Contactin-1 autoimmunity

Dubey, Divyanshu; Honorat, Josephe A.; Shelly, Shahar; Klein, Christopher J.; Komorowski, Lars; Mills, John R.; Brakopp, Stefanie; Probst, Christian; Lennon, Vanda A.; Pittock, Sean J.; McKeon, Andrew

doi:10.1212/nxi.0000000000000771

Cited by 19 publications

(29 citation statements)

References 16 publications

(19 reference statements)

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“…Two patients (1 with CISP and 1 with CISP-plus) were positive for contactin-1 antibodies, which are known to be associated with inflammatory sensory-predominant neuropathies. 5 , 6 Finding co-occurring autoimmune diseases supports our hypothesis that CISP-plus and CISP are immune-mediated neuropathies.…”

Section: Discussionsupporting

confidence: 73%

“…Although chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) usually presents with weakness, 1 , 2 sensory-predominant forms have been described, 3 , 4 including the recently recognized paranodal neuropathies (contactin-1–associated CIDP). 5 , 6 In 2004, our group described a restricted form of sensory CIDP, chronic immune sensory polyradiculopathy (CISP), characterized by selective involvement of sensory nerve roots. 7 A similar acute form of immune-mediated pure sensory polyradiculopathy has been described recently.…”

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confidence: 99%

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Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy

et al. 2021

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Objectives:Sensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, non-pure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiological and pathological features.Methods:CISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986-2019).Results:We identified 44 CISP-plus and 28 CISP cases (n=72) with 86% (38/44) of CISP-plus and 79% (22/28) of CISP patients experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of CISP-plus and 96% (27/28) of CISP. Gait ataxia was evident in 93% (41/44) of CISP-plus and 79% (22/28) of CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all CISP-plus and were normal (by definition) in all CISP. Elevated cerebral spinal fluid (CSF) protein, slowing of somatosensory evoked potentials and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formation most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of CISP-plus and 93% (14/15) of CISP cases with return to normal neurological examination in half (25/46).Conclusion:The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure-CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy

et al. 2021

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“…IgG4 is regarded as the main pathogenic IgG subtype of anti-CNTN1 antibodies. Similar to previous studies, our patients showed few responses to IVIg when they visited our clinic (9,17). This may be because the major effector function of IVIg is complement binding through binding to various Fc receptors and complement activation, while IgG4 does not bind Fc receptors and does not activate the complement pathway (18).…”

Section: Discussionsupporting

confidence: 87%

“…Similar to other IgG4 autoimmune diseases such as myasthenia gravis with antibodies to muscle-specific kinase (MuSK-MG), anti-CNTN1 autoimmune nodopathy generally responds well to rituximab, a monoclonal antibody against B lymphocyte membrane protein CD20 (5,6). Specifically, improvements in neurological symptoms including gait, tremor, muscle strength, and a decrease in antibody titer can be seen, especially in those who are resistant to IVIg and prednisone (7)(8)(9). However, the high cost of the common-dose rituximab regimen such as 375 mg/ m 2 /week over 4 weeks, and some adverse events have restricted its widespread use in China.…”

Section: Introductionmentioning

confidence: 95%

Effect of low-dose rituximab treatment on autoimmune nodopathy with anti-contactin 1 antibody

Hou

Zhang²,

Yu³

et al. 2022

Front. Immunol.

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BackgroundAutoimmune nodopathy with anti-contactin-1 (CNTN1) responds well to rituximab instead of traditional therapies. Although a low-dose rituximab regimen was administered to patients with other autoimmune diseases, such as myasthenia gravis and neuromyelitis optica spectrum disorders, and satisfactory outcomes were obtained, this low-dose rituximab regimen has not been trialed in anti-CNTN1-positive patients.MethodsAnti–CNTN1 nodopathy patients were enrolled in this prospective, open-label, self-controlled pilot study. A cell-based assay was used to detect anti-CNTN1 antibodies and their subclasses in both serum and cerebrospinal fluid. Clinical features were evaluated at baseline, 2 days, 14 days, and 6 months after single low-dose rituximab treatment (600 mg). The titers of the subclasses of anti-CNTN1 antibody and peripheral B cells were also evaluated at baseline, 2 days, and 6 months after the rituximab regimen.ResultsTwo patients with anti–CNTN1 antibodies were enrolled. Both patients had neurological symptoms including muscle weakness, tremor, sensory ataxia, numbness and mild nephrotic symptoms. In the field of neurological symptoms, sensory ataxia markedly improved, and the titer of anti-CNTN1 antibody as well as CD19+ B cells decreased only two days following low-dose rituximab treatment. Other neurological symptoms improved within two weeks of rituximab treatment. At the 6-month follow-up, all neurological symptoms steadily improved with steroid reduction, and both the anti-CNTN1 antibody titer and CD19+ B cells steadily decreased. No adverse events were observed after this single low-dose rituximab treatment.ConclusionsWe confirmed the clinical efficacy of low-dose rituximab by B cell depletion in autoimmune nodopathy with anti-CNTN1 antibody. This rapid and long-lasting response suggests that low-dose rituximab is a promising option for anti-CNTN1 nodopathy.

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“…Recent studies focusing on the clinical symptoms of anti-CNTN1 seropositive patients reported sensory ataxia as one of the disabling symptoms, 12 , 20 , 26 , 27 raising the suspicion that the paranodes may not be the only site of pathogenicity. DRG are easily accessible by autoantibodies because of the lack of a sufficient neurovascular barrier, 28 and our data give evidence of a direct effect of anti-CNTN1 autoantibodies on DRG, thus supporting the notion of DRG as another site of pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

Anti–contactin-1 Antibodies Affect Surface Expression and Sodium Currents in Dorsal Root Ganglia

Grüner

Stengel

Werner

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesAs autoantibodies to contactin-1 from patients with chronic inflammatory demyelinating polyradiculoneuropathy not only bind to the paranodes where they are supposed to cause conduction failure but also bind to other neuronal cell types, we aimed to investigate the effect of anti–contactin-1 autoantibodies on contactin-1 surface expression in cerebellar granule neurons, dorsal root ganglion neurons, and contactin-1–transfected human embryonic kidney 293 cells.MethodsImmunocytochemistry including structured illumination microscopy and immunoblotting was used to determine expression levels of contactin-1 and/or sodium channels after long-term exposure to autoantibodies from 3 seropositive patients. For functional analysis of sodium channels, whole-cell recordings of sodium currents were performed on dorsal root ganglion neurons incubated with anti–contactin-1 autoantibodies.ResultsWe found a reduction in contactin-1 expression levels on dorsal root ganglion neurons, cerebellar granule neurons, and contactin-1–transfected human embryonic kidney 293 cells and decreased dorsal root ganglion sodium currents after long-term exposure to anti–contactin-1 autoantibodies. Sodium channel density did not decrease.DiscussionOur results demonstrate a direct effect of anti–contactin-1 autoantibodies on the surface expression of contactin-1 and sodium currents in dorsal root ganglion neurons. This may be the pathophysiologic correlate of sensory ataxia reported in these patients.

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Contactin-1 autoimmunity

Cited by 19 publications

References 16 publications

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy

Effect of low-dose rituximab treatment on autoimmune nodopathy with anti-contactin 1 antibody

Anti–contactin-1 Antibodies Affect Surface Expression and Sodium Currents in Dorsal Root Ganglia

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