PMID- 27547772
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20160822
LR  - 20181113
IS  - 2328-9503 (Print)
IS  - 2328-9503 (Electronic)
IS  - 2328-9503 (Linking)
VI  - 3
IP  - 6
DP  - 2016 Jun
TI  - Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia 
      gravis.
PG  - 443-54
LID - 10.1002/acn3.311 [doi]
AB  - OBJECTIVE: Myasthenia gravis (MG) is an autoimmune condition in which 
      neurotransmission is impaired by binding of autoantibodies to acetylcholine 
      receptors (AChR) or, in a minority of patients, to muscle specific kinase (MuSK). 
      There are differences in the dominant IgG subclass, pathogenic mechanisms, and 
      treatment responses between the two MG subtypes (AChR or MuSK). The antibodies 
      are thought to be T-cell dependent, but the mechanisms underlying their 
      production are not well understood. One aspect not previously described is 
      whether defects in central and peripheral tolerance checkpoints, which allow 
      autoreactive B cells to accumulate in the naive repertoire, are found in both or 
      either form of MG. METHODS: An established set of assays that measure the 
      frequency of both polyreactive and autoreactive B cell receptors (BCR) in naive 
      populations was applied to specimens collected from patients with either AChR or 
      MuSK MG and healthy controls. Radioimmuno- and cell-based assays were used to 
      measure BCR binding to AChR and MuSK. RESULTS: The frequency of polyreactive and 
      autoreactive BCRs (n = 262) was higher in both AChR and MuSK MG patients than in 
      healthy controls. None of the MG-derived BCRs bound AChR or MuSK. INTERPRETATION: 
      The results indicate that both these MG subtypes harbor defects in central and 
      peripheral B cell tolerance checkpoints. Defective B cell tolerance may represent 
      a fundamental contributor to autoimmunity in MG and is of particular importance 
      when considering the durability of myasthenia gravis treatment strategies, 
      particularly biologics that eliminate B cells.
FAU - Lee, Jae-Yun
AU  - Lee JY
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
FAU - Stathopoulos, Panos
AU  - Stathopoulos P
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
FAU - Gupta, Sasha
AU  - Gupta S
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
FAU - Bannock, Jason M
AU  - Bannock JM
AD  - Department of Immunobiology Yale School of Medicine New Haven Connecticut.
FAU - Barohn, Richard J
AU  - Barohn RJ
AD  - Department of Neurology University of Kansas Medical Center Kansas City Kansas.
FAU - Cotzomi, Elizabeth
AU  - Cotzomi E
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
FAU - Dimachkie, Mazen M
AU  - Dimachkie MM
AD  - Department of Neurology University of Kansas Medical Center Kansas City Kansas.
FAU - Jacobson, Leslie
AU  - Jacobson L
AD  - Nuffield Department of Clinical Neurosciences John Radcliffe Hospital, University 
      of Oxford Oxford UK.
FAU - Lee, Casey S
AU  - Lee CS
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
FAU - Morbach, Henner
AU  - Morbach H
AD  - Department of Immunobiology Yale School of Medicine New Haven Connecticut.
FAU - Querol, Luis
AU  - Querol L
AD  - Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau Universitat 
      Autonoma de Barcelona Spain.
FAU - Shan, Jing-Li
AU  - Shan JL
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
FAU - Vander Heiden, Jason A
AU  - Vander Heiden JA
AD  - Interdepartmental Program in Computational Biology and Bioinformatics Yale 
      University New Haven Connecticut.
FAU - Waters, Patrick
AU  - Waters P
AD  - Nuffield Department of Clinical Neurosciences John Radcliffe Hospital, University 
      of Oxford Oxford UK.
FAU - Vincent, Angela
AU  - Vincent A
AD  - Nuffield Department of Clinical Neurosciences John Radcliffe Hospital, University 
      of Oxford Oxford UK.
FAU - Nowak, Richard J
AU  - Nowak RJ
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
FAU - O'Connor, Kevin C
AU  - O'Connor KC
AD  - Department of Neurology Yale School of Medicine New Haven Connecticut.
LA  - eng
GR  - R01 AI114780/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20160427
PL  - United States
TA  - Ann Clin Transl Neurol
JT  - Annals of clinical and translational neurology
JID - 101623278
PMC - PMC4891998
EDAT- 2016/08/23 06:00
MHDA- 2016/08/23 06:01
PMCR- 2016/04/27
CRDT- 2016/08/23 06:00
PHST- 2016/01/29 00:00 [received]
PHST- 2016/03/26 00:00 [revised]
PHST- 2016/03/29 00:00 [accepted]
PHST- 2016/08/23 06:00 [entrez]
PHST- 2016/08/23 06:00 [pubmed]
PHST- 2016/08/23 06:01 [medline]
PHST- 2016/04/27 00:00 [pmc-release]
AID - ACN3311 [pii]
AID - 10.1002/acn3.311 [doi]
PST - epublish
SO  - Ann Clin Transl Neurol. 2016 Apr 27;3(6):443-54. doi: 10.1002/acn3.311. 
      eCollection 2016 Jun.