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Neurology. 2015 Sep 8;85(10):890-7. doi: 10.1212/WNL.0000000000001907. Epub 2015 Aug 19.

Anti-DPPX encephalitis: pathogenic effects of antibodies on gut and brain neurons.

Author information

1
From the Department of Neurology (J.P., K.R.), Institute for Integrative Neuroanatomy (J.P., M.H., C.D., G.A.-H.), and Department of Nuclear Medicine (R.B.), Charité-Universitätsmedizin Berlin; the Department of Human Biology (K.M., Q.L., M.S.), Technische Universität München, Munich, Germany; the Department of Physiology (Q.L.), Shangdong University School of Medicine, China; St. Josefs-Krankenhaus Potsdam (C.O.); the Institute for Experimental Immunology (C.P., W.S.), affiliated to Euroimmun AG, Lübeck; Molecular Neuroimmunology and Department of Neurology (S.J., B.B., H.-M.M.), University of Heidelberg, Germany; and the Catalan Institution of Research and Advanced Studies (ICREA) and Biomedical Research Institute August Pi i Sunyer (IDIBAPS) (J.D.), Hospital Clinic, University of Barcelona, Spain.
2
From the Department of Neurology (J.P., K.R.), Institute for Integrative Neuroanatomy (J.P., M.H., C.D., G.A.-H.), and Department of Nuclear Medicine (R.B.), Charité-Universitätsmedizin Berlin; the Department of Human Biology (K.M., Q.L., M.S.), Technische Universität München, Munich, Germany; the Department of Physiology (Q.L.), Shangdong University School of Medicine, China; St. Josefs-Krankenhaus Potsdam (C.O.); the Institute for Experimental Immunology (C.P., W.S.), affiliated to Euroimmun AG, Lübeck; Molecular Neuroimmunology and Department of Neurology (S.J., B.B., H.-M.M.), University of Heidelberg, Germany; and the Catalan Institution of Research and Advanced Studies (ICREA) and Biomedical Research Institute August Pi i Sunyer (IDIBAPS) (J.D.), Hospital Clinic, University of Barcelona, Spain. klemens.ruprecht@charite.de.

Abstract

OBJECTIVE:

To characterize pathogenic effects of antibodies to dipeptidyl-peptidase-like protein 6 (DPPX), a subunit of Kv4.2 potassium channels, on gut and brain neurons.

METHODS:

We identified a new patient with anti-DPPX encephalitis and analyzed the effects of the patient's serum and purified immunoglobulin G (IgG), and of serum of a previous patient with anti-DPPX encephalitis, on the activity of enteric neurons by voltage-sensitive dye imaging in guinea pig myenteric and human submucous plexus preparations. We studied the subcellular localization of DPPX by immunocytochemistry in cultured murine hippocampal neurons using sera of 4 patients with anti-DPPX encephalitis. We investigated the influence of anti-DPPX-containing serum and purified IgG on neuronal surface expression of DPPX and Kv4.2 by immunoblots of purified murine hippocampal neuron membranes.

RESULTS:

The new patient with anti-DPPX encephalitis presented with a 2-month episode of diarrhea, which was followed by tremor, disorientation, and mild memory impairment. Anti-DPPX-IgG-containing sera and purified IgG increased the excitability and action potential frequency of guinea pig and human enteric nervous system neurons. Patient sera revealed a somatodendritic and perisynaptic neuronal surface staining that colocalized with the signal of commercial anti-DPPX and Kv4.2 antibodies. Incubation of hippocampal neurons with patient serum and purified IgG resulted in a decreased expression of DPPX and Kv4.2 in neuronal membranes.

CONCLUSIONS:

Hyperexcitability of enteric nervous system neurons and downregulation of DPPX and Kv4.2 from hippocampal neuron membranes mirror the clinical phenotype of patients with anti-DPPX encephalitis and support a pathogenic role of anti-DPPX antibodies in anti-DPPX encephalitis.

PMID:
26291285
PMCID:
PMC4560062
DOI:
10.1212/WNL.0000000000001907
[Indexed for MEDLINE]
Free PMC Article

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