Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Molecular basis of 9G4 B cell autoreactivity in human SLE

ABSTRACT: 9G4+ IgG antibodies expand in SLE in a disease specific fashion and react with different lupus antigens including B cell antigens and apoptotic cells. Their shared use of VH4-34 represents a unique system to understand the molecular basis of lupus autoreactivity. Understanding the participation of apoptotic cells, a rich source of self-antigens including chromatin, in the diversification and selection of autoreactive memory B cells is particularly important in SLE where these cells accumulate in the germinal centers and may activate pathogenic autoreactive B cells. Our findings indicate that the three mabs with strong apoptotic binding recognized chromatin and individual histones as documented by glomerular proteome microarrays. While the actual antigens mediating APCB remain to be formally elucidating, our initial studies indicate that binding to histone/chromatin may mediate such autoreactivity in at least a fraction of these antibodies

ORGANISM(S): Mus musculus Rattus norvegicus Homo sapiens

PROVIDER: GSE50609 | GEO | 2013/09/05

SECONDARY ACCESSION(S): PRJNA218077

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Molecular basis of 9G4 B cell autoreactivity in human SLE

Project description:9G4+ IgG antibodies expand in SLE in a disease specific fashion and react with different lupus antigens including B cell antigens and apoptotic cells. Their shared use of VH4-34 represents a unique system to understand the molecular basis of lupus autoreactivity. Understanding the participation of apoptotic cells, a rich source of self-antigens including chromatin, in the diversification and selection of autoreactive memory B cells is particularly important in SLE where these cells accumulate in the germinal centers and may activate pathogenic autoreactive B cells. Our findings indicate that the three mabs with strong apoptotic binding recognized chromatin and individual histones as documented by glomerular proteome microarrays. While the actual antigens mediating APCB remain to be formally elucidating, our initial studies indicate that binding to histone/chromatin may mediate such autoreactivity in at least a fraction of these antibodies Single VH4-34 B cells sorted from IgD-CD27+ memory B cells of SLE patient are sorted and single -RT-PCR is performed to generate monoclonal antibody. 3 monoclonals which were strong apoptotic binders tested for protein array against Chromatin, Histone1, Histone 2A, Histone 2B, Histone 3, Histone 4 and total histones

2013-09-05 | E-GEOD-50609 | biostudies-arrayexpress

Neoself-antigens are the primary target for autoreactive T cells in human lupus

Project description:Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE.

2024-08-13 | GSE214855 | GEO

Neoself-antigens are the primary target for autoreactive T cells in human lupus

2024-08-13 | GSE265793 | GEO

Allelic Polymorphism Gates Autoreactivity and Vaccine-Elicitation of Human Broadly Neutralizing Antibodies Against Influenza Virus

Project description:Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of group 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine (F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstrate that both alleles encode for human IAV bnAbs that employ structurally convergent modes of contact to the same epitope. To resolve differences in lineage-expandability, we compared F54 vs L54 as substrate within humanized mice where antibodies develop with human-like CDRH3 diversity but are restricted to single VH-genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supported elicitation of heterosubtypic serum bnAbs following immunization with a stalk-only nanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cells and autoreactive stalk antibodies that were cleared from B cell memory. Moreover, human stalk antibodies also demonstrated L54-dependent autoreactivity. IGHV1-69 polymorphism, which is skewed ethnically, therefore gates tolerance and vaccine-expandability of influenza bnAbs.

2022-07-02 | GSE207054 | GEO

Single cell RNA sequencing of femur bone marrow cells from the NZBWF1 systemic lupus erythematosus mouse model and its progenitors.

Project description:Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by failure of self-tolerance mechanisms and the resultant production of autoreactive antibodies. The NZBWF1 mouse spontaneously develops a lupus-like syndrome and is used as model of SLE. The NZBWF1 model represents the F1 generation of a cross between New Zealand Black (NZB) and New Zealand White (NZW) mice. In this study we investigated the model and its progenitors (NZB, NZW) gene expression with single cell RNA sequencing on cells isolated from bone marrow and processed with the 10X Chromium.

2021-05-20 | GSE174728 | GEO

Single cell Ig VDJ sequencing (10X Genomics) of human blood B cells from SLE pateints and healthy controls

Project description:B cells positive for Ig kappa and Ig lambda are observed by flow cytometry in one fourth of patients with Systemic Lupus Erythematosus (SLE). Single cell Ig VDJ sequencing (10X Genomics) reveals that kappa/lambda B cells are at the same frequency (about 1.5%) in these SLE patients as in healthy controls. Cells observed by flow cytometry are instead decorated with VH4-34 IgM (kappa or lambda) autoantibodies that are present in some but not all SLE patients.

2022-01-26 | GSE183051 | GEO

Smith-specific regulatory T cells halt the progression of lupus nephritis

Project description:Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. We identified a novel HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identified high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduced our lead Sm-specific TCR onto Tregs derived from patients with SLE who were anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppressed Sm-specific pro-inflammatory responses in vitro and suppressed disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

2023-11-28 | GSE242152 | GEO

Investigating the effect of NIK SMI1, a small molecule inhibitor of NIK, on TWEAK-stimulated Mouse renal proximal tubule-interstitial epithelial cells (RPTEC)

Project description:Systemic lupus erythematosus (SLE) is often considered a disease driven by autoreactive B cells and anti-nuclear antibodies. However, therapeutic targeting of B cells, for example through BAFF blockade, has been only partially effective in SLE. NF-κB Inducing Kinase (NIK) mediates non-canonical NF-κB signaling downstream of disease relevant TNF family members, such as BAFF, TWEAK, CD40, and OX40. We hypothesized that NIK inhibition might be more efficacious than BAFF blockade in lupus, and therefore generated highly selective and potent small molecule inhibitors (SMI) of NIK to test this hypothesis. RNASeq was used to investigate the effects of one of these SMIs of NIK, NIK SMI1, on TWEAK-stimulated Mouse renal proximal tubule-interstitial epithelial cells (RPTEC).

2017-10-26 | GSE89195 | GEO

Complement C3 deposition on nucleic acids is characteristic of immune complex initiated classical pathway overdrive in lupus erythematosus

Project description:Systemic lupus erythematosus is progressive, immune complex-mediated autoimmune disease targeting numerous organs. A central feature of the disease is the development of antibodies against nuclear components, including DNA. Antibodies against double-stranded DNA are so characteristic of this disease that their detection constitutes one of the criteria for diagnosis. We examined the formation of immune complexes on the surface of autoantigen microarrays incubated in the sera of 39 inactive and 22 active lupus patients and of 31 control subjects. Three different kinds of nucleic acids, dsDNA, ssDNA and RNA were used as antigens, along with chromatin (nucleosomal extract) and several other reference molecules. The composition with respect to IgG, IgM and complement components C3 and C4 was determined. We find that while IgM and C4 are physiological components of immune complexes formed from nucleic acids, both IgG and C3 are extremely characteristic of lupus patients. Complement C4 deposition changes were not consistent: these increased on ssDNA and RNA, decreased on chromatin and did not change significantly on dsDNA. The presence of IgG and C3 in the immune complexes formed from different nucleic acids was characteristic for both active and inactive lupus patients. Receiver-operating curve statistics indicate that C3 deposition measurements can improve the efficiency of identification of inactive lupus patients. These observations reveal the complexity of immune profile changes accompanying SLE. C3, IgM, C4 and IgG binding in 92 human serum samples were examined using custom-made protein arrays

2012-09-30 | E-GEOD-26768 | biostudies-arrayexpress

Pre-B cell leukemia homeobox protein Pbx1 is associated with lupus susceptibility in mice and humans

Project description:Sle1a.1 is part of the Sle1a lupus susceptibility locus which results in the production of activated and autoreactive CD4+ T cells as well as a reduction in the peripheral regulatory T cell (Treg) pool. Sle1a.1 CD4+ T cells showed a defective response to retinoic acid (RA) expansion of TGFÎ²-induced Tregs. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d over-expression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells, and to decrease their apoptotic response to RA. PBX1-d is expressed more frequently in lupus patients than in healthy controls, and its presence correlates with an increased memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance. Total RNA from CD4+ T cells from C57BL/6 (B6) and B6.Sle1a.1 (Sle) mice was isolated, with 4 biological replicates each. Gene expression data from C57BL/6 mice were compared with data from B6.Sle2c1 mice.

2010-07-08 | E-GEOD-22313 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data