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J Autoimmun. 2019 Aug;102:150-158. doi: 10.1016/j.jaut.2019.05.002. Epub 2019 May 10.

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

Author information

1
CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
2
Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR - S1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Service d'Immunologie Biologique, Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
3
CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; UFR Médecine, Université de Strasbourg, Strasbourg, France.
4
IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM, U1258, CNRS, UMR7104, Université de Strasbourg, Illkirch, France.
5
Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
6
Blood and Marrow Stem Cell Transplant Program, Department of Internal Medicine and The James P. Wilmot Cancer Center, University of Rochester, New York 14642, USA.
7
Department of Infectious Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
8
CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; UFR Sciences pharmaceutiques, Université de Strasbourg, Illkirch-Graffenstaden, France.
9
Departement of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
10
CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; UFR Médecine, Université de Strasbourg, Strasbourg, France. Electronic address: korganow@unistra.fr.

Abstract

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.

KEYWORDS:

CD19; Interferon; Systemic lupus erythematosus; TLR9; Transitional B cells

PMID:
31085070
PMCID:
PMC6642027
[Available on 2020-08-01]
DOI:
10.1016/j.jaut.2019.05.002

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