Modulation of IgG–FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration

Zhang, Gang; Lin, Jian-Xin; Ghauri, Sameera; Sheikh, Kazim A.

doi:10.1007/s00401-017-1730-x

Cited by 11 publications

(4 citation statements)

References 8 publications

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“…FcRn promotes the development and progression of diseases of the nervous system, including Guillain–Barré syndrome (GBS), MS and MG. In an antibody-mediated model of axonal GBS, reduced levels of pathogenic anti-glycan/ganglioside antibodies were found both in wild type mice therapeutically treated with IgG1 MST-HN (or Abdeg) and in Fcgrt −/− mice, and there was improved nerve regeneration 156 . In experimental autoimmune encephalomyelitis (EAE) or antibody-mediated EAE models of human MS, Abdegs caused degradation of total IgGs, including disease-specific antibodies in the brain and spinal cord, and reduced disease activity.…”

Section: Pathophysiological Functions Of Fcrnmentioning

confidence: 99%

The therapeutic age of the neonatal Fc receptor

et al. 2023

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IgGs are essential soluble components of the adaptive immune response that evolved to protect the body from infection. Compared with other immunoglobulins, the role of IgGs is distinguished and enhanced by their high circulating levels, long half-life and ability to transfer from mother to offspring, properties that are conferred by interactions with neonatal Fc receptor (FcRn). FcRn binds to the Fc portion of IgGs in a pH-dependent manner and protects them from intracellular degradation. It also allows their transport across polarized cells that separate tissue compartments, such as the endothelium and epithelium. Further, it is becoming apparent that FcRn functions to potentiate cellular immune responses when IgGs, bound to their antigens, form IgG immune complexes. Besides the protective role of IgG, IgG autoantibodies are associated with numerous pathological conditions. As such, FcRn blockade is a novel and effective strategy to reduce circulating levels of pathogenic IgG autoantibodies and curtail IgG-mediated diseases, with several FcRn-blocking strategies on the path to therapeutic use. Here, we describe the current state of knowledge of FcRn–IgG immunobiology, with an emphasis on the functional and pathological aspects, and an overview of FcRn-targeted therapy development.

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Section: Pathophysiological Functions Of Fcrnmentioning

confidence: 99%

The therapeutic age of the neonatal Fc receptor

et al. 2023

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“…AMSAN is distinguished by its aggressive clinical course and poor prognosis, with rapid progression to respiratory failure and ventilatory dependence. [ 58 , 59 ] Diagnostic challenges in AMSAN include distinguishing it from other causes of acute flaccid paralysis, such as acute poliomyelitis or toxin-mediated neuropathies, and identifying features suggestive of axonal involvement on electrodiagnostic testing, such as absent or markedly reduced compound muscle action potentials. [ 60 ] Management of AMSAN focuses on aggressive supportive care, early initiation of immunomodulatory therapies, and consideration of adjunctive treatments, such as mechanical ventilation and intensive rehabilitation, to optimize outcomes and minimize disability.…”

Section: Discussionmentioning

confidence: 99%

Clinical presentation and symptomatology of Guillain-Barré syndrome: A literature review

Elendu,

Osamuyi,

Afolayan

et al. 2024

Medicine

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Guillain-Barré Syndrome (GBS) is a rare but potentially life-threatening neurological disorder characterized by acute onset ascending paralysis and sensory abnormalities. This article provides a comprehensive overview of GBS, covering its epidemiology, etiology, clinical presentation, diagnostic evaluation, management and treatment, prognosis, psychosocial impact, recent advances in research, public health implications, and ethical considerations. Epidemiological data reveal variations in GBS prevalence, incidence rates, and geographical distribution influenced by climate, infectious disease prevalence, and genetic susceptibility. Etiological factors include preceding infections, vaccinations, and autoimmune mechanisms, although the precise pathophysiology remains incomplete. Clinical presentation encompasses prodromal symptoms, motor deficits, sensory abnormalities, autonomic dysfunction, and variants such as Miller-Fisher Syndrome and Bickerstaff brainstem encephalitis. Neurological examination findings include weakness, paralysis, sensory deficits, and reflex changes, while autonomic dysfunction manifests as cardiovascular, respiratory, and gastrointestinal symptoms. Diagnostic evaluation relies on clinical criteria, laboratory tests (e.g., cerebrospinal fluid analysis, nerve conduction studies), and consideration of differential diagnoses. Management strategies encompass supportive care, immunomodulatory therapies (e.g., intravenous immunoglobulin, plasma exchange), and rehabilitation interventions to optimize functional outcomes and promote recovery. Prognosis varies depending on clinical features, treatment response, and complications such as respiratory failure and autonomic instability. Psychosocial impact encompasses psychological effects on patients and caregivers, highlighting the importance of coping strategies and support systems. Recent advances in research focus on emerging treatments, genetic predisposition, and biomarker discovery, offering promise for improving GBS outcomes. Public health implications include vaccination safety concerns and healthcare system considerations for GBS management. Ethical considerations encompass patient autonomy, resource allocation, and end-of-life decision-making.

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“…43 In a murine GBS model with antiglycan ganglioside antibodies, FcRn inhibition using a recombinant antibody, resulted in increased degradation of the pathogenic antibodies and reduced nerve injury. 44 Nonetheless, there are currently no trials registered for FcRn inhibitors for the treatment of GBS.…”

Section: Potential Neuromuscular Diseases Not Currently In Clinical T...mentioning

confidence: 99%

Neonatal Fc Receptor Inhibitor Therapeutics in Neuromuscular Disease

Jaffry,

Menkes,

Shaikh

et al. 2023

Journal of Clinical Neuromuscular Disease

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The Neonatal Fc Receptor (FcRn) is integral to a wide variety of processes including IgG recycling, serum albumin turnover, and bacterial opsonization. Thus, targeting FcRn will increase antibody degradation including pathogenic IgGs. FcRn inhibition provides a novel therapeutic mechanism by which autoantibody titers are reduced resulting in clinical improvement and disease abatement. The FcRn targeting mechanism is similar to that of intravenous immunoglobulin (IVIg) in which saturated FcRn facilitates accelerated pathogenic IgG degradation. Recently, the FcRn inhibitor efgartigimod was approved for the treatment of myasthenia gravis. Subsequently, clinical trials of this agent have been conducted for numerous inflammatory conditions involving pathogenic autoantibodies. These disorders include the Guillain–Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and inflammatory myositis. Other disorders traditionally treated with IVIg may also benefit from FcRn inhibition in certain contexts. This manuscript discusses the mechanism of FcRn inhibition, preclinical data, and the results of clinical trials of this agent for a wide range of neuromuscular diseases.

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Modulation of IgG–FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration

Cited by 11 publications

References 8 publications

The therapeutic age of the neonatal Fc receptor

The therapeutic age of the neonatal Fc receptor

Clinical presentation and symptomatology of Guillain-Barré syndrome: A literature review

Neonatal Fc Receptor Inhibitor Therapeutics in Neuromuscular Disease

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