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• Pathogenesis of anti-contactin-1 associated paranodopathy
  Kathrin Doppler
  Published on: 13 April 2016
• Sensory Ataxia and Anti-contactin-1 IgG4-Associated Paranodopathy
  Nobuhiro Yuki
  Published on: 13 April 2016

• Published on: 13 April 2016

  Pathogenesis of anti-contactin-1 associated paranodopathy

  • Kathrin Doppler, MD
  • Other Contributors:
    • Claudia Sommer

  We thank Drs. Yuki and Wong for their interest in our paper. We agree that the finding that anti-CNTN1 autoantibodies in patients are mostly of the IgG4 subtype is important for our understanding of the pathophysiology of anti-CNTN1-associated neuropathy. However, in the study by Miura as well as in our study, IgG2 and IgG3 autoantibodies were detected in some patients (1, 2). The two patients from our study with predomina...

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  We thank Drs. Yuki and Wong for their interest in our paper. We agree that the finding that anti-CNTN1 autoantibodies in patients are mostly of the IgG4 subtype is important for our understanding of the pathophysiology of anti-CNTN1-associated neuropathy. However, in the study by Miura as well as in our study, IgG2 and IgG3 autoantibodies were detected in some patients (1, 2). The two patients from our study with predominance of IgG3 autoantibodies were tested in the acute phase of disease (1). It would be of interest to learn if the samples of the patients with IgG2/IgG3 autoantibodies from Miura's study might also have been taken at the beginning of disease, as this might suggest a switch of IgG subclasses during the course of disease. As pointed out by Yuki and Wong, the study by Miura et al. provides additional findings shedding further light on the pathogenicity of anti- CNTN1 IgG4 autoantibodies (2). Although fulfilling clinical and electrophysiological criteria of chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy with anti-CNTN1 autoantibodies more and more evolves to be an independent disease differing from classical CIDP. Yuki and Wong addressed the binding of sera of patients with anti-CNTN1 IgG4 autoantibodies to dorsal root ganglia (DRG), a finding that was first described in the study by Miura et al. (2). This raises the question if anti-CNTN1-IgG4-associated neuropathy should be categorized as a ganglionopathy rather than a neuropathy or paranodopathy. Indeed, several studies provide evidence that binding of anti-CNTN1 autoantibodies is not restricted to the paranodes but can also be found on hippocampal neurons, in the cerebellum and DRG, presumably correlating with clinical symptoms like tremor or sensory ataxia (1-3). Nevertheless, in our opinion, anti- CNTN1-IgG4-associated neuropathy should be considered a paranodopathy as there is ample evidence that the paranodes are the major site of action in this disease: Neuropathic symptoms are the first and predominant symptoms in all patients described so far (1, 3). Morphological analysis of paranodes shows severe destruction of paranodal architecture as a correlate of impaired nerve conduction (1). Electrophysiological studies showing conduction block, prolonged distal motor latency and slowing of nerve conduction velocities are well in line with the concept of paranodopathy (4). Distal onset of sensory symptoms further strengthens this notion and argues against a ganglionopathy as a major cause of sensory loss. Damage to DRG might contribute to sensory ataxia, especially in truncal forms as decribed by Miura et al. (2), but all in all the clinical and electrophysiological phenotype of these patients suggests to consider anti-CNTN1-IgG4-associated disease a paranodopathy (or paranodopathy plus). Further studies are needed to 1) elucidate the pathogenesis of this disease on the molecular level and to 2) better characterize the clinical phenotype in a larger cohort of patients.

  1. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 2015. 2. Miura Y, Devaux JJ, Fukami Y, et al. Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015. 3. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013;73:370-380. 4. Uncini A, Susuki K, Yuki N. Nodo-paranodopathy: beyond the demyelinating and axonal classification in anti-ganglioside antibody- mediated neuropathies. Clin Neurophysiol 2013;124:1928-1934.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 13 April 2016

  Sensory Ataxia and Anti-contactin-1 IgG4-Associated Paranodopathy

  • Nobuhiro Yuki, Nobuhiro Yuki
  • Other Contributors:
    • Anna Hiu Yi Wong

  With interest, we read an excellent paper written by a German group, in which four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) carried IgG autoantibodies against contactin-1 (CNTN1) expressed at the paranodes in the peripheral nerves.[1] Human IgG antibodies consist of four subclasses (IgG1-4) with different structural and functional characteristics. IgG4 are generally believed to be non- infla...

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  With interest, we read an excellent paper written by a German group, in which four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) carried IgG autoantibodies against contactin-1 (CNTN1) expressed at the paranodes in the peripheral nerves.[1] Human IgG antibodies consist of four subclasses (IgG1-4) with different structural and functional characteristics. IgG4 are generally believed to be non- inflammatory antibodies because they poorly bind to complement and Fc receptors Three of their patients had anti-CNTN1 IgG4 and sera from these three patients bound the paranodes in the mouse teased nerve fibers. On the other hand, the remaining patient with no anti-CNTN1 IgG4 antibodies in the serum did not bind the paranodes.

  In a large cohort of Japanese patients with CIDP (n = 533) and Guillain-Barre syndrome (GBS) (n = 200), our group identified anti-CNTN1 IgG antibodies in 16 sera from patients with CIDP and five with GBS.[2] IgG4 antibodies to CNTN1 were identified in 13 of 16 patients with CIDP, but none of those with GBS. IgG2 antibodies to CNTN1 were identified in three patients with CIDP and in five patients with GBS. We also blindly tested the sera on mouse teased fibers. Of interest, all the IgG4-positive CIDP sera strongly reacted against the paranodal domains but not for the IgG2-positive sera from patients with CIDP or GBS. These results are in line with those of the German group,[1] suggesting that only the IgG4 antibodies are pathogenic.

  We further tested whether these sera activate the complement pathway in vitro.[2] None of the sera with anti-CNTN1 IgG4 antibodies induced the deposition of activated C3 components on enzyme-linked immunosorbent assay plates. These results support that anti-CNTN1 IgG4 antibodies do not fix complement.

  The German group found out a typical clinical picture among the CIDP patients with anti-CNTN1 antibodies, namely acute onset of disease and severe motor symptoms, with three out of four patients manifesting action tremor.[1] However, in our cohort we found out that presence of anti-CNTN1 IgG4 antibodies was significantly associated with the clinical sign of sensory ataxia.[2] CNTN1 was widely expressed in large dorsal root ganglion neurons. Similarly, CIDP sera with anti-CNTN1 IgG4 antibodies stained large neurons in dorsal root ganglion sections and co-localized with CNTN1 staining in the soma and at the paranodes of sensory axons. These results support that the anti-CNTN1 autoantibodies induce the development of sensory ataxia. Nonetheless, the clinical feature of our patients contrasted with previous studies where none of the three German patients and only one of four Spanish patients with anti-CNTN1 IgG4 antibodies showed sensory ataxia.[1,3] The reason for this discrepancy is unclear, but this discrepancy should motivate international study groups to investigate the clinical feature of the anti-CNTN1 IgG4 antibodies among different countries, and their underlying mechanism.

  References 1. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 2015 Feb 18. pii:jnnp-2014- 309916. doi: 10.1136/jnnp-2014-309916. 2. Miura Y, Devaux N, Fukami Y, et al. Contactin 1 IgG4 associated to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015 Mar 25. pii: awv054. 3. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013;73:370-80.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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