The autoimmune vulnerability of the node of Ranvier

Querol, Luís; Delmont, Émilien; Lleixà, Cinta

doi:10.1111/jns.12570

Cited by 4 publications

(2 citation statements)

References 157 publications

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“…It is well established that autoantibodies are a mechanism to cause peripheral neuropathy. For example, in inflammatory neuropathies such as GBS and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), antibodies targeting antigens within the PNS are known to drive pathology through mechanisms including macrophage or complement activation, as well as target disruption ( Querol et al, 2023 ). Furthermore, autoantibodies can directly impact sensory neuron physiology by disrupting ion channel function ( Dawes et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…Dysfunction of the immune system is thought to contribute with around 20% of SFN cases being associated with autoimmune conditions (e.g., Sjorgen’s syndrome, sarcoidosis) ( de Greef et al, 2018 ). Autoimmunity includes the action of autoantibodies and autoantibodies targeting antigens within the nervous system are known to have a role in other peripheral neuropathies and contribute to disease progression ( Querol et al, 2023 ). Furthermore, studies have shown that autoantibodies can directly drive neuropathic pain in patients by targeting antigens on sensory neurons ( Dawes et al, 2018 ), proposing similar mechanisms in SFN.…”

Section: Introductionmentioning

confidence: 99%

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A role for pathogenic autoantibodies in small fiber neuropathy?

Daifallah,

Farah,

Dawes

2023

Front. Mol. Neurosci.

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The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen’s syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A role for pathogenic autoantibodies in small fiber neuropathy?

Daifallah,

Farah,

Dawes

2023

Front. Mol. Neurosci.

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ITPR3‐associated neuropathy: Report of a further family with adult onset intermediate Charcot–Marie–Tooth disease

Cabello‐Murgui,

Jiménez‐Jiménez,

Vílchez

et al. 2024

Euro J of Neurology

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Background and PurposeITPR3 encodes type 3 inositol‐tri‐phosphate receptor (IP3R3), a protein expressed in Schwann cells, predominantly in the paranodal region, and involved in the regulation of Ca2+ release from the endoplasmic reticulum. Dominant variants in ITPR3 have recently been recognized as a rare cause of intermediate Charcot–Marie–Tooth disease (CMT).MethodsWe collected the clinical data of a family with autosomal dominant neuropathy whose proband was diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) for many years. The genetic diagnosis was achieved by whole exome sequencing.ResultsThe proband developed symmetrical sensory–motor neuropathy with demyelinating features at 32 years old. He was diagnosed with CIDP and received numerous immunomodulatory treatments. However, his condition progressed, leading to severe proximal leg and hand atrophy that confined him to a wheelchair at 60 years. The patient's two sons began to exhibit symptoms suggestive of neuropathy shortly after age 30 years, and the condition was reoriented as inherited. Exome sequencing identified a heterozygous c.4271C > T variant in the ITPR3 gene segregating with the disease. Nerve conduction studies showed a combination of demyelinating and axonal features that vary by nerve, disease duration, and patient. A uniform thickening of the nerves was identified on nerve echography, as was distal symmetric fatty infiltration in lower limb muscle imaging.ConclusionsThe c.4271C > T ITPR3 variant causes a late onset CMT that can be considered an intermediate CMT. Considering the electrophysiological findings and the distribution of IP3R3, we hypothesize that this variant could start as nodal dysfunction that progresses to widespread nerve degeneration.

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Microscopical anatomy of the peripheral nervous system: An essential notion for understanding the pathophysiology of very early classic Guillain‐Barré syndrome

Berciano

2024

Neuropathology

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The aim of this paper is to analyze the pathophysiological mechanisms acting in very early classic Guillain‐Barré syndrome (GBS) (≤4 days of symptomatic onset). In this inaugural period, both in GBS and its animal model, experimental autoimmune neuritis, the outstanding pathological feature is inflammatory edema predominating in proximal nerve trunks, particularly spinal nerves, and possibly in preterminal nerve segments. Nerve trunks external to the subarachnoid angle possess epi‐ perineurium that is relatively inelastic and of low compliance. Here such edema can increase endoneurial fluid pressure that, when sufficiently critical, may stretch the perineurium and constrict transperineurial microcirculation, compromising blood flow and producing the potential for ischemic nerve injury, whose consequence is rapid partial or complete loss of nerve excitability. These histopathological features correlate well with electrophysiological and imaging findings reported in early GBS stages. Spinal nerve edema and ischemia help to understand the pattern of Wallerian‐like degeneration observed in the axonal form of GBS, predominating in motor spinal roots at their exit from the dura matter (spinal nerves) with centrifugal distribution in more distant motor nerve trunks, and centripetal extension to the distal portion of intrathecal roots. The similarity of initial pathogenic mechanisms between demyelinating and axonal forms of GBS explains why an early increase of serum biomarkers of axonal damage is detected in both forms. In conclusion, knowledge of the microscopic anatomy of the peripheral nervous system is an essential step for a reliable understanding of pathophysiological mechanisms operating in the early phase of any classic GBS subtype.

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The autoimmune vulnerability of the node of Ranvier

Cited by 4 publications

References 157 publications

A role for pathogenic autoantibodies in small fiber neuropathy?

A role for pathogenic autoantibodies in small fiber neuropathy?

ITPR3‐associated neuropathy: Report of a further family with adult onset intermediate Charcot–Marie–Tooth disease

Microscopical anatomy of the peripheral nervous system: An essential notion for understanding the pathophysiology of very early classic Guillain‐Barré syndrome

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