Abstract

Objective: To determine the pathogenic mechanisms of autoantibodies to the cell adhesion molecule Caspr2 in acquired neuromyotonia and autoimmune encephalitis.

Methods: Caspr2 positive samples were confirmed using a cell-based assay, and their IgG subtypes were determined by ELISA and cell-based assay. A solid phase binding assay quantified the binding of Caspr2 to contactin-2 in the presence of Caspr2 autoantibodies. Living cultures of primary rat hippocampal neurons were incubated with Caspr2-positive or control sera and the distribution of Caspr2-positive immunofluorescent puncta and total surface Caspr2 were quantified. HEK cells transfected to express Caspr2 were incubated with Caspr2-positive or control samples, and cell-surface biotinylation and Western blot were used to assess total, internalized, and surface levels of Caspr2.

Results: We confirmed six samples with strong Caspr2 reactivity. IgG4 Caspr2 antibodies were present in all six cases. Caspr2 interacted with another cell adhesion molecule, contactin-2, with nanomolar affinity in the solid phase assay, and Caspr2 autoantibodies inhibited this interaction. Caspr2 autoantibodies did not affect the surface expression of Caspr2 in rat primary hippocampal neurons or transfected HEK cells.

Interpretation: Caspr2 autoantibodies inhibit the interaction of Caspr2 with contactin-2 but do not cause internalization of Caspr2. Functional blocking of cell adhesion molecule interactions represents a potential mechanism with therapeutic implications for IgG4 autoantibodies to cell adhesion molecules in neurological diseases. This article is protected by copyright. All rights reserved.

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