scholarly journals Regulation of Anti-DNA B Cells in Recombination-activating Gene–deficient Mice

1998 ◽  
Vol 188 (7) ◽  
pp. 1247-1254 ◽  
Author(s):  
Hui Xu ◽  
Hui Li ◽  
Elisabeth Suri-Payer ◽  
Richard R. Hardy ◽  
Martin Weigert
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Bone Marrow ◽  
B Cells ◽  
Lupus Erythematosus ◽  
High Concentration ◽  
Systemic Lupus ◽  
Normal Individuals ◽  
Recombination Activating Gene ◽  
Dna Antibodies ◽  
Deficient Mice

Anti-DNA antibodies are regulated in normal individuals but are found in high concentration in the serum of systemic lupus erythematosus (SLE) patients and the MRL lpr/lpr mouse model of SLE. We previously studied the regulation of anti–double-stranded (ds)DNA and anti–single-stranded (ss)DNA B cells in a nonautoimmune background by generating mice carrying immunoglobulin transgenes coding for anti-DNAs derived from MRL lpr/lpr. Anti-dsDNA B cells undergo receptor editing, but anti-ssDNA B cells seem to be functionally silenced. Here we have investigated how anti-DNA B cells are regulated in recombination- activating gene (RAG)-2−/− mice. In this setting, anti-dsDNA B cells are eliminated by apoptosis in the bone marrow and anti-ssDNA B cells are partially activated.

scholarly journals IMMUNOLOGICAL STUDIES CONCERNING THE NEPHRITIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

1967 ◽  
Vol 126 (4) ◽  
pp. 607-624 ◽  
Author(s):  
David Koffler ◽  
Peter H. Schur ◽  
Henry G. Kunkel
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Antinuclear Antibodies ◽  
Specific Activity ◽  
High Specific Activity ◽  
High Concentration ◽  
Systemic Lupus ◽  
Complex Hypothesis ◽  
Antibody Complex ◽  
Dna Antibodies

Antibodies were eluted from the isolated glomeruli prepared from the kidneys of 10 patients with the nephritis of systemic lupus erythematosus. Antibodies reacting primarily with buffer extracts of nuclei were eluted by acid treatment, and antibodies reacting mainly with DNA and nucleoprotein were eluted with deoxyribonuclease. Quantitative immunochemical studies revealed a high concentration of antinuclear antibody per milligram of γ-globulin in glomerular eluates compared with that in the corresponding serums. The γ-globulin of two eluates was found to consist predominantly of antinucleoprotein antibody. The selective elution of antinuclear antibodies was also indicated by the absence of other serum antibodies in the eluates. DNA antigen was demonstrated in the glomeruli of two kidneys with nephritis by means of isolated anti-DNA antibody labeled with fluorescein. In one of these cases, anti-DNA antibodies were also found concentrated in the glomeruli and, in the second, circulating anti-DNA antibodies were demonstrated in the patient's serum. The immunochemical evidence for the high specific activity of antinuclear antibodies and the association of DNA antigen with DNA antibody in glomeruli add further support for the antigen-antibody complex hypothesis for renal injury in systemic lupus erythematosus.

scholarly journals MRL-lpr/lpr Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti–double-stranded DNA B Cells

1999 ◽  
Vol 189 (11) ◽  
pp. 1799-1814 ◽  
Author(s):  
Laura Mandik-Nayak ◽  
Su-jean Seo ◽  
Caroline Sokol ◽  
Kathryn M. Potts ◽  
Anh Bui ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Genetic Background ◽  
Systemic Lupus ◽  
Autoreactive B Cells ◽  
Developmental Arrest ◽  
Double Stranded Dna ◽  
Dna Antibodies ◽  
Cell Defect

A hallmark of systemic lupus erythematosus and the MRL murine model for lupus is the presence of anti–double-stranded (ds)DNA antibodies (Abs). To identify the steps leading to the production of these Abs in autoimmune mice, we have compared the phenotype and localization of anti-dsDNA B cells in autoimmune (MRL+/+ and lpr/lpr) mice with that in nonautoimmune (BALB/c) mice. Anti-dsDNA B cells are actively regulated in BALB/c mice as indicated by their developmental arrest and accumulation at the T–B interface of the splenic follicle. In the MRL genetic background, anti-dsDNA B cells are no longer developmentally arrested, suggesting an intrinsic B cell defect conferred by MRL background genes. With intact Fas, they continue to exhibit follicular exclusion; however, in the presence of the lpr/lpr mutation, anti-dsDNA B cells are now present in the follicle. Coincident with the altered localization of anti-dsDNA B cells is a follicular infiltration of CD4 T cells. Together, these data suggest that MRL mice are defective in maintaining the developmental arrest of autoreactive B cells and indicate a role for Fas in restricting entry into the follicle.

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 THU0044 SINGLE CELL ANALYSIS OF BONE MARROW AND PERIPHERAL ALTERED B CELL DIFFERENTIATION IN PATIENTS WITH ACTIVE SLE AND THE MECHANISM OF ABNORMAL EARLY B CELL DEVELOPMENT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 234.3-235
Author(s):  
T. Fu ◽  
Y. Yang ◽  
X. Gu ◽  
C. Dong ◽  
R. Zhao ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:B cell differentiation and dysfunction play a key role in the pathogenesis of Systemic lupus erythematosus (SLE). Bone marrow (BM) is the development organ of B cells, and also the home and residence place of plasma cells and memory B cells. However, there is a lack of studies on B cells in BM with lupus.Objectives:To map the development of BM and peripheral B cells and investigate the mechanism of abnormal early B cell development in SLE.Methods:A total of 11 SLE patients and 5 age- and sex-matched controls were recruited.BM and peripheral B cell subsets were measured by flow cytometry. sorting-purified B cell subsets were subject toSingle-cell RNA sequencing (scRNA-seq) and functional studies. Plasma cytokines and secreted immunoglobulins were detected by Luminex or ELISA. Disease activity of SLE patients was measured using the SLE Disease Activity Index (SLEDAI).Results:In the present study, we find out that the percentage of monocytes in MNC (p=0.070) and plasma cells(p=0.001)in CD19+ were significantly decreased in BM of SLE, compared to healthy controls. While, SLE patients had increased T%MNC(p=0.008) and B%CD19+(p=0.002) in BM that controls. In detail, the B cell subsets of bone marrow in patients with active lupus (SLEDAI≥8 score) were seriously disordered, showing the increasing T%MNC(p=0.049), propre-B%CD19+ (p=0.006)and immature B cell%CD19+ (p=0.010) than healthy donors. propre-B%CD19+ exhibited good relationship with SLEDAI. By integrating single B cell expression profiling and repertoire analysis, we map the development of B cells in BM and peripheral and pathogenic characteristics of early B cells, especially propre-B.Conclusion:These findings demonstrated that early B cells in BM, especially propre-B are abnormally differentiated with dysregulations. BM is an important organ targeted by SLE. This studyis not only to clarify the internal mechanism of the disorder of differentiation of B cells, but also to provide new clues for the targeted diagnosis and treatment of SLE.References:[1]Palanichamy, A., et al.,Neutrophil-mediated IFN activation in the bone marrow alters B cell development in human and murine systemic lupus erythematosus.J Immunol, 2014.192(3): p. 906-18.[2]Papadaki, H.A., J.C. Marsh, and G.D. Eliopoulos,Bone marrow stem cells and stromal cells in autoimmune cytopenias.Leuk Lymphoma, 2002.43(4): p. 753-60.[3]Karrar, S. and D.S. Cunninghame Graham,Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us.Arthritis Rheumatol, 2018.70(4): p. 496-507.[4]Woods, M., Y.R. Zou, and A. Davidson,Defects in Germinal Center Selection in SLE.Front Immunol, 2015.6: p. 425.[5]Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients.Cell Signal, 2012.24(12): p. 2307-14.Disclosure of Interests:None declared

Author response for "Dnase1 -deficient mice spontaneously develop a Systemic Lupus Erythematosus-like disease"

2018 ◽  
Author(s):  
Elaine F. Kenny ◽  
Bärbel Raupach ◽  
Ulrike Abu Abed ◽  
Volker Brinkmann ◽  
Arturo Zychlinsky
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Author Response ◽  
Systemic Lupus ◽  
Deficient Mice
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