Effect of complement and its regulation on myasthenia gravis pathogenesis

Abstract

Myasthenia gravis (MG) is primarily caused by antibodies directed towards the skeletal muscle acetylcholine receptor, leading to muscle weakness. Although these antibodies may induce compromise of neuromuscular transmission by blocking acetylcholine receptor function or antigenic modulation, the predominant mechanism of injury to the neuromuscular junction is complement-mediated lysis of the postsynaptic membrane. The vast majority of data to support the role of complement derives from experimentally acquired MG (EAMG). In this article, we review studies that demonstrate the central role of complement in EAMG and MG pathogenesis along with the emerging role of complement in T-and B-cell function, as well as the potential for complement inhibitor-based therapy to treat human MG.

Myasthenia gravis: the role of complement at the neuromuscular junction

“…The majority of evidence for the role of complement in MG has been established on the basis of data from a range of animal models, and this is reviewed in detail . Additional and confirmatory data that have been gained from patient studies are also presented.…”

Applying complement therapeutics to rare diseases

“…Apart from the presence of the MAC at the neuromuscular junction during the disease, the blockade of complement components such as C1q, C3, C5, and C6 has been shown to protect against experimental MG [106]. Furthermore, the absence of the complement regulators DAF and CD59 is directly correlated with a more severe course of the disease during experimental MG [107].…”

Autoantibodies and their potential roles in diseases of the nervous system

“…In animal models of myasthenia gravis, binding of IgG antibody specific for AChR activates the membrane attack complex, resulting in lysis of the muscle endplate, and leading to distortion and simplification of the post‐synaptic muscle membrane . Although the evidence for a similar mechanism is not as strong in humans, it is likely that this is one of several mechanisms by which autoantibodies could cause the muscle weakness and clinical signs typical of myasthenia gravis in humans.…”

“…In animal models of myasthenia gravis, binding of IgG antibody specific for AChR activates the membrane attack complex, resulting in lysis of the muscle endplate, and leading to distortion and simplification of the post-synaptic muscle membrane. 112 Although the evidence for a similar mechanism is not as strong in humans, it is likely that this is one of several mechanisms by which autoantibodies could cause the muscle weakness and clinical signs typical of myasthenia gravis in humans. It has generally been considered that antibodies specific for the muscle-specific kinase (MuSK), which are present in approximately 40% of patients with anti-AChR antibody-negative myasthe-nia gravis, do not cause complement-mediated lysis, as they are usually of the IgG4 isotype and thus unable to activate complement; however, it has been found that a small proportion of anti-MuSK antibodies are IgG1, and capable of activating complement when bound to MuSK on the cell surface.…”