scholarly journals Serine Phosphorylation of the STAT1 Transactivation Domain Promotes Autoreactive B Cell and Systemic Autoimmunity Development

2020 ◽  
Vol 204 (10) ◽  
pp. 2641-2650 ◽  
Author(s):  
Sathi Babu Chodisetti ◽  
Adam J. Fike ◽  
Phillip P. Domeier ◽  
Stephanie L. Schell ◽  
Taryn E. Mockus ◽  
...  
Keyword(s):  
B Cell ◽  
Serine Phosphorylation ◽  
Transactivation Domain ◽  
Systemic Autoimmunity

scholarly journals Deep Phenotyping of CD11c+ B Cells in Systemic Autoimmunity and Controls

2021 ◽  
Vol 12 ◽  
Author(s):  
Hector Rincon-Arevalo ◽  
Annika Wiedemann ◽  
Ana-Luisa Stefanski ◽  
Marie Lettau ◽  
Franziska Szelinski ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
B Cell Activation ◽  
Membrane Expression ◽  
Ki 67 ◽  
Inflammatory Conditions ◽  
Systemic Autoimmunity ◽  
Enhanced Expression

Circulating CD11c+ B cells are a key phenomenon in certain types of autoimmunity but have also been described in the context of regular immune responses (i.e., infections, vaccination). Using mass cytometry to profile 46 different markers on individual immune cells, we systematically initially confirmed the presence of increased CD11c+ B cells in the blood of systemic lupus erythematosus (SLE) patients. Notably, significant differences in the expression of CD21, CD27, and CD38 became apparent between CD11c− and CD11c+ B cells. We observed direct correlation of the frequency of CD21−CD27− B cells and CD21−CD38− B cells with CD11c+ B cells, which were most pronounced in SLE compared to primary Sjögren's syndrome patients (pSS) and healthy donors (HD). Thus, CD11c+ B cells resided mainly within memory subsets and were enriched in CD27−IgD−, CD21−CD27−, and CD21−CD38− B cell phenotypes. CD11c+ B cells from all donor groups (SLE, pSS, and HD) showed enhanced CD69, Ki-67, CD45RO, CD45RA, and CD19 expression, whereas the membrane expression of CXCR5 and CD21 were diminished. Notably, SLE CD11c+ B cells showed enhanced expression of the checkpoint molecules CD86, PD1, PDL1, CD137, VISTA, and CTLA-4 compared to HD. The substantial increase of CD11c+ B cells with a CD21− phenotype co-expressing distinct activation and checkpoint markers, points to a quantitative increased alternate (extrafollicular) B cell activation route possibly related to abnormal immune regulation as seen under the striking inflammatory conditions of SLE which shows a characteristic PD-1/PD-L1 upregulation.

scholarly journals PTIP chromatin regulator controls development and activation of B cell subsets to license humoral immunity in mice

2017 ◽  
Vol 114 (44) ◽  
pp. E9328-E9337 ◽  
Author(s):  
Dan Su ◽  
Stijn Vanhee ◽  
Rebeca Soria ◽  
Elin Jaensson Gyllenbäck ◽  
Linda M. Starnes ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Cell Activation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Transactivation Domain ◽  
B Cell Activation ◽  
Chromatin Regulator ◽  
B Cell Subsets

B cell receptor signaling and downstream NF-κB activity are crucial for the maturation and functionality of all major B cell subsets, yet the molecular players in these signaling events are not fully understood. Here we use several genetically modified mouse models to demonstrate that expression of the multifunctional BRCT (BRCA1 C-terminal) domain-containing PTIP (Pax transactivation domain-interacting protein) chromatin regulator is controlled by B cell activation and potentiates steady-state and postimmune antibody production in vivo. By examining the effects of PTIP deficiency in mice at various ages during ontogeny, we demonstrate that PTIP promotes bone marrow B cell development as well as the neonatal establishment and subsequent long-term maintenance of self-reactive B-1 B cells. Furthermore, we find that PTIP is required for B cell receptor- and T:B interaction-induced proliferation, differentiation of follicular B cells during germinal center formation, and normal signaling through the classical NF-κB pathway. Together with the previously identified role for PTIP in promoting sterile transcription at the Igh locus, the present results establish PTIP as a licensing factor for humoral immunity that acts at several junctures of B lineage maturation and effector cell differentiation by controlling B cell activation.

scholarly journals CRISP-3, a protein with homology to plant defense proteins, is expressed in mouse B cells under the control of Oct2.

1996 ◽  
Vol 16 (11) ◽  
pp. 6160-6168 ◽  
Author(s):  
P Pfisterer ◽  
H König ◽  
J Hess ◽  
G Lipowsky ◽  
B Haendler ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Transcriptional Activation ◽  
Regulatory Elements ◽  
Expression Vectors ◽  
Transactivation Domain ◽  
Defense Proteins ◽  
Lymphoid Lineage ◽  
Octamer Motif ◽  
B Lymphoid

The Oct2 transcription factor is expressed throughout the B-lymphoid lineage and plays an essential role during the terminal phase of B-cell differentiation. Several genes specifically expressed in B lymphocytes have been identified that contain a functional octamer motif in their regulatory elements. However, expression of only a single gene, the murine CD36 gene, has been shown to date to be dependent on Oct2. Here, we present the identification and characterization of a further gene, coding for cysteine-rich secreted protein 3 (CRISP-3), whose expression in B cells is regulated by Oct2. We show that CRISP-3 is expressed in the B-lymphoid lineage specifically at the pre-B-cell stage. By using different experimental strategies, including nuclear run-on experiments, we demonstrate that this gene is transcriptionally activated by Oct2. Furthermore, analysis of CRISP-3 expression in primary B cells derived from either wild-type or Oct2-deficient mice demonstrates the dependence on Oct2. Two variant octamer motifs were identified in the upstream promoter region of the crisp-3 gene, and Oct2 interacts with both of them in vitro. Cotransfection experiments with expression vectors for Oct1 and Oct2 together with a reporter driven by the crisp-3 promoter showed that transcriptional activation of this promoter can only be achieved with Oct2. The C-terminal transactivation domain of Oct2 is required for this activation. Finally, introducing specific mutations in the two variant octamer motifs revealed that both of them are important for full transcriptional activation by Oct2.

An Activating Mutation (Ser525Pro) within the Transactivation Domain of REL in Two Patients with Human B-Cell Lymphomas Enhances REL’s In Vitro Transforming Activity.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2617-2617
Author(s):  
Heiko Trautmann ◽  
Daniel T. Starczynowski ◽  
Christiane Pott ◽  
Lana Harder ◽  
Norbert Arnold ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Transactivation Domain ◽  
Wild Type ◽  
Spleen Cells ◽  
B Cell Lymphomas ◽  
Chicken Spleen ◽  
Human B Cell

Abstract REL/NF-κB transcription factors are implicated in the control of apoptosis and cell growth particular in hematopoetic lineages. The REL locus at chromosomal region 2p13–16 is frequently amplified in B-cell lymphomas including diffuse-large B-cell lymphoma (DLBCL) and may play a role in lymphomagenesis. Overexpression of wild-type REL can transform chicken lymphoid cells in culture, and several experimentally-generated mutations within the REL C-terminal transactivation domain (TAD) have been previously shown to enhance REL’s transforming ability. We analysed 83 B-cell lymphomas included in the ‘Deutsche Krebshilfe’ funded network „Molecular Mechanisms in Malignant Lymphoma“ for the presence of activating mutations in the coding region of REL. We performed a systematic dHPLC screening for mutation discovery and identified an identical point mutation in two human B-cell lymphomas (a t(14;18)-positive follicular lymphoma and a mediastinal B-cell lymphoma) that changes Ser525 to Pro within the REL TAD. In the mediastinal B-cell lymphoma, the mutation in REL was proven to be of germline origin. FISH showed an amplification of the REL locus in the tumor cells of this case. Quantitative allelic discrimination of S525P indicates that the mutant REL gene was over-represented in both cases. By in vitro experiments we could show that the S525P mutation enhances the in vitro transforming ability of REL in chicken spleen cells. In addition, REL-S525P differs from wild-type REL in its ability to activate certain κB site-containing reporter plasmids in transient transfection assays. In particular, REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein is over-expressed in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 of REL falls within a sequence that is similar to other known phosphorylation sites of the IκB kinase, and REL-S525P shows a reduced ability to be phosphorylated by IKKα in vitro. The S525P mutation reduces IKKα- and TNFα-stimulated transactivation by REL, as measured in GAL4 reporter assays. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFα-induced cell death than cells transformed by wild-type REL. These results represent the first identification of a tumor-derived activating mutation in the REL proto-oncogene, and they suggest that the S525P mutation contributes to the development of human B-cell lymphomas by altering REL’s ability to induce target gene expression by affecting an IKKα-regulated transactivation activity.

scholarly journals B Cell-Derived IL-10 Does Not Regulate Spontaneous Systemic Autoimmunity in MRL.Faslpr Mice

2011 ◽  
Vol 188 (2) ◽  
pp. 678-685 ◽  
Author(s):  
Lino L. Teichmann ◽  
Michael Kashgarian ◽  
Casey T. Weaver ◽  
Axel Roers ◽  
Werner Müller ◽  
...  
Keyword(s):  
B Cell ◽  
Systemic Autoimmunity

scholarly journals B Cell-Specific Deletion of Protein-Tyrosine Phosphatase Shp1 Promotes B-1a Cell Development and Causes Systemic Autoimmunity

Immunity ◽  
2007 ◽  
Vol 27 (1) ◽  
pp. 35-48 ◽  
Author(s):  
Lily I. Pao ◽  
Kong-Peng Lam ◽  
Joel M. Henderson ◽  
Jeffery L. Kutok ◽  
Marat Alimzhanov ◽  
...  
Keyword(s):  
B Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Development ◽  
Protein Tyrosine ◽  
Systemic Autoimmunity ◽  
Specific Deletion

scholarly journals Evidence for Selective Transformation of Autoreactive Immature Plasma Cells in Mice Deficient in Fasl

2004 ◽  
Vol 200 (11) ◽  
pp. 1467-1478 ◽  
Author(s):  
Jian Qiao Zhang ◽  
Cheryl Okumura ◽  
Thomas McCarty ◽  
Min Sun Shin ◽  
Partha Mukhopadhyay ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Gene Repertoire ◽  
Altered Expression ◽  
Autoreactive B Cells ◽  
Systemic Autoimmunity ◽  
The Relationship

Germline mutations in Fas and Fasl induce nonmalignant T cell hyperplasia and systemic autoimmunity and also greatly increase the risk of B cell neoplasms. B lymphomas occurring in Fasl mutant (gld) mice usually are immunoglobulin (Ig) isotype switched, secrete Ig, and are plasmacytoid in appearance but lack Myc translocations characteristic of other plasma cell (PC) neoplasms. Here, we explore the relationship between B cell autoreactivity and transformation and use gene expression profiling to further classify gld plasmacytoid lymphomas (PLs) and to identify genes of potential importance in transformation. We found that the majority of PLs derive from antigen-experienced autoreactive B cells producing antinuclear antibody or rheumatoid factor and exhibit the skewed Ig V gene repertoire and Ig gene rearrangement patterns associated with these specificities. Gene expression profiling revealed that both primary and transplanted PLs share a transcriptional profile that places them at an early stage in PC differentiation and distinguishes them from other B cell neoplasms. In addition, genes were identified whose altered expression might be relevant in lymphomagenesis. Our findings provide a strong case for targeted transformation of autoreactive B cells in gld mice and establish a valuable model for understanding the relationship between systemic autoimmunity and B cell neoplasia.

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