title: Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Jae-Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Panos
authors.initials: P
authors.lastname: Stathopoulos
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Sasha
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Immunobiology Yale School of Medicine New Haven Connecticut.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bannock
authors.affiliation: Department of Neurology University of Kansas Medical Center Kansas City Kansas.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barohn
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cotzomi
authors.affiliation: Department of Neurology University of Kansas Medical Center Kansas City Kansas.
authors.forename: Mazen M
authors.initials: MM
authors.lastname: Dimachkie
authors.affiliation: Nuffield Department of Clinical Neurosciences John Radcliffe Hospital, University of Oxford Oxford UK.
authors.forename: Leslie
authors.initials: L
authors.lastname: Jacobson
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Casey S
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Immunobiology Yale School of Medicine New Haven Connecticut.
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.affiliation: Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau Universitat Autónoma de Barcelona Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Querol
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Jing-Li
authors.initials: JL
authors.lastname: Shan
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Vander Heiden
authors.affiliation: Nuffield Department of Clinical Neurosciences John Radcliffe Hospital, University of Oxford Oxford UK.
authors.forename: Patrick
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authors.lastname: Waters
authors.affiliation: Nuffield Department of Clinical Neurosciences John Radcliffe Hospital, University of Oxford Oxford UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Nowak
authors.affiliation: Department of Neurology Yale School of Medicine New Haven Connecticut.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor