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Lee JY, Stathopoulos P, Gupta S, et al. Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Ann Clin Transl Neurol. 2016;3(6):443-54doi: 10.1002/acn3.311.
Lee, J. Y., Stathopoulos, P., Gupta, S., Bannock, J. M., Barohn, R. J., Cotzomi, E., Dimachkie, M. M., Jacobson, L., Lee, C. S., Morbach, H., Querol, L., Shan, J. L., Vander Heiden, J. A., Waters, P., Vincent, A., Nowak, R. J., & O'Connor, K. C. (2016). Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Annals of clinical and translational neurology, 3(6), 443-54. https://doi.org/10.1002/acn3.311
Lee, Jae-Yun, et al. "Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis." Annals of clinical and translational neurology vol. 3,6 (2016): 443-54. doi: https://doi.org/10.1002/acn3.311
Lee JY, Stathopoulos P, Gupta S, Bannock JM, Barohn RJ, Cotzomi E, Dimachkie MM, Jacobson L, Lee CS, Morbach H, Querol L, Shan JL, Vander Heiden JA, Waters P, Vincent A, Nowak RJ, O'Connor KC. Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Ann Clin Transl Neurol. 2016 Apr 27;3(6):443-54. doi: 10.1002/acn3.311. eCollection 2016 Jun. PMID: 27547772; PMCID: PMC4891998.
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Ann Clin Transl Neurol. 2016 Apr 27;3(6):443-54. doi: 10.1002/acn3.311. eCollection 2016 Jun.

Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis.

Annals of clinical and translational neurology

Jae-Yun Lee, Panos Stathopoulos, Sasha Gupta, Jason M Bannock, Richard J Barohn, Elizabeth Cotzomi, Mazen M Dimachkie, Leslie Jacobson, Casey S Lee, Henner Morbach, Luis Querol, Jing-Li Shan, Jason A Vander Heiden, Patrick Waters, Angela Vincent, Richard J Nowak, Kevin C O'Connor

Affiliations

  1. Department of Neurology Yale School of Medicine New Haven Connecticut.
  2. Department of Immunobiology Yale School of Medicine New Haven Connecticut.
  3. Department of Neurology University of Kansas Medical Center Kansas City Kansas.
  4. Nuffield Department of Clinical Neurosciences John Radcliffe Hospital, University of Oxford Oxford UK.
  5. Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau Universitat Autónoma de Barcelona Spain.
  6. Interdepartmental Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut.

PMID: 27547772 PMCID: PMC4891998 DOI: 10.1002/acn3.311

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.

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.

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