%0 Journal Article
%A Terroba-Navajas, Paula
%A Spatola, Marianna
%A Chuquisana, Omar
%A Joubert, Bastien
%A de Vries, Juna M
%A Dik, Andre
%A Marmolejo, Laura
%A Jönsson, Friederike
%A Lauc, Gordan
%A Kovac, Stjepana
%A Prüss, Harald
%A Wiendl, Heinz
%A Titulaer, Maarten J
%A Honnorat, Jérôme
%A Lünemann, Jan D
%T Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.
%J Med
%V 6
%N 2
%@ 2666-6340
%C Amsterdam
%I Elsevier
%M DZNE-2025-00322
%P 100515
%D 2025
%X Immunoglobulin (Ig) G4 auto-antibodies (Abs) against contactin-associated protein-like 2 (Caspr2), a transmembrane cell adhesion protein expressed in the central and peripheral nervous system, are found in patients with a broad spectrum of neurological symptoms. While the adoptive transfer of Caspr2-specific IgG induces brain pathology in susceptible rodents, the mechanisms by which Caspr2-Abs mediate neuronal dysfunction and translate into clinical syndromes are incompletely understood.We use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral biosignatures in patients with Caspr2-Ab-associated neurological syndromes.We identify two signatures strongly associated with two major clinical phenotypes, limbic encephalitis (LE) and predominant peripheral nerve hyperexcitability without LE (non-LE). Caspr2-IgG Fc-driven pro-inflammatory features, characterized by increased binding affinities for activating Fcγ receptors (FcγRs) and C1q, along with a higher prevalence of IgG1-class Abs, in addition to IgG4, are strongly associated with LE. Both the occurrence of Caspr2-specific IgG1 and higher serum levels of interleukin (IL)-6 and IL-15, along with increased concentrations of biomarkers reflecting neuronal damage and glial cell activation, are associated with poorer clinical outcomes at 1-year follow-up.The presence of IgG1 isotypes and Fc-mediated effector functions control the pathogenicity of Caspr2-specific Abs to induce LE. Biologics targeting FcR function might potentially restrain Caspr2-Ab-induced pathology and improve clinical outcomes.This study was funded by a German-French joint research program supported by the German Research Foundation (DFG) and the Agence Nationale de la Recherche (ANR) and by the Interdisciplinary Centre for Clinical Research (IZKF) Münster.
%K Humans
%K Nerve Tissue Proteins: immunology
%K Immunoglobulin G: blood
%K Immunoglobulin G: immunology
%K Membrane Proteins: immunology
%K Autoantibodies: blood
%K Autoantibodies: immunology
%K Phenotype
%K Male
%K Female
%K Biomarkers: blood
%K Middle Aged
%K Receptors, IgG: immunology
%K Adult
%K Fc receptors (Other)
%K IgG1 (Other)
%K IgG4 (Other)
%K Translation to patients (Other)
%K antibody (Other)
%K autoimmunity (Other)
%K biosignature (Other)
%K innate immunity (Other)
%K limbic encephalitis (Other)
%K ouctome (Other)
%K precision medicine (Other)
%K CNTNAP2 protein, human (NLM Chemicals)
%K Nerve Tissue Proteins (NLM Chemicals)
%K Immunoglobulin G (NLM Chemicals)
%K Membrane Proteins (NLM Chemicals)
%K Autoantibodies (NLM Chemicals)
%K Biomarkers (NLM Chemicals)
%K Receptors, IgG (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39393351
%R 10.1016/j.medj.2024.09.004
%U https://pub.dzne.de/record/276797