Indexat a

Llicència i ús

Citacions

Altmetrics

Anàlisi d'autories institucional

Compartir

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

Publicat a:Med (N Y). S2666-6340 (24): 00371-4 - 2024-10-01 S2666-6340(24), DOI: 10.1016/j.medj.2024.09.004

Autors: Terroba-Navajas P; Spatola M; Chuquisana O; Joubert B; de Vries JM; Dik A; Marmolejo L; Jönsson F; Lauc G; Kovac S; Prüss H; Wiendl H; Titulaer MJ; Honnorat J; Lünemann JD

Afiliacions

Resum

BackgroundImmunoglobulin (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.MethodsWe 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.FindingsWe 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.ConclusionsThe 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.FundingThis 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.

Paraules clau