期刊
JOURNAL OF AUTOIMMUNITY
卷 102, 期 -, 页码 150-158出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2019.05.002
关键词
Systemic lupus erythematosus; Transitional B cells; Interferon; CD19; TLR9
类别
资金
- National Institutes of Health Clinical and Translational Science Award [5UL1TR000042-10]
- Center for Musculoskeletal Research Training Grant [2 T32AR053459]
- Rheumatology Research Foundation (RRF) Scientist Development Award
- French Ministry of Health [PHRC IR 2011]
- Societe Nationale Francaise de Medecine Interne (SNFMI)
- Hopitaux Universitaires de Strasbourg (HUS)
- EU
- NIAMS Accelerated Medicines Partnership [1UH2AR067690]
- Bertha and Louis Weinstein research fund
- [AI563262]
- [A1078907]
- [AR071670]
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 naive 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 down regulation). 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.
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