Defective Early B Cell Tolerance Checkpoints in Patients With Systemic Sclerosis Allow the Production of <scp>Self Antigen</scp>–Specific Clones
Salomé Glauzy, Brennan Olson, Christopher May, Daniele Parisi, Christopher Massad, James E. Hansen, Changwan Ryu, Erica L. Herzog, Eric Meffre
Abstract
OBJECTIVE: Early selection steps preventing autoreactive naive B cell production are often impaired in patients with autoimmune diseases, but central and peripheral B cell tolerance checkpoints have not been assessed in patients with systemic sclerosis (SSc). This study was undertaken to characterize early B cell tolerance checkpoints in patients with SSc. METHODS: CD27- new emigrant/transitional B cells and 190 CD19+CD21+CD10-IgM+CD27- mature naive B cells from 10 patients with SSc. RESULTS: Compared to serum from healthy donors, serum from patients with SSc displayed elevated proportions of polyreactive and antinuclear-reactive new emigrant/transitional B cells that recognize topoisomerase I, suggesting that defective central B cell tolerance contributes to the production of serum autoantibodies characteristic of the disease. Frequencies of autoreactive mature naive B cells were also significantly increased in SSc patients compared to healthy donors, thus indicating that a peripheral B cell tolerance checkpoint may be impaired in SSc. CONCLUSION: Defective counterselection of developing autoreactive naive B cells in SSc leads to the production of self antigen-specific B cells that may secrete autoantibodies and allow the formation of immune complexes, which promote fibrosis in SSc.