Anti-topoisomerase, but not anti-centromere B cell responses in systemic sclerosis display active, Ig-secreting cells associated with lung fibrosis

OBJECTIVES: Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these phenotypes are ill-defined. To understand how B cell autoreactivity and disease pathology connect, we determined phenotypic and functional characteristics of autoreactive B cells in ATA-positive and ACA-positive patients. METHODS: Levels and isotypes of autoantibodies secreted by ex vivo cultured peripheral blood mononuclear cells from patients with ATA-positive (n=22) and ACA-positive (n=20) SSc were determined. Antibody secreting cells (ASCs) were isolated by cell sorting and cultured separately. Correlations were studied between the degree of spontaneous autoantibody production and the presence and degree of interstitial lung disease (ILD). RESULTS: Circulating B cells secreting either ATA-immunoglobulin G (IgG) or ACA-IgG on stimulation was readily detectable in patients. The ATA response, but not the ACA response, showed additional secretion of autoreactive IgA. ATA-IgG and ATA-IgA were also secreted spontaneously. Additional cell sorting confirmed the presence of ATA-secreting plasmablasts. The degree of spontaneous ATA-secretion was higher in patients with ILD than in those without (p<0.001) and correlated with the degree of pulmonary fibrosis (p<0.001). CONCLUSION: In contrast to ACA-positive patients, ATA-positive patients show signs of recent activation of the B cell response that hallmarks this disease. The degree of activation correlates with the presence and severity of ILD, the most deleterious disease manifestation. This could explain differential responsiveness to B cell depleting therapy. The abundant and spontaneous secretion of ATA-IgG and ATA-IgA may point toward a continuously activating trigger.