasthenia gravis

Ruksana Huda, Erdem Tüzün, Premkumar Christadoss

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 antiacetylcholine 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 complementinhibited 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.

Original languageEnglish (US)
Pages (from-to)575-583
Number of pages9
JournalReviews in the Neurosciences
Volume25
Issue number4
DOIs
StatePublished - Aug 1 2014

Fingerprint

Complement Inactivating Agents
Myasthenia Gravis
Neuromuscular Junction
Complement C6
Autoimmune Experimental Myasthenia Gravis
CD55 Antigens
Complement Membrane Attack Complex
Complement C3
Antibodies
Immunoglobulin Isotypes
Muscle Weakness
Therapeutics
Immunosuppressive Agents
Autoantibodies
Immunosuppression
Small Interfering RNA
Autoimmune Diseases
Immunity
Clinical Trials
Cytokines

Keywords

  • Autoimmunity
  • Complement
  • Complement regulators
  • Experimental autoimmune myasthenia gravis
  • Myasthenia gravis
  • SiRNA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Targeting complement system to treat myasthenia gravis. / Huda, Ruksana; Tüzün, Erdem; Christadoss, Premkumar.

In: Reviews in the Neurosciences, Vol. 25, No. 4, 01.08.2014, p. 575-583.

Research output: Contribution to journalArticle

Huda, Ruksana ; Tüzün, Erdem ; Christadoss, Premkumar. / Targeting complement system to treat myasthenia gravis. In: Reviews in the Neurosciences. 2014 ; Vol. 25, No. 4. pp. 575-583.
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