Acetylcholine receptor antibody–mediated animal models of myasthenia gravis and the role of complement

Kusner, Linda L.; Sengupta, Manjistha; Kaminski, Henry J.

doi:10.1111/nyas.13555

Cited by 17 publications

(14 citation statements)

References 42 publications

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“…In animals that are deficient in complement C3, C4, C5 or C6, the incidence of experimental autoimmune myasthenia gravis is substantially lower than in non-deficient animals, and IgG deposits at the neuromuscular junction do not lead to MAC formation 70,71 . Anti-C1q and anti-C6 antibodies effectively inhibited MAC formation and reduced symptoms of experimental autoimmune myasthenia gravis in active and passive transfer models 72,73 .…”

Section: Diseases Of the Neuromuscular Junctionmentioning

confidence: 94%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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The human complement system is an effector of innate and adaptive humoral immunity. The system comprises soluble membrane-bound proteins (opsonins) that act collectively to recognize pathogens and non-self material and subsequently initiate opsonization and phagocytosis or lysis of pathogens. The proteolytic fragments that derive from complement activation can be targeted by white blood cells and endothelial cells, leading to extravasation and migration of immune cells at the sites of inflammation. Other physiological functions of complement include timely removal of altered and senescent self, tissue remodelling, cell lysis, chemotaxis, opsonization, inflammation and immune cell stimulation 1-4. Complement activation products link the innate and adaptive immune systems by acting directly on receptors on T cells and B cells or by modulating dendritic cell functions 5-8. Disruption of the delicate coordination required for complement activation and control is fundamental in the pathogenic mechanism of several autoimmune neurological disorders, and is even emerging as a contributor in some neurodegenerative diseases. As a result, interest is increasing in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several difficult-to-treat neurological diseases. In this Review, we provide an overview of the main components of the initial complement activation pathways, the lytic pathway and the factors associated with inappropriate complement activation or control in disease initiation and progression. We consider the role of complement in the tissue destruction that is responsible for the genesis of the most common autoimmune neurological diseases, including complement-mediated myopathies, myasthenia gravis, neuropathies and CNS disorders. We also discuss the role of complement in some neurodegenerative disorders, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington disease, traumatic brain injury and even schizophrenia. Finally, we discuss emerging complement-targeted therapies, such as monoclonal antibodies, fusion proteins and cyclic peptides, that inhibit the functions of individual complement proteins, especially therapies that disrupt the lytic pathway. Some of these therapeutic agents have been approved or are being tested in phase I-III clinical trials and promise to change the therapeutic armamentarium for treatment of neurological conditions that respond poorly to existing immunotherapies.

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Section: Diseases Of the Neuromuscular Junctionmentioning

confidence: 94%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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“…Two basic animal models are used to study MG. Passive transfer MG (PTMG) consists of administration of autoantibodies (9,26). For AChR-antibody PTMG, monoclonal antibodies, syngeneic polyclonal serum, and highly concentrated human MG sera with a source of active complement have been used.…”

Section: Evidence Of Complement As An Effector Mechanism In Myasthenimentioning

confidence: 99%

“…In antigenic modulation of AChR, binding of antibody and subsequent cross-linking lead to an increase in the natural degradation cycle of the receptors. The third, and likely most critical mechanism, is for AChR antibodies to activate complement with ultimate formation of the terminal complement component (TCC) causing damage to the muscle membrane (Figure 1) (3,9). The role of complement activation in patients without AChR antibodies is poorly defined (10).…”

Section: Introductionmentioning

confidence: 99%

Complement Inhibitor Therapy for Myasthenia Gravis

2020

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Complement activation as a driver of pathology in myasthenia gravis (MG) has been appreciated for decades. The terminal complement component [membrane attack complex (MAC)] is found at the neuromuscular junctions of patients with MG. Animals with experimental autoimmune MG are dependent predominantly on an active complement system to develop weakness. Mice deficient in intrinsic complement regulatory proteins demonstrate a significant increase in the destruction of the neuromuscular junction. As subtypes of MG have been better defined, it has been appreciated that acetylcholine receptor antibody-positive disease is driven by complement activation. Preclinical assessments have confirmed that complement inhibition would be a viable therapeutic approach. Eculizumab, an antibody directed toward the C5 component of complement, was demonstrated to be effective in a Phase 3 trial with subsequent approval by the Federal Drug Administration of the United States and other worldwide regulatory agencies for its use in acetylcholine receptor antibodypositive MG. Second-and third-generation complement inhibitors are in development and approaching pivotal efficacy evaluations. This review will summarize the history and present the state of knowledge of this new therapeutic modality.

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“…The target for ~85% of cases of myasthenia gravis as the AChR was established almost by accident when a rabbit immunised against AChR isolated from Electrophorus electricus electric organ; for the purposes of generating anti-AChR antibodies; itself became flaccid with abnormal electromyography, an effect reversed by AChE inhibition [ 88 ]. Since this time many animal models have been utilised to study the immunobiology and physiology of the acquired myasthenias (reviewed [ 89 , 90 , 91 , 92 ]). Animal models have also been vital in establishing the direct pathogenicity of other autoimmune antigens such as MuSK [ 93 , 94 ] and investigating the role of LRP4 and the potential pathogenicity of these autoantibodies [ 95 , 96 , 97 ].…”

Section: Animal Models In Myasthenia Gravismentioning

confidence: 99%

Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes

Webster

2018

IJMS

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The neuromuscular junction is the point of contact between motor nerve and skeletal muscle, its vital role in muscle function is reliant on the precise location and function of many proteins. Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders of neuromuscular transmission with 30 or more implicated proteins. The use of animal models has been instrumental in determining the specific role of many CMS-related proteins. The mouse neuromuscular junction (NMJ) has been extensively studied in animal models of CMS due to its amenability for detailed electrophysiological and histological investigations and relative similarity to human NMJ. As well as their use to determine the precise molecular mechanisms of CMS variants, where an animal model accurately reflects the human phenotype they become useful tools for study of therapeutic interventions. Many of the animal models that have been important in deconvolving the complexities of neuromuscular transmission and revealing the molecular mechanisms of disease are highlighted.

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Acetylcholine receptor antibody–mediated animal models of myasthenia gravis and the role of complement

Cited by 17 publications

References 42 publications

Complement in neurological disorders and emerging complement-targeted therapeutics

Complement in neurological disorders and emerging complement-targeted therapeutics

Complement Inhibitor Therapy for Myasthenia Gravis

Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes

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