Details

Autor(en) / Beteiligte

• Vander Heiden, Jason A
• Stathopoulos, Panos
• Zhou, Julian Q
• Chen, Luan
• Gilbert, Tamara J
• Bolen, Christopher R
• Barohn, Richard J
• Dimachkie, Mazen M
• Ciafaloni, Emma
• Broering, Teresa J
• Vigneault, Francois
• Nowak, Richard J
• Kleinstein, Steven H
• O'Connor, Kevin C

Titel

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

Ist Teil von

• The Journal of immunology (1950), 2017-02, Vol.198 (4), p.1460-1473

Ort / Verlag

United States: American Association of Immunologists

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 V and V sequences from sorted naive and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both V and V 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 V CDR and altered V CDR3 physicochemical properties. The V repertoire of MuSK-MG was specifically characterized by reduced V-J segment distance in recombined sequences, suggesting diminished V 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.