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J Immunol. 2017 Feb 15;198(4):1460-1473. doi: 10.4049/jimmunol.1601415. Epub 2017 Jan 13.

Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing.

Author information

1
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511.
2
Department of Neurology, Yale School of Medicine, New Haven, CT 06511.
3
AbVitro, Inc., Boston, MA 02210.
4
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
5
Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160.
6
Department of Neurology, University of Rochester School of Medicine, Rochester, NY 14642.
7
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511; kevin.oconnor@yale.edu steven.kleinstein@yale.edu.
8
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06511; and.
9
Department of Pathology, Yale School of Medicine, New Haven, CT 06511.
10
Department of Neurology, Yale School of Medicine, New Haven, CT 06511; kevin.oconnor@yale.edu steven.kleinstein@yale.edu.

Abstract

Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20-50 people per 100,000. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK-MG). The autoantibodies are pathogenic, but whether their generation is associated with broader defects in the B cell repertoire is unknown. To address this question, we performed deep sequencing of the BCR repertoire of AChR-MG, MuSK-MG, and healthy subjects to generate ∼518,000 unique VH and VL sequences from sorted naive and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both VH and VL sequences within the naive and memory compartments. The memory compartment of AChR-MG was further characterized by reduced positive selection of somatic mutations in the VH CDR and altered VH CDR3 physicochemical properties. The VL repertoire of MuSK-MG was specifically characterized by reduced V-J segment distance in recombined sequences, suggesting diminished VL receptor editing during B cell development. Our results identify large-scale abnormalities in both the naive and memory B cell repertoires. Particular abnormalities were unique to either AChR-MG or MuSK-MG, indicating that the repertoires reflect the distinct properties of the subtypes. These repertoire abnormalities are consistent with previously observed defects in B cell tolerance checkpoints in MG, thereby offering additional insight regarding the impact of tolerance defects on peripheral autoimmune repertoires. These collective findings point toward a deformed B cell repertoire as a fundamental component of MG.

PMID:
28087666
PMCID:
PMC5296243
DOI:
10.4049/jimmunol.1601415
[Indexed for MEDLINE]
Free PMC Article

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