PMID- 32573488
OWN - NLM
STAT- MEDLINE
DCOM- 20210521
LR  - 20210919
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 5
IP  - 14
DP  - 2020 Jul 23
TI  - Single-cell repertoire tracing identifies rituximab-resistant B cells during 
      myasthenia gravis relapses.
LID - 136471 [pii]
LID - 10.1172/jci.insight.136471 [doi]
LID - e136471
AB  - Rituximab, a B cell-depleting therapy, is indicated for treating a growing number 
      of autoantibody-mediated autoimmune disorders. However, relapses can occur after 
      treatment, and autoantibody-producing B cell subsets may be found during 
      relapses. It is not understood whether these autoantibody-producing B cell 
      subsets emerge from the failed depletion of preexisting B cells or are generated 
      de novo. To further define the mechanisms that cause postrituximab relapse, we 
      studied patients with autoantibody-mediated muscle-specific kinase (MuSK) 
      myasthenia gravis (MG) who relapsed after treatment. We carried out single-cell 
      transcriptional and B cell receptor profiling on longitudinal B cell samples. We 
      identified clones present before therapy that persisted during relapse. 
      Persistent B cell clones included both antibody-secreting cells and memory B 
      cells characterized by gene expression signatures associated with B cell 
      survival. A subset of persistent antibody-secreting cells and memory B cells were 
      specific for the MuSK autoantigen. These results demonstrate that rituximab is 
      not fully effective at eliminating autoantibody-producing B cells and provide a 
      mechanistic understanding of postrituximab relapse in MuSK MG.
FAU - Jiang, Ruoyi
AU  - Jiang R
AD  - Department of Immunobiology and.
FAU - Fichtner, Miriam L
AU  - Fichtner ML
AD  - Department of Immunobiology and.
AD  - Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.
FAU - Hoehn, Kenneth B
AU  - Hoehn KB
AD  - Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
FAU - Pham, Minh C
AU  - Pham MC
AD  - Department of Immunobiology and.
FAU - Stathopoulos, Panos
AU  - Stathopoulos P
AD  - Department of Immunobiology and.
AD  - Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.
FAU - Nowak, Richard J
AU  - Nowak RJ
AD  - Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.
FAU - Kleinstein, Steven H
AU  - Kleinstein SH
AD  - Department of Immunobiology and.
AD  - Interdepartmental Program in Computational Biology & Bioinformatics, Yale 
      University, New Haven, Connecticut, USA.
AD  - Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
FAU - O'Connor, Kevin C
AU  - O'Connor KC
AD  - Department of Immunobiology and.
AD  - Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.
LA  - eng
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
GR  - R01 AI104739/AI/NIAID NIH HHS/United States
GR  - T32 GM007205/GM/NIGMS NIH HHS/United States
GR  - R01 AI114780/AI/NIAID NIH HHS/United States
GR  - R21 AI142198/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200723
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Autoantibodies)
RN  - 0 (Receptors, Cholinergic)
RN  - 4F4X42SYQ6 (Rituximab)
RN  - EC 2.7.10.1 (MUSK protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Autoantibodies/*immunology
MH  - Autoimmune Diseases/*immunology/pathology/prevention & control
MH  - B-Lymphocyte Subsets/immunology
MH  - B-Lymphocytes/drug effects
MH  - Humans
MH  - Myasthenia Gravis/immunology/pathology
MH  - Receptor Protein-Tyrosine Kinases/*genetics
MH  - Receptors, Cholinergic/*genetics
MH  - Rituximab/*pharmacology
MH  - Single-Cell Analysis
MH  - Transcriptome/genetics
PMC - PMC7453893
OTO - NOTNLM
OT  - Autoimmunity
OT  - B cells
OT  - Immunology
OT  - Immunotherapy
OT  - Neuromuscular disease
COIS- Conflict of interest: KCO has received research support from Ra Pharmaceuticals, 
      Inc. (now part of UCB), and is a consultant and equity shareholder of Cabaletta 
      Bio. KCO is the recipient of a sponsored research subaward from the University of 
      Pennsylvania, the primary financial sponsor of which is Cabaletta Bio. SHK 
      receives consulting fees from Northrop Grumman. RJN has received research support 
      from Alexion Pharmaceuticals, Genentech, Grifols, and Ra Pharmaceuticals, Inc., 
      and has served as a paid consultant for Alexion Pharmaceuticals; Momenta; Ra 
      Pharmaceuticals, Inc.; Roivant Sciences; Shire (now part of Takeda); and Grifols. 
      MLF has received research support from Grifols.
EDAT- 2020/06/24 06:00
MHDA- 2021/05/22 06:00
PMCR- 2020/07/23
CRDT- 2020/06/24 06:00
PHST- 2020/01/15 00:00 [received]
PHST- 2020/06/11 00:00 [accepted]
PHST- 2020/06/24 06:00 [pubmed]
PHST- 2021/05/22 06:00 [medline]
PHST- 2020/06/24 06:00 [entrez]
PHST- 2020/07/23 00:00 [pmc-release]
AID - 136471 [pii]
AID - 10.1172/jci.insight.136471 [doi]
PST - epublish
SO  - JCI Insight. 2020 Jul 23;5(14):e136471. doi: 10.1172/jci.insight.136471.