TY - JOUR
AU - Terroba-Navajas, Paula
AU - Spatola, Marianna
AU - Chuquisana, Omar
AU - Joubert, Bastien
AU - de Vries, Juna M
AU - Dik, Andre
AU - Marmolejo, Laura
AU - Jönsson, Friederike
AU - Lauc, Gordan
AU - Kovac, Stjepana
AU - Prüss, Harald
AU - Wiendl, Heinz
AU - Titulaer, Maarten J
AU - Honnorat, Jérôme
AU - Lünemann, Jan D
TI - Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.
JO - Med
VL - 6
IS - 2
SN - 2666-6340
CY - Amsterdam
PB - Elsevier
M1 - DZNE-2025-00322
SP - 100515
PY - 2025
AB - 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.
KW - Humans
KW - Nerve Tissue Proteins: immunology
KW - Immunoglobulin G: blood
KW - Immunoglobulin G: immunology
KW - Membrane Proteins: immunology
KW - Autoantibodies: blood
KW - Autoantibodies: immunology
KW - Phenotype
KW - Male
KW - Female
KW - Biomarkers: blood
KW - Middle Aged
KW - Receptors, IgG: immunology
KW - Adult
KW - Fc receptors (Other)
KW - IgG1 (Other)
KW - IgG4 (Other)
KW - Translation to patients (Other)
KW - antibody (Other)
KW - autoimmunity (Other)
KW - biosignature (Other)
KW - innate immunity (Other)
KW - limbic encephalitis (Other)
KW - ouctome (Other)
KW - precision medicine (Other)
KW - CNTNAP2 protein, human (NLM Chemicals)
KW - Nerve Tissue Proteins (NLM Chemicals)
KW - Immunoglobulin G (NLM Chemicals)
KW - Membrane Proteins (NLM Chemicals)
KW - Autoantibodies (NLM Chemicals)
KW - Biomarkers (NLM Chemicals)
KW - Receptors, IgG (NLM Chemicals)
LB - PUB:(DE-HGF)16
C6 - pmid:39393351
DO - DOI:10.1016/j.medj.2024.09.004
UR - https://pub.dzne.de/record/276797
ER -