Journal Article DZNE-2025-00322

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Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.

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2025
Elsevier Amsterdam

Med 6(2), 100515 () [10.1016/j.medj.2024.09.004]

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Abstract: 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.

Keyword(s): Humans (MeSH) ; Nerve Tissue Proteins: immunology (MeSH) ; Immunoglobulin G: blood (MeSH) ; Immunoglobulin G: immunology (MeSH) ; Membrane Proteins: immunology (MeSH) ; Autoantibodies: blood (MeSH) ; Autoantibodies: immunology (MeSH) ; Phenotype (MeSH) ; Male (MeSH) ; Female (MeSH) ; Biomarkers: blood (MeSH) ; Middle Aged (MeSH) ; Receptors, IgG: immunology (MeSH) ; Adult (MeSH) ; Fc receptors ; IgG1 ; IgG4 ; Translation to patients ; antibody ; autoimmunity ; biosignature ; innate immunity ; limbic encephalitis ; ouctome ; precision medicine ; CNTNAP2 protein, human ; Nerve Tissue Proteins ; Immunoglobulin G ; Membrane Proteins ; Autoantibodies ; Biomarkers ; Receptors, IgG

Classification:

Contributing Institute(s):
  1. Autoimmune Encephalopathies (AG Prüß)
Research Program(s):
  1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025
Database coverage:
Medline ; Creative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0 ; OpenAccess ; Clarivate Analytics Master Journal List ; Emerging Sources Citation Index ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection
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 Record created 2025-02-19, last modified 2025-03-23


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