Complement associated pathogenic mechanisms in myasthenia gravis

Tüzün, Erdem; Christadoss, Premkumar

doi:10.1016/j.autrev.2013.03.003

Cited by 91 publications

(45 citation statements)

References 152 publications

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“…A series of studies have suggested that accumulation of autoantibodies to AChR and subsequent activation of the complement cascade on postsynaptic membrane result in the assembly of membrane attack complex (MAC), thereby destroying AChRs and disrupting synaptic morphology (166, 171, 183) (Figure 5). It seems likely that complement-mediated destruction of the postsynaptic muscle membrane is more pathologically significant than antigenic modulation in MG pathogenesis (175, 184). These findings have promoted the development of novel therapies based on inhibition of complement pathways in MG treatment (185).…”

Section: Disruption Of Neural Transmission By Autoantibodiesmentioning

confidence: 99%

Mechanisms of Autoantibody-Induced Pathology

et al. 2017

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Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

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Section: Disruption Of Neural Transmission By Autoantibodiesmentioning

confidence: 99%

Mechanisms of Autoantibody-Induced Pathology

et al. 2017

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“…Damage to the NMJ ion channels is autoantibody mediated where autoantibodies bind and result in the formation of the membrane attack complex consisting of C5b, C6, C7, C8, and C9 leading to muscular membrane damage and muscle weakness [2, 173]. The most common autoantibodies involved are anti-AChR antibodies presenting in 85% of patients, anti-muscle-specific kinase presenting in 5–8%, and anti-low density lipoprotein receptor-related protein in 2–46% of patients [69, 174, 175].…”

Section: Main Textmentioning

confidence: 99%

Regulatory T cells in multiple sclerosis and myasthenia gravis

Danikowski

Jayaraman

Prabhakar

2017

J Neuroinflammation

265

171

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Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system primarily mediated by T lymphocytes with specificity to neuronal antigens in genetically susceptible individuals. On the other hand, myasthenia gravis (MG) primarily involves destruction of the neuromuscular junction by antibodies specific to the acetylcholine receptor. Both autoimmune diseases are thought to result from loss of self-tolerance, which allows for the development and function of autoreactive lymphocytes. Although the mechanisms underlying compromised self-tolerance in these and other autoimmune diseases have not been fully elucidated, one possibility is numerical, functional, and/or migratory deficits in T regulatory cells (Tregs). Tregs are thought to play a critical role in the maintenance of peripheral immune tolerance. It is believed that Tregs function by suppressing the effector CD4+ T cell subsets that mediate autoimmune responses. Dysregulation of suppressive and migratory markers on Tregs have been linked to the pathogenesis of both MS and MG. For example, genetic abnormalities have been found in Treg suppressive markers CTLA-4 and CD25, while others have shown a decreased expression of FoxP3 and IL-10. Furthermore, elevated levels of pro-inflammatory cytokines such as IL-6, IL-17, and IFN-γ secreted by T effectors have been noted in MS and MG patients. This review provides several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs. Strategies focusing on enhancing the Treg function find importance in cytokines TGF-β, IDO, interleukins 10, 27, and 35, and ligands Jagged-1 and OX40L. Likewise, strategies which affect Treg migration involve chemokines CCL17 and CXCL11. In pre-clinical animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG), several strategies have been shown to ameliorate the disease and thus appear promising for treating patients with MS or MG.

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“…The major pathogenic mechanisms involve bivalent AChR autoantibodies cross‐linking adjacent AChR to cause accelerated AChR degradation (antigenic modulation) and complement‐mediated damage to the postsynaptic membrane (Baggi et al. ; Tüzün and Christadoss ; Ban and Phillips ). However, a proportion of MG patients instead express autoantibodies that target the extracellular domains of muscle‐specific (tyrosine) kinase (MuSK; Hoch et al.…”

Section: Introductionmentioning

confidence: 99%

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

et al. 2015

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We investigated the influence of postsynaptic tyrosine kinase signaling in a mouse model of muscle‐specific kinase (MuSK) myasthenia gravis (MG). Mice administered repeated daily injections of IgG from MuSK MG patients developed impaired neuromuscular transmission due to progressive loss of acetylcholine receptor (AChR) from the postsynaptic membrane of the neuromuscular junction. In this model, anti‐MuSK‐positive IgG caused a reduction in motor endplate immunolabeling for phosphorylated Src‐Y418 and AChR β‐subunit‐Y390 before any detectable loss of MuSK or AChR from the endplate. Adeno‐associated viral vector (rAAV) encoding MuSK fused to enhanced green fluorescent protein (MuSK‐EGFP) was injected into the tibialis anterior muscle to increase MuSK synthesis. When mice were subsequently challenged with 11 daily injections of IgG from MuSK MG patients, endplates expressing MuSK‐EGFP retained more MuSK and AChR than endplates of contralateral muscles administered empty vector. Recordings of compound muscle action potentials from myasthenic mice revealed less impairment of neuromuscular transmission in muscles that had been injected with rAAV‐MuSK‐EGFP than contralateral muscles (empty rAAV controls). In contrast to the effects of MuSK‐EGFP, forced expression of rapsyn‐EGFP provided no such protection to endplate AChR when mice were subsequently challenged with MuSK MG IgG. In summary, the immediate in vivo effect of MuSK autoantibodies was to suppress MuSK‐dependent tyrosine phosphorylation of proteins in the postsynaptic membrane, while increased MuSK synthesis protected endplates against AChR loss. These results support the hypothesis that reduced MuSK kinase signaling initiates the progressive disassembly of the postsynaptic membrane scaffold in this mouse model of MuSK MG.

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Complement associated pathogenic mechanisms in myasthenia gravis

Cited by 91 publications

References 152 publications

Mechanisms of Autoantibody-Induced Pathology

Mechanisms of Autoantibody-Induced Pathology

Regulatory T cells in multiple sclerosis and myasthenia gravis

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

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