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Intrathecal B-cell activation in LGI1 antibody encephalitis.

  • Author(s): Lehmann-Horn, Klaus
  • Irani, Sarosh R
  • Wang, Shengzhi
  • Palanichamy, Arumugam
  • Jahn, Sarah
  • Greenfield, Ariele L
  • Dandekar, Ravi
  • Lepennetier, Gildas
  • Michael, Sophia
  • Gelfand, Jeffrey M
  • Geschwind, Michael D
  • Wilson, Michael R
  • Zamvil, Scott S
  • von Büdingen, H-Christian
  • et al.
Abstract

OBJECTIVE:To study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis. METHODS:Paired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB. RESULTS:Serum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls. CONCLUSIONS:Our results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

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