Transitional B cells in quiescent SLE: An early checkpoint imprinted by IFN

• Published in: Journal of autoimmunity Vol. 102; pp. 150 - 158
• Main Authors: Dieudonné, Yannick, Gies, Vincent, Guffroy, Aurélien, Keime, Céline, Bird, Anna K., Liesveld, Jane, Barnas, Jennifer L., Poindron, Vincent, Douiri, Nawal, Soulas-Sprauel, Pauline, Martin, Thierry, Meffre, Eric, Anolik, Jennifer H., Korganow, Anne-Sophie
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2019; Elsevier
• Subjects: CD19; Cellular Biology; Interferon; Life Sciences; Systemic lupus erythematosus; TLR9; Transitional B cells; TLR9; Interferon; Systemic lupus erythematosus; CD19; Transitional B cells
• ISSN: 0896-8411; 1095-9157; 1095-9157
• DOI: 10.1016/j.jaut.2019.05.002

Systemic lupus (SLE) is characterized by a break of B cell tolerance that plays a central role in disease pathophysiology. An early checkpoint defect occurs at the transitional stage leading to the survival of autoreactive B cells and consequently the production of pathogenic autoantibodies. The main purpose of our work was to determine whether transitional B cells, as the most immature naïve B cell subset upstream of pathogenic B cells, display specific features compared to healthy non SLE subjects. Through extensive analysis of transitional B cells from untreated or low treated, mostly Caucasian, SLE patients, we demonstrated that transitional (T1 and T2) B cell frequencies were increased in SLE and positively correlated with disease activity. SLE transitional B cells displayed defects in two closely inter-related molecules (i.e. TLR9 defective responses and CD19 downregulation). RNA sequencing of sorted transitional B cells from untreated patients revealed a predominant overexpression of interferon stimulated genes (ISGs) even out of flares. In addition, early transitional B cells from the bone marrow displayed the highest interferon score, reflecting a B cell interferon burden of central origin. Hence, the IFN signature in transitional B cells is not confined to African American SLE patients and exists in quiescent disease since the medullary stage. These results suggest that in SLE these 3 factors (i.e. IFN imprintment, CD19 downregulation and TLR9 responses impairment) could take part at the early transitional B cell stage in B cell tolerance by-pass, ultimately leading in periphery to the expansion of autoantibodies-secreting cells. •SLE transitional B cells display CD19 downregulation and impaired TLR9 response.•IFN signature exists since the B-cell medullary stage, even out of flares.•IFN signature in transitional B cells is not confined to African American SLE.•IFN score correlates with the increase in peripheral transitional B cells.