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  -