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

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.

SUBMITTER: Dieudonne Y

PROVIDER: S-EPMC6642027 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Dieudonné Yannick Y Gies Vincent V Guffroy Aurélien A Keime Céline C Bird Anna K AK Liesveld Jane J Barnas Jennifer L JL Poindron Vincent V Douiri Nawal N Soulas-Sprauel Pauline P Martin Thierry T Meffre Eric E Anolik Jennifer H JH Korganow Anne-Sophie AS

Journal of autoimmunity 20190510

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 subj ...[more]

PMID: 31085070

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Project description:BackgroundPatients with SLE display marked clinical and immunlogical heterogeneity. The purpose of the study was to investigate patterns of serum cytokines in patients with active and stable systemic lupus erythematosus (SLE) and to determine how they relate to clinical phenotype.MethodsSerum levels of 10 cytokines were measured retrospectively in a cohort of patients with SLE and in healthy controls using a high-sensitivity multiplex bead array. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG-2004) indices. Logistic regression models were used to determine the association between cytokine levels and active SLE. Principal component analysis (PCA) and cluster analysis was then used to identify subgroups of patients on the basis of cytokine levels.ResultsSerum chemokine (C-X-C motif) ligand 10 (CXCL10) and CXCL13 were significantly higher in patients with SLE compared to healthy controls. Two cytokines (pentraxin-related protein (PTX3) and CXCL10) were significantly higher in patients with active disease after adjustment for potential confounding factors. Measurement of four cytokines (CXCL10, IL-10, IL-21 and PTX3) significantly improved the performance of a model to identify patients with clinically active disease. Cluster analysis revealed that the patients formed 3 distinct groups, characterised by higher levels of interferon alpha (IFN?) and B lymphocyte stimulator (BLyS) (group 1), increased CXCL10 and CXCL13 (group 2) or low levels of cytokines (group 3). Group 2 had significantly lower serum complement and higher anti-double-stranded DNA antibodies and increased prevalence of inflammatory arthritis.ConclusionsMultiplex analysis has identified a serum cytokine signature for active SLE. Within the SLE population distinct cytokine subgroups were identified, with differing clinical and immunological phenotypes that appeared stable over time. Assessment of cytokine profiles may reveal unique insights into disease heterogeneity.

Project description:Background/objectiveType-I interferons contribute to pathogenesis in systemic lupus erythematosus, including nephritis. Interferons consist of a family of 16 proteins yet are often characterized in patients without knowledge of the specific interferon subtypes involved. Different interferons may function in the kidneys, and other organs, relative to what is often measured in patient blood. Moreover, antibodies to interferons may potentially modulate systemic or organ-specific interferon activity. The aim of this study was to characterize global interferon activity levels and identify autoantibodies to the 12 interferon α subtypes in patient serum and urine.MethodsInterferon activity levels in serum and urine were measured using an interferon bioassay. Anti-interferon and anti-cytokine autoantibodies were measured by ELISA. Serum and urine samples were also characterized for their ability to neutralize the biological activity of exogenously added interferons.ResultsSerum interferon activity was increased in 62% of systemic lupus erythematosus patient samples, relative to healthy donor controls, whereas binding interferon α autoantibodies to at least one interferon α subtype were found in 68% of the samples evaluated. High Systemic Lupus Erythematosus Disease Activity Index scores were significantly (p = 0.001) associated with patient samples containing interferon α autoantibodies to three or more interferon α subtypes in their serum. Interferon α autoantibodies that potently block interferon activity were rare (∼5% of samples), but collectively bound to all 12 interferon α subtypes. Urine interferon activity and interferon α autoantibody profiles did not correlate with their serum counterparts, suggesting immune responses in systemic lupus erythematosus kidneys can be distinct from those measured in serum. Analysis of autoantibodies to 15 additional cytokines in serum identified higher frequencies of granulocyte-macrophage colony-stimulating factor and interleukin 17A autoantibodies, suggesting these signaling pathways may potentially contribute, with interferons, to systemic lupus erythematosus pathogenesis.ConclusionsThe measurement of autoantibodies to multiple interferon subtypes in serum and urine may provide an alternative method for following interferon-mediated systemic lupus erythematosus disease activity. The results suggest autoantibodies might be used for patient monitoring and/or identifying additional cytokine signaling pathways that are functioning in different systemic lupus erythematosus patients.

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

Publications

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

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