Anti-DPPX encephalitis: pathogenic effects of antibodies on gut and brain neurons.
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.
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.
Johannes
J
Piepgras
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.
Markus
M
Höltje
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.
Klaus
K
Michel
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.
Qin
Q
Li
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.
Carolin
C
Otto
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.
Christoph
C
Drenckhahn
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.
Christian
C
Probst
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.
Michael
M
Schemann
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.
Sven
S
Jarius
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.
Winfried
W
Stöcker
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.
Bettina
B
Balint
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.
Hans-Michael
HM
Meinck
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.
Ralph
R
Buchert
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.
Josep
J
Dalmau
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.
Gudrun
G
Ahnert-Hilger
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.
Klemens
K
Ruprecht
D000368:Aged; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000097:blood*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000008:administration & dosage / Q000097:blood*; D004660:Encephalitis / Q000097:blood* / Q000175:diagnosis; D006168:Guinea Pigs; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood; D008297:Male; D051379:Mice; D009197:Myenteric Plexus / Q000187:drug effects / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000097:blood*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D015221:Potassium Channels / Q000008:administration & dosage / Q000097:blood*; D051381:Rats
D000888:Antibodies, Anti-Idiotypic; D007074:Immunoglobulin G; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases