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

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.

• Authors: Johannes Piepgras, Markus Höltje, Klaus Michel, Qin Li, Carolin Otto, Christoph Drenckhahn, Christian Probst, Michael Schemann, Sven Jarius, Winfried Stöcker, Bettina Balint, Hans-Michael Meinck, Ralph Buchert, Josep Dalmau, Gudrun Ahnert-Hilger, Klemens Ruprecht
• Journal: Neurology (Neurology) Vol. 85 Issue 10 Pg. 890-7 (Sep 08 2015) ISSN: 1526-632X [Electronic] United States
• PMID: 26291285 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Academy of Neurology.

Chemical References

• Antibodies, Anti-Idiotypic
• Immunoglobulin G
• Nerve Tissue Proteins
• Potassium Channels
• DPP6 protein, human
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases

Topics

• Aged
• Animals
• Antibodies, Anti-Idiotypic (administration & dosage, blood)
• Brain (drug effects, pathology)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (administration & dosage, blood)
• Encephalitis (blood, diagnosis)
• Guinea Pigs
• Humans
• Immunoglobulin G (administration & dosage, blood)
• Male
• Mice
• Myenteric Plexus (drug effects, pathology)
• Nerve Tissue Proteins (administration & dosage, blood)
• Neurons (drug effects, pathology)
• Potassium Channels (administration & dosage, blood)
• Rats