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

Paula Terroba-Navajas; Marianna Spatola; Omar Chuquisana; Bastien Joubert; Juna M de Vries; Andre Dik; Laura Marmolejo; Friederike Jönsson; Gordan Lauc; Stjepana Kovac; Harald Prüss; Heinz Wiendl; Maarten J Titulaer; Jérôme Honnorat; Jan D Lünemann

doi:10.1016/j.medj.2024.09.004

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

Med. 2024 Oct 3:S2666-6340(24)00371-4. doi: 10.1016/j.medj.2024.09.004. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
² Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Caixa Research Institute, Barcelona, Spain. Electronic address: marianna.spatola@gmail.com.
³ French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Lyon, France; MeLiS - UCBL - CNRS UMR 5284 - INSERM U1314, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France; Service de Neurologie, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.
⁴ Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
⁶ CNRS & Institut Pasteur, Université Paris Cité, INSERM UMR1222, Antibodies in Therapy and Pathology, 75015 Paris, France.
⁷ Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovačića 1, Zagreb, Croatia; Genos, Ltd., Borongajska Cesta 83H, Zagreb, Croatia.
⁸ Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Charitéplatz 1, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
⁹ French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Lyon, France; MeLiS - UCBL - CNRS UMR 5284 - INSERM U1314, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
¹⁰ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany. Electronic address: jan.luenemann@ukmuenster.de.

PMID: 39393351
DOI: 10.1016/j.medj.2024.09.004

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Conclusions: 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.

Funding: 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: Fc receptors; IgG1; IgG4; Translation to patients; antibody; autoimmunity; biosignature; innate immunity; limbic encephalitis; ouctome; precision medicine.