scholarly journals Breakdown of B cell tolerance in a mouse model of systemic lupus erythematosus.

1995 ◽  
Vol 181 (3) ◽  
pp. 1157-1167 ◽  
Author(s):  
J H Roark ◽  
C L Kuntz ◽  
K A Nguyen ◽  
A J Caton ◽  
J Erikson
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Tolerance ◽  
Systemic Lupus ◽  
B Cell Tolerance ◽  
Dna Antibodies

Anti-DNA antibodies, specifically those that stain nuclei in a homogenous nuclear (HN) fashion, are diagnostic of systemic lupus erythematosus (SLE) and the MRL-lpr/lpr SLE murine model. We have used a heavy chain transgene that increases the frequency of anti-HN antibodies to address whether their production in SLE is the consequence of a defect in B cell tolerance. Anti-HN B cells were undetectable in nonautoimmune-prone transgenic mice, but in MRL-lpr/lpr transgenic mice their Ig was evident in the sera and they were readily retrievable as hybridomas. We conclude that nonautoimmune animals actively delete anti-HN-specific B cells, and that MRL-lpr/lpr mice are defective in this process possibly because of the lpr defect in the fas gene.

scholarly journals Balancing diversity and tolerance

2005 ◽  
Vol 202 (3) ◽  
pp. 341-344 ◽  
Author(s):  
Annett M. Jacobi ◽  
Betty Diamond
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Tolerance ◽  
Systemic Lupus ◽  
Cell Repertoire ◽  
B Cell Tolerance ◽  
Repertoire Selection ◽  
B Cell Repertoire ◽  
Disease Systemic Lupus Erythematosus

The autoimmune disease systemic lupus erythematosus (SLE) is caused by a failure of B cell tolerance. Recent studies in mouse models of SLE have identified several distinct tolerance checkpoints that must each function appropriately to protect against disease. However, studies of B cell repertoire selection in humans are essential to understand which checkpoints are defective in human autoimmune diseases.

scholarly journals AB0140 BAFF NEUTRALIZATION HAS JANUS-FACED EFFECT ON ATHEROSCLEROSIS ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1370.3-1370
Author(s):  
F. Saidoune ◽  
N. Charles ◽  
J. Chezel ◽  
B. Escoubet ◽  
T. Papo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Intima Media Thickness ◽  
The Body ◽  
Systemic Lupus ◽  
Media Thickness ◽  
Cholesterol Levels

Background:Cardiovascular diseases (CVD) are the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus and anti-BAFF therapy has been approved in SLE. Since mature B cells also promote atherosclerosis, BAFF neutralization is expected to have an atheroprotective effect in SLE.Objectives:The aim of our study was to test this hypothesis using a new mouse model with a mix susceptibility to lupus and atherosclerosis that received or not an anti-BAFF treatment, and in a cohort of SLE patients in whom we monitored carotid plaques, the B cell compartment and BAFF levels.Methods:The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis- and lupus-proneApoe°D227Kmouse model and in a cohort of SLE patients. Mice were treated with a blocking anti-BAFF monoclonal antibody (Ab), while fed with a standard chow diet. Carotid plaque and carotid intima media thickness were assessed by ultrasound at baseline and during follow-up in SLE patients asymptomatic for CVD.Results:Anti-BAFF Ab inApoe°D227Kmice i/ induced a B cell depletion, ii/ efficiently treated lupus, iii/improved atherosclerosis lesions in mice that had low plasma cholesterol levels but worsened the lesions in mice with high cholesterol levels. In that case, the atheroprotective effect of the BAFF-BAFFR signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF-TACI signaling inhibition on macrophages. In SLE patients, BAFF blood levels were associated with subclinical atherosclerosis. Anti-BAFF Ab treatment had a differential effect on the intima media thickness progression in SLE patients depending on the body mass indexConclusion:Depending on the balance between metabolic- and B cell-induced proatherogenic conditions, anti-BAFF could be respectively detrimental or beneficial on atherosclerosis development in SLEAcknowledgments:Guillaume Even, Yasmine Lamri, Anh-Thu Gaston,Disclosure of Interests:Fanny Saidoune Grant/research support from: supported by a research partnerships between the academic and GlaxoSmithKline France.Anti-BAFF mAb (IgG1, clone 10F4B) in mice was provided by Glaxosmithkline, Nicolas Charles: None declared, Julie Chezel: None declared, Brigitte Escoubet: None declared, Thomas Papo: None declared, Antonino Nicoletti: None declared, karim sacre: None declared

scholarly journals OP0073 SINGLE-CELL TRANSCRIPTOMICS UNCOVERS DEFECTIVE BONE MARROW EARLY B CELL DEVELOPMENT IN A SUBSET OF LUPUS PATIENTS ASSOCIATED WITH AGGRAVATED INFLAMMATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 39.2-39
Author(s):  
C. Dong ◽  
X. Gu ◽  
J. Ji ◽  
X. Zhang ◽  
Z. Gu
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Tolerance ◽  
Systemic Lupus ◽  
B Cell Tolerance ◽  
Healthy Donors

Background:Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that occurs when the body’s immune system attacks own tissues and organs. B cells play a central role in SLE pathogenesis by producing autoantibodies as well as antibody-independent functions. Peripheral B cell abnormality is well known in lupus patients such as expansions of plasmablasts and atypical memory B cells, which are associated with active diseases. However, little is known about the B cell development in the bone marrow of lupus patients.Objectives:We conduct this survey to explore the disorder of the B cell development in the bone marrow of lupus patients.Methods:In this study, we have performed the scRNASeq to profile the bone marrow B cell compartment in lupus patients and healthy donors.Results:We identified that in a subset of lupus patients, the early B cells (proB and preB cells) were strongly decreased, which were confirmed by flow cytometry in an expanded cohort. Furthermore, bone marrow B cells from these patients showed a strong proinflammatory signature revealed by pathway analysis. Interestingly, BCR repertoire analysis showed that the IGHV-4-34 was highly enriched in these patients, indicating an enhanced B cell tolerance defect. Finally, a panel of proinflammatory cytokines (TNF-a, IL-1a, IL-12p70, IFN-g, et al.) were strongly increased in the bone marrow plasma of these patients compared with early B normal patients and healthy donors, confirming a localized proinflammatory microenvironment.Conclusion:Altogether, the current study has revealed that a defective early B cell development in lupus patients is associated with a more severe B cell tolerance defect and aggravated inflammation, which may shed new light on developing novel therapies by targeting relevant pathways.References:[1]Min Wang, Hua Chen, Jia Qiu, et al. Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development. J Autoimmun 2020.[2]A M Jacobi, D M Goldenberg, F Hiepe, et al. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann Rheum Dis, 2008.Acknowledgements:This work was funded by Special project of clinical medicine of Nantong University (Grant/Award number: 2019LQ001), National Natural Science Foundation of China (Grant/Award number: 81671616, 81871278 and 82071838).Disclosure of Interests:None declared

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