Molecular dissection of an immunodominant epitope in Kv1.2-exclusive autoimmunity

Front Immunol. 2024 Apr 11:15:1329013. doi: 10.3389/fimmu.2024.1329013. eCollection 2024.

Abstract

Introduction: Subgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response.

Methods: Binding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers.

Results: 83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes.

Discussion: Systematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.

Keywords: KCNA2; Kv channel; autoantibodies; autoimmune encephalitis; critical; dementia; epitope mapping; immunodominant antigen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Autoantibodies* / blood
  • Autoantibodies* / immunology
  • Autoantigens / immunology
  • Autoimmunity*
  • Epitope Mapping
  • Female
  • Humans
  • Immunodominant Epitopes* / immunology
  • Kv1.2 Potassium Channel* / immunology
  • Male
  • Middle Aged

Substances

  • Autoantibodies
  • Kv1.2 Potassium Channel
  • Immunodominant Epitopes
  • Autoantigens

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. HM and KD acknowledge funding by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) of Würzburg, project number A-F-N-419. HM further received funding from the Junior Group Leader program of the Rudolf Virchow Center, the excellent ideas programme of the University of Würzburg and the Emmy Noether Programme of the DFG (MA6957/1-1). KK acknowledges funding by the Graduate School of Life Sciences of the University of Würzburg. ME received funding from DFG under Germany´s Excellence Strategy – EXC-2049 – 390688087, Collaborative Research Center ReTune TRR 295-424778381, BMBF, DZNE, DZHK, EU, Corona Foundation, and Foundation Leducq. Plus: KFO 5023 (HP/ME). CV acknowledges funding by the Research unit SYNABS FOR3004 and KFO 5001 (CV/KD). HP acknowledges funding by the German Research Foundation (DFG; grants FOR3004, PR1274/3-1, PR1274/5-1, PR1274/9-1, Research Unit FOR3004 "Synabs", and Clinical Research Unit 5023/1 "BECAUSE-Y"), by the Helmholtz Association (HIL-A03 BaoBab), and by the German Federal Ministry of Education and Research (Connect-Generate 01GM1908D).