% Encoding: UTF-8
@COMMENT{BibTeX export based on data in FAU CRIS: https://cris.fau.de/}
@COMMENT{For any questions please write to cris-support@fau.de}
@article{faucris.280342996,
abstract = {Chronic lymphocytic leukemia (CLL) is a frequent lymphoproliferative disorder of B cells. Although inhibitors targeting signal proteins involved in B-cell antigen receptor (BCR) signaling constitute an important part of the current therapeutic protocols for CLL patients, the exact role of BCR signaling, as compared to genetic aberration, in the development and progression of CLL is controversial. In order to investigate whether BCR expression per se is pivotal for the development and maintenance of CLL B cells, we used the TCL1 mouse model. By ablating the BCR in CLL cells from TCL1 transgenic mice, we show that CLL cells cannot survive without BCR signaling and are lost within 8 weeks in diseased mice. Furthermore, we tested whether mutations augmenting B-cell signaling influence the course of CLL development and its severity. The phosphatidylinositol-3-kinase (PI3K) signaling pathway is an integral part of the BCR signaling machinery and its activity is indispensable for B-cell survival. It is negatively regulated by the lipid phosphatase PTEN, whose loss mimics PI3K pathway activation. Herein, we show that PTEN has a key regulatory function in the development of CLL, as deletion of the Pten gene resulted in greatly accelerated onset of the disease. By contrast, deletion of the gene TP53, which encodes the tumor suppressor p53 and is highly mutated in CLL, did not accelerate disease development, confirming that development of CLL was specifically triggered by augmented PI3K activity through loss of PTEN and suggesting that CLL driver consequences most likely affect BCR signaling. Moreover, we could show that in human CLL patient samples, 64% and 81% of CLL patients with a mutated and unmutated IgH VH, respectively, show downregulated PTEN protein expression in CLL B cells if compared to healthy donor B cells. Importantly, we found that B cells derived from CLL patients had higher expression levels of the miRNA-21 and miRNA-29, which suppresses PTEN translation, compared to healthy donors. The high levels of miRNA-29 might be induced by increased PAX5 expression of the B-CLL cells. We hypothesize that downregulation of PTEN by increased expression levels of miR-21, PAX5 and miR-29 could be a novel mechanism of CLL tumorigenesis that is not established yet. Together, our study demonstrates the pivotal role for BCR signaling in CLL development and deepens our understanding of the molecular mechanisms underlying the genesis of CLL and for the development of new treatment strategies.},
author = {Schmid, Vera Kristin and Khadour, Ahmad and Ahmed, Nabil and Brandl, Carolin and Nitschke, Lars and Rajewsky, Klaus and Jumaa, Hassan and Hobeika, Elias},
doi = {10.3324/haematol.2021.279924},
faupublication = {yes},
journal = {Haematologica},
note = {CRIS-Team Scopus Importer:2022-08-12},
pages = {1796-1814},
peerreviewed = {unknown},
title = {{B}-cell antigen receptor expression and phosphatidylinositol 3-kinase signaling regulate genesis and maintenance of mouse chronic lymphocytic leukemia},
volume = {107},
year = {2022}
}
@article{faucris.121146564,
abstract = {Intravenous immunoglobulins (IVIgs) efficiently suppress a variety of autoimmune diseases. Over the past few years several potential mechanisms underlying this antiinflammatory activity have become apparent. Among these, terminal sialic acid residues in the sugar moiety of the immunoglobulin G constant fragment have been shown to be critical for the antiinflammatory activity of IVIgs in models of rheumatoid arthritis and immunothrombocytopenia (ITP). More recently, B cells and the sialic acid-binding protein CD22 were suggested to be involved in this IVIg-dependent immunomodulatory pathway. To study whether B cells are directly involved in IVIg-mediated suppression of acute autoimmune diseases, we tested the activity of IVIgs in mice deficient in B cells or CD22. We show that neither B cells nor CD22 are critical for the immediate antiinflammatory activity of IVIgs in mouse models of rheumatoid arthritis and ITP.},
author = {Schwab, Inessa and Seeling, Michaela and Biburger, Markus and Aschermann, Susanne and Nitschke, Lars and Nimmerjahn, Falk},
doi = {10.1002/eji.201242710},
faupublication = {yes},
journal = {European journal of immunology},
pages = {3302-3309},
peerreviewed = {No},
title = {{B} cells and {CD22} are dispensable for the immediate antiinflammatory activity of intravenous immunoglobulins in vivo},
volume = {42},
year = {2012}
}
@article{faucris.262966715,
abstract = {Germinal center reactions are established during a thymus-dependent immune response. Germinal center (GC) B cells are rapidly proliferating and undergo somatic hypermutation in Ab genes. This results in the production of high-affinity Abs and establishment of long-lived memory cells. GC B cells show lower BCR-induced signaling when compared with naive B cells, but the functional relevance is not clear. CD22 is a member of the Siglec family and functions as an inhibitory coreceptor on B cells. Interestingly, GC B cells downregulate sialic acid forms that serve as high-affinity ligands for CD22, indicating a role for CD22 ligand binding during GC responses. We studied the role of CD22 in the GC with mixed bone marrow chimeric mice and found a disadvantage of CD222/2 GC B cells during the GC reaction. Mechanistic investigations ruled out defects in dark zone/light zone distribution and affinity maturation. Rather, an increased rate of apoptosis in CD222/2 GC B cells was responsible for the disadvantage, also leading to a lower GC output in plasma cells and memory B cells. CD222/2 GC B cells showed a clearly increased calcium response upon BCR stimulation, which was almost absent in wild-type GC B cells. We conclude that the differential expression of the low-affinity cis CD22 ligands in the GC normally results in a strong attenuation of BCR signaling in GC B cells, probably due to higher CD22-BCR interactions. Therefore, attenuation of BCR signaling by CD22 is involved in GC output and B cell fate.},
author = {Meyer, Sarah Johanna and Steffensen, Marie and Acs, Andreas and Weisenburger, Thomas and Wadewitz, Charlotte and Winkler, Thomas and Nitschke, Lars},
doi = {10.4049/jimmunol.2100132},
faupublication = {yes},
journal = {Journal of Immunology},
note = {CRIS-Team Scopus Importer:2021-08-20},
pages = {1018-1032},
peerreviewed = {Yes},
title = {{Cd22} controls germinal center b cell receptor signaling, which influences plasma cell and memory b cell output},
volume = {207},
year = {2021}
}
@article{faucris.108708204,
abstract = {A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can down-modulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in alpha 2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca2+ signaling by controlling the CD22 association to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca2+ signaling. In contrast, mice with mutated CD22 immunoreceptor tyrosine-based inhibition motifs have increased B-cell Ca2+ responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunit},
author = {Müller, Jennifer and Obermeier, Ingrid and Wöhner, Miriam and Brandl, Carolin and Mrotzek, Sarah Johanna and Angermüller, Sieglinde and Maity, Palash C. and Reth, Michael and Nitschke, Lars},
doi = {10.1073/pnas.1304888110},
faupublication = {yes},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {B-lymphocyte differentiation;B-lymphocyte signaling;Siglecs},
pages = {12402-12407},
peerreviewed = {Yes},
title = {{CD22} ligand-binding and signaling domains reciprocally regulate {B}-cell {Ca2}+ signaling},
volume = {110},
year = {2013}
}
@article{faucris.239397715,
abstract = {B lymphocytes are important players of the adaptive immune system. However, not just activation of B cells but also regulation of B cell signaling is important to prevent hyperactivity and dysregulation of the immune response. Different mechanisms and proteins contribute to this balance. One of these is CD22, a member of the Siglec family. It is an inhibitory coreceptor of the BCR and inhibits B cell activation. Upon BCR stimulation, CD22-dependent inhibition of BCR signaling results in a decreased calcium mobilization. Although some CD22 binding partners have already been identified, the knowledge about the CD22 interactome is still incomplete. In this study, quantitative affinity purification-mass spectrometry enabled the delineation of the CD22 interactome in the B cell line DT40. These data will clarify molecular mechanisms and CD22 signaling events after BCR activation and revealed several new CD22-associated proteins. One new identified interaction partner is the E3 ubiquitin ligase cullin 3, which was revealed to regulate CD22 surface expression and clathrin-dependent CD22 internalization after BCR stimulation. Furthermore cullin 3 was identified to be important for B lymphocytes in general. B cell-specific cullin 3-deficient mice show reduced developing B cells in the bone marrow and a severe pro-B cell proliferation defect. Mature B cells in the periphery are also reduced and characterized by increased CD22 expression and additionally by preactivated and apoptotic phenotypes. The findings reveal novel functions of cullin 3 in B lymphocytes, namely regulating CD22 surface expression and internalization after B cell activation, as well as promoting proliferation of pro-B cells.},
author = {Meyer, Sarah Johanna and Böser, Alexander and Korn, Marina and Koller, Claudia and Bertocci, Barbara and Reimann, Lena and Warscheid, Bettina and Nitschke, Lars},
doi = {10.4049/jimmunol.1900925},
faupublication = {yes},
journal = {Journal of Immunology},
note = {CRIS-Team Scopus Importer:2020-06-19},
pages = {3360-3374},
peerreviewed = {Yes},
title = {{Cullin} 3 {Is} {Crucial} for {Pro}-{B} {Cell} {Proliferation}, {Interacts} with {CD22}, and {Controls} {CD22} {Internalization} on {B} {Cells}},
volume = {204},
year = {2020}
}
@article{faucris.294855709,
abstract = {Systemic lupus erythematosus (SLE) is a severe autoimmune disease that displays considerable heterogeneity not only in its symptoms, but also in its environmental and genetic causes. Studies in SLE patients have revealed that many genetic variants contribute to disease development. However, often its etiology remains unknown. Existing efforts to determine this etiology have focused on SLE in mouse models revealing not only that mutations in specific genes lead to SLE development, but also that epistatic effects of several gene mutations significantly amplify disease manifestation. Genome-wide association studies for SLE have identified loci involved in the two biological processes of immune complex clearance and lymphocyte signaling. Deficiency in an inhibitory receptor expressed on B lymphocytes, Siglec-G, has been shown to trigger SLE development in aging mice, as have mutations in DNA degrading DNase1 and DNase1l3, that are involved in clearance of DNA-containing immune complexes. Here, we analyze the development of SLE-like symptoms in mice deficient in either Siglecg and DNase1 or Siglecg and DNase1l3 to evaluate potential epistatic effects of these genes. We found that germinal center B cells and follicular helper T cells were increased in aging Siglecg-/- x Dnase1-/- mice. In contrast, anti-dsDNA antibodies and anti-nuclear antibodies were strongly increased in aging Siglecg-/- x Dnase1l3-/- mice, when compared to single-deficient mice. Histological analysis of the kidneys revealed glomerulonephritis in both Siglecg-/- x Dnase1-/- and Siglecg-/- x Dnase1l3-/- mice, but with a stronger glomerular damage in the latter. Collectively, these findings underscore the impact of the epistatic effects of Siglecg with DNase1 and Dnase1l3 on disease manifestation and highlight the potential combinatory effects of other gene mutations in SLE.},
author = {Korn, Marina and Steffensen, Marie and Brandl, Carolin and Royzman, Dmytro and Daniel, Christoph and Winkler, Thomas and Nitschke, Lars},
doi = {10.3389/fimmu.2023.1095830},
faupublication = {yes},
journal = {Frontiers in Immunology},
keywords = {autoimmunity; B cell signaling; inhibitory receptors; lymphocytes; mouse models},
note = {CRIS-Team Scopus Importer:2023-03-31},
peerreviewed = {Yes},
title = {{Epistatic} effects of {Siglec}-{G} and {DNase1} or {DNase1l3} deficiencies in the development of systemic lupus erythematosus},
volume = {14},
year = {2023}
}
@inproceedings{faucris.288287787,
address = {HOBOKEN},
author = {Gleußner, Nina and Schneider, Andrea and Brey, Stefanie and Nimmerjahn, Falk and Winkler, Thomas},
booktitle = {EUROPEAN JOURNAL OF IMMUNOLOGY},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2023-01-27},
pages = {241-242},
peerreviewed = {unknown},
publisher = {WILEY},
title = {he role of {Fc} gamma {RIIB} expression on {B} cells for anti-{DNA} autoantibody development in {SLE}},
year = {2022}
}
@article{faucris.264851790,
abstract = {Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a myc-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22+ lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22+ lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22+ lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.},
author = {Gsottberger, Franziska and Brandl, Carolin and Wendland, Kerstin and Petkovic, Srdjan and Emmerich, Charlotte and Erber, Ramona and Geppert, Carol-Immanuel and Hartmann, Arndt and Mackensen, Andreas and Nitschke, Lars and Müller, Fabian},
doi = {10.3390/ijms221910433},
faupublication = {yes},
journal = {International Journal of Molecular Sciences},
keywords = {CD22; Checkpoint molecule; Immunotoxin; Lymphoma microenvironment; MDSCs; Mouse model; Myc-driven lymphoma; Myeloid derived suppressor cells; PD-L1; Tumor microenvironment},
note = {CRIS-Team Scopus Importer:2021-10-08},
peerreviewed = {Yes},
title = {{Human} {CD22}-transgenic, primary murine lymphoma challenges immunotherapies in organ-specific tumor microenvironments},
volume = {22},
year = {2021}
}
@inproceedings{faucris.212498642,
address = {WASHINGTON},
author = {Wagner, Franziska and Brandl, Carolin and Emmerich, Charlotte and Mackensen, Andreas and Nitschke, Lars and Müller, Fabian},
booktitle = {BLOOD},
date = {2018-12-01/2018-12-04},
doi = {10.1182/blood-2018-99-110284},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2019-03-06},
peerreviewed = {unknown},
publisher = {AMER SOC HEMATOLOGY},
title = {{Myc}-{Driven}, {Primary} {Mouse} {Lymphoma} {Expressing} {Human} {CD22} {Are} {Highly} {Infiltrated} {By} {Syngeneic} {Immune} {Cells} and {Provide} a {Unique} {Model} to {Test} {CD22}-{Targeted} {Therapies}},
venue = {San Diego, CA},
year = {2018}
}
@inproceedings{faucris.228171022,
address = {PHILADELPHIA},
author = {Britzen-Laurent, Nathalie and Guo, Wei and Langer, Victoria and Khoziainova, Svetlana and Weisenburger, Thomas and Winkler, Thomas and Straube, Julia and Waldner, Maximilian and Becker, Christoph and Naschberger, Elisabeth and Skottke, Lisa and Tripal, Philipp and Grivennikov, Sergei and Stürzl, Michael},
booktitle = {CANCER RESEARCH},
date = {2019-03-29/2019-04-03},
doi = {10.1158/1538-7445.SABCS18-5162},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2019-10-22},
peerreviewed = {unknown},
publisher = {AMER ASSOC CANCER RESEARCH},
title = {{Role} of {IFN}-gamma-activation of distinct tumor and stromal cell populations in colorectal carcinoma pathogenesis},
venue = {Atlanta, GA},
year = {2019}
}
@article{faucris.278505593,
abstract = {Sialic acids (Sias) on the B cell membrane are involved in cell migration, in the control of the complement system and, as sialic acid–binding immunoglobulin-like lectin (Siglec) ligands, in the regulation of cellular signaling. We studied the role of sialoglycans on B cells in a mouse model with B cell–specific deletion of cytidine monophosphate sialic acid synthase (CMAS), the enzyme essential for the synthesis of sialoglycans. Surprisingly, these mice showed a severe B cell deficiency in secondary lymphoid organs. Additional depletion of the complement factor C3 rescued the phenotype only marginally, demonstrating a complement-independent mechanism. The B cell survival receptor BAFF receptor was not up-regulated, and levels of activated caspase 3 and processed caspase 8 were high in B cells of Cmas-deficient mice, indicating ongoing apoptosis. Overexpressed Bcl-2 could not rescue this phenotype, pointing to extrinsic apoptosis. These results show that sialoglycans on the B cell surface are crucial for B cell survival by counteracting several death-inducing pathways.},
author = {Linder, Alexandra and Schmidt, Michael and Hitschfel, Julia and Abeln, Markus and Schneider, Pascal and Gerardy-Schahn, Rita and Münster-Kühnel, Anja K. and Nitschke, Lars},
doi = {10.1073/pnas.2201129119},
faupublication = {yes},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {B cell development; extrinsic apoptosis; sialic acids; Siglec},
note = {CRIS-Team Scopus Importer:2022-07-22},
peerreviewed = {Yes},
title = {{Sialic} acids on {B} cells are crucial for their survival and provide protection against apoptosis},
volume = {119},
year = {2022}
}
@article{faucris.307872494,
abstract = {Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults in the Western world. B cell receptor (BCR) signaling is known to be crucial for the pathogenesis and maintenance of CLL cells which develop from mature CD5+ B cells. BCR signaling is regulated by the inhibitory co-receptor Siglec-G and Siglec-G-deficient mice have an enlarged CD5+ B1a cell population. Here, we determine how Siglec-G expression influences the severity of CLL. Our results show that Siglec-G deficiency leads to earlier onset and more severe course of the CLL-like disease in the murine Eμ-TCL1 model. In contrast, mice overexpressing Siglec-G on the B cell surface are almost completely protected from developing CLL-like disease. Furthermore, we observe a downmodulation of the human ortholog Siglec-10 from the surface of human CLL cells. These results demonstrate a critical role for Siglec-G in disease progression in mice, and suggest that a similar mechanism for Siglec-10 in human CLL may exist.},
author = {Röder, Bettina and Fahnenstiel, Hannah and Schäfer, Simon and Budeus, Bettina and Dampmann, Maria and Eichhorn, Melanie and Angermüller, Sieglinde and Brost, Christa and Winkler, Thomas and Seifert, Marc and Nitschke, Lars},
doi = {10.15252/embr.202256420},
faupublication = {yes},
journal = {EMBO Reports},
keywords = {BCR signaling; CLL; Siglec-10; Siglec-G overexpressing mice; Siglecs},
note = {CRIS-Team Scopus Importer:2023-07-21},
peerreviewed = {Yes},
title = {{The} inhibitory receptor {Siglec}-{G} controls the severity of chronic lymphocytic leukemia},
year = {2023}
}