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@ARTICLE{TerrobaNavajas:276797,
      author       = {Terroba-Navajas, Paula and Spatola, Marianna and
                      Chuquisana, Omar and Joubert, Bastien and de Vries, Juna M
                      and Dik, Andre and Marmolejo, Laura and Jönsson, Friederike
                      and Lauc, Gordan and Kovac, Stjepana and Prüss, Harald and
                      Wiendl, Heinz and Titulaer, Maarten J and Honnorat, Jérôme
                      and Lünemann, Jan D},
      title        = {{H}umoral signatures of {C}aspr2-antibody spectrum disorder
                      track with clinical phenotypes and outcomes.},
      journal      = {Med},
      volume       = {6},
      number       = {2},
      issn         = {2666-6340},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DZNE-2025-00322},
      pages        = {100515},
      year         = {2025},
      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.},
      keywords     = {Humans / Nerve Tissue Proteins: immunology / Immunoglobulin
                      G: blood / Immunoglobulin G: immunology / Membrane Proteins:
                      immunology / Autoantibodies: blood / Autoantibodies:
                      immunology / Phenotype / Male / Female / Biomarkers: blood /
                      Middle Aged / Receptors, IgG: immunology / Adult / Fc
                      receptors (Other) / IgG1 (Other) / IgG4 (Other) /
                      Translation to patients (Other) / antibody (Other) /
                      autoimmunity (Other) / biosignature (Other) / innate
                      immunity (Other) / limbic encephalitis (Other) / ouctome
                      (Other) / precision medicine (Other) / CNTNAP2 protein,
                      human (NLM Chemicals) / Nerve Tissue Proteins (NLM
                      Chemicals) / Immunoglobulin G (NLM Chemicals) / Membrane
                      Proteins (NLM Chemicals) / Autoantibodies (NLM Chemicals) /
                      Biomarkers (NLM Chemicals) / Receptors, IgG (NLM Chemicals)},
      cin          = {AG Prüß},
      ddc          = {610},
      cid          = {I:(DE-2719)1810003},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39393351},
      doi          = {10.1016/j.medj.2024.09.004},
      url          = {https://pub.dzne.de/record/276797},
}