PT  - JOURNAL ARTICLE
AU  - Lehmann-Horn, Klaus
AU  - Irani, Sarosh R.
AU  - Wang, Shengzhi
AU  - Palanichamy, Arumugam
AU  - Jahn, Sarah
AU  - Greenfield, Ariele L.
AU  - Dandekar, Ravi
AU  - Lepennetier, Gildas
AU  - Michael, Sophia
AU  - Gelfand, Jeffrey M.
AU  - Geschwind, Michael D.
AU  - Wilson, Michael R.
AU  - Zamvil, Scott S.
AU  - von Büdingen, H.-Christian
TI  - Intrathecal B-cell activation in LGI1 antibody encephalitis
AID  - 10.1212/NXI.0000000000000669
DP  - 2020 Mar 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e669
VI  - 7
IP  - 2
4099  - http://nn.neurology.org/content/7/2/e669.short
4100  - http://nn.neurology.org/content/7/2/e669.full
SO  - Neurol Neuroimmunol Neuroinflamm2020 Mar 01; 7
AB  - 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.BBB=blood-brain barrier; BCR=B-cell receptor; cDNA=complementary DNA; DIRS=deep B-cell immune repertoire sequencing; IgD=immunoglobulin D; IgG=immunoglobulin G; IgM=immunoglobulin M; LGI1=leucine-rich, glioma-inactivated 1; NMDAR=NMDA receptor; PB=peripheral blood; SHM=somatic hypermutation; SM=switched memory; UCSF=University of California, San Francisco; VH=heavy chain variable region