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Neuro-inflammation
Research paper
Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies
  1. Bethan Lang1,
  2. Mateusz Makuch1,
  3. Teresa Moloney1,
  4. Inga Dettmann2,
  5. Swantje Mindorf2,
  6. Christian Probst2,
  7. Winfried Stoecker2,
  8. Camilla Buckley1,
  9. Charles R Newton3,
  10. M Isabel Leite1,
  11. Paul Maddison4,
  12. Lars Komorowski2,
  13. Jane Adcock1,
  14. Angela Vincent1,
  15. Patrick Waters1,
  16. Sarosh R Irani1
  1. 1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
  2. 2Institute for Experimental Immunology, Lubeck, Germany
  3. 3Department of Psychiatry, University of Oxford, Oxford, UK
  4. 4Department of Neurology, Queen's Medical Centre, Nottingham, UK
  1. Correspondence to Professor Sarosh R Irani, West Wing, Level 6, John Radcliffe Hospital, Oxford OX3 9DU, UK; sarosh.irani{at}ndcn.ox.ac.uk

Abstract

Objectives Autoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. However, in routine testing, VGKC complex antibodies without LGI1 or CASPR2 reactivities (double-negative) are more common than LGI1 or CASPR2 specificities. Therefore, the target(s) and clinical associations of double-negative antibodies need to be determined.

Methods Sera (n=1131) from several clinically defined cohorts were tested for IgG radioimmunoprecipitation of radioiodinated α-dendrotoxin (125I-αDTX)-labelled VGKC complexes from mammalian brain extracts. Positive samples were systematically tested for live hippocampal neuron reactivity, IgG precipitation of 125I-αDTX and 125I-αDTX-labelled Kv1 subunits, and by cell-based assays which expressed Kv1 subunits, LGI1 and CASPR2.

Results VGKC complex antibodies were found in 162 of 1131 (14%) sera. 90 of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, 10 (14%) immunoprecipitated 125I-αDTX itself, and 27 (38%) bound to solubilised co-expressed Kv1.1/1.2/1.6 subunits and/or Kv1.2 subunits alone, at levels proportionate to VGKC complex antibody levels (r=0.57, p=0.0017). The sera with LGI1 and CASPR2 antibodies immunoprecipitated neither preparation. None of the 27 Kv1-precipitating samples bound live hippocampal neurons or Kv1 extracellular domains, but 16 (59%) bound to permeabilised Kv1-expressing human embryonic kidney 293T cells. These intracellular Kv1 antibodies mainly associated with non-immune disease aetiologies, poor longitudinal clinical–serological correlations and a limited immunotherapy response.

Conclusions Double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits and occasionally against non-mammalian αDTX. These antibodies should no longer be classified as neuronal-surface antibodies. They consequently lack pathogenic potential and do not in themselves support the use of immunotherapies.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/jnnp-2016-314758

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    Footnotes

    • Funding BL is supported by Epilepsy Research UK (ERUK; P1201); SRI is supported by a Wellcome Trust Intermediate Fellowship (104079/Z/14/Z), BMA Research Grants—Vera Down grant (2013) , the Fulbright UK-US commission and the MS society. Research in the Neuroimmunology Laboratory is supported by the Oxford NIHR Biomedical Research Centre. PW and MIL are supported by the NHS National Specialized Commissioning Group for Neuromyelitis optica, UK.

    • Competing interests AV, SRI, BL and PW are coapplicants and receive royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. BL and SRI had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    • Ethics approval Oxfordshire Regional Ethical Committee A (RECA).

    • Provenance and peer review Not commissioned; externally peer reviewed.