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September 2020; 7 (5) ArticleOpen Access

Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy

View ORCID ProfileLuise Appeltshauser, Anna-Michelle Brunder, Annika Heinius, View ORCID ProfilePeter Körtvélyessy, View ORCID ProfileKlaus-Peter Wandinger, Ralf Junker, View ORCID ProfileCarmen Villmann, View ORCID ProfileClaudia Sommer, View ORCID ProfileFrank Leypoldt, View ORCID ProfileKathrin Doppler
First published July 24, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000817
Luise Appeltshauser
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Anna-Michelle Brunder
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Annika Heinius
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Peter Körtvélyessy
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Klaus-Peter Wandinger
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Ralf Junker
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Carmen Villmann
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Claudia Sommer
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Frank Leypoldt
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Kathrin Doppler
From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.
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Citation
Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy
Luise Appeltshauser, Anna-Michelle Brunder, Annika Heinius, Peter Körtvélyessy, Klaus-Peter Wandinger, Ralf Junker, Carmen Villmann, Claudia Sommer, Frank Leypoldt, Kathrin Doppler
Neurol Neuroimmunol Neuroinflamm Sep 2020, 7 (5) e817; DOI: 10.1212/NXI.0000000000000817

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    Figure 1 Detection of antiparanodal autoantibodies by binding assays on teased fibers, CBA, and preabsorption assay

    (A) Colocalization overlay photomicrographs of double immunofluorescence assays with commercial autoantibody displayed in red and human serum in green. Colocalization at the paranodes (arrows) appears yellow and indicates antiparanodal autoantibodies in patients 1–5 (A.b–A.f), but not in the negative control serum (A.a). (B) The specific target of the autoantibodies is illustrated by colocalization overlay photomicrographs on transfected HEK293 cells (arrowheads) with commercial antibody in red, serum in green, and nucleus staining in blue. Colocalization appears yellow (merge) and confirms anti–contactin-1 in patients 2 (B.c), 3 (B.d), and 4 (B.e), but not in patients 1 (B.b), 5 (B.f), and the negative control (B.a). Sera of patients 1, 2, 4, and 5 (B.h, B.i, B.k, and B.l) colocalize on Caspr-1 (CNTNAP1)–transfected HEK293 cells as proof of anti–Caspr-1 autoantibodies, whereas sera of the negative control (B.g) and patient 3 (B.j) do not show anti–Caspr-1 positivity. (C) Single immunofluorescence on murine teased fibers after HEK293 contactin-1 and Caspr-1 preabsorption shows that antiparanodal autoantibodies disappear after contactin-1 preabsorption in patient 3 (C.d) and after Caspr-1 preabsorption in patient 4 (C.f), proving specificity to the respective target antigen. Scale bar = 10 µm. CBA = cell-based assay; HEK = human embryonic kidney.

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    Figure 2 Serum subclass analysis at baseline and at follow-up with IgG subclass switch

    (A) Results of anti–contactin-1 and anti–Caspr-1 ELISA with baseline sera and subclass-specific IgG1-4 autoantibodies (grayscale) are shown as % of the OD of the total IgG (using anti-human IgG autoantibody) on y-axis. In patient 1, ELISA IgG subclasses were not measurable. ELISA revealed mainly IgG2 subclass in patient 2 (GBS), IgG2/IgG4 in patient 3 (A-CIDP), and IgG2/3 in patients 4 and 5 (A-CIDP). (B) Acute phase teased fibers subclass analysis with baseline sera showed binding to the paranodal regions (arrows) only when using IgG3-specific secondary antibody in patients 1 (GBS) and 4 (A-CIDP), visualized by photomicrographs of single immunofluorescence staining on teased fibers. (C) Anti–Caspr-1 IgG subclass ELISA with follow-up serum of patient 4 now revealed IgG 2/4 subclass. Photomicrographs show immunofluorescence staining of murine teased fibers with subclass-specific IgG3 and IgG4 autoantibodies at follow-up. Paranodal binding disappeared using IgG3 antibody, but occurred using IgG4 subclass-specific antibody, proving subclass switch in patient 4. Scale bar = 10 µm. A-CIDP = acute-onset chronic inflammatory demyelinating polyradiculoneuropathy; GBS = Guillain-Barré syndrome.

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    Figure 3 Antiparanodal IgG autoantibodies at follow-up assessment

    (A) Contactin-1 IgG ELISA of all patients at first assessment, of 66/161 patients at follow-up, and of 40 healthy controls. Optical density (OD) at 450 nm is displayed on the y-axis. The threshold for positive results is set at 5 SDs above the mean of controls (0.615). Patients 2–4 show positive results at first assessment. The other patients and controls show values below the threshold. Sera of patients 2, 4, and 5 are negative in anti–contactin-1 IgG ELISA at follow-up, as well as 63 other follow-up sera. Patients 1 and 3 were lost to follow-up. (B) Overlay photomicrographs of teased fibers double immunofluorescence and (C) contactin-1– and Caspr-1 (CNTNAP1)–transfected HEK293 cells show loss of anti–contactin-1/Caspr-1 autoantibodies in patient 2 (GBS) at follow-up (B.a, C.a, C.d), but colocalization of commercial anti–Caspr-1 antibody and sera at paranodes in patients 4 and 5 with A-CIDP (B.b, B.c, arrows). Both sera bind to Caspr-1 (CNTNAP1)–transfected HEK293 cells (C.e, C.f, arrowheads), but not to contactin-1–transfected cells (C.b, C.c). Scale bar = 10 µm. A-CIDP = acute-onset chronic inflammatory demyelinating polyradiculoneuropathy; GBS = Guillain-Barré syndrome; HEK = human embryonic kidney.

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    Figure 4 Scheme of the autoantibody status in the course of disease in seropositive patients

    The course of disease is shown on the x-axis by pseudo-logarithmic display of the time course. Time point 0 is set at baseline assessment of serum/CSF. The color code indicates severity of symptoms. Results of serum assessment are displayed in black. Patients 1 and 3 were lost to follow-up.

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