Publications by authors named "Pascal Schneider"

163 Publications

An Outside-In Switch in Integrin Signaling Caused by Chemical and Mechanical Signals in Reactive Astrocytes.

Front Cell Dev Biol 2021 23;9:712627. Epub 2021 Aug 23.

Cellular Communication Laboratory, Program of Cellular and Molecular Biology, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile.

Astrocyte reactivity is associated with poor repair capacity after injury to the brain, where chemical and physical changes occur in the damaged zone. Astrocyte surface proteins, such as integrins, are upregulated, and the release of pro-inflammatory molecules and extracellular matrix (ECM) proteins upon damage generate a stiffer matrix. Integrins play an important role in triggering a reactive phenotype in astrocytes, and we have reported that α β Integrin binds to the Thy-1 (CD90) neuronal glycoprotein, increasing astrocyte contractility and motility. Alternatively, α β Integrin senses mechanical forces generated by the increased ECM stiffness. Until now, the association between the α β Integrin mechanoreceptor response in astrocytes and changes in their reactive phenotype is unclear. To study the response to combined chemical and mechanical stress, astrocytes were stimulated with Thy-1-Protein A-coated magnetic beads and exposed to a magnetic field to generate mechanical tension. We evaluated the effect of such stimulation on cell adhesion and contraction. We also assessed traction forces and their effect on cell morphology, and integrin surface expression. Mechanical stress accelerated the response of astrocytes to Thy-1 engagement of integrin receptors, resulting in cell adhesion and contraction. Astrocyte contraction then exerted traction forces onto the ECM, inducing faster cell contractility and higher traction forces than Thy-1 alone. Therefore, cell-extrinsic chemical and mechanical signals regulate in an outside-in manner, astrocyte reactivity by inducing integrin upregulation, ligation, and signaling events that promote cell contraction. These changes in turn generate cell-intrinsic signals that increase traction forces exerted onto the ECM (inside-out). This study reveals α β Integrin mechanoreceptor as a novel target to regulate the harmful effects of reactive astrocytes in neuronal healing.
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http://dx.doi.org/10.3389/fcell.2021.712627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419233PMC
August 2021

Correction of Vertebral Bone Development in Ectodysplasin A1-Deficient Mice by Prenatal Treatment With a Replacement Protein.

Front Genet 2021 11;12:709736. Epub 2021 Aug 11.

Department of Pediatrics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

X-linked hypohidrotic ectodermal dysplasia with the cardinal symptoms hypodontia, hypotrichosis and hypohidrosis is caused by a genetic deficiency of ectodysplasin A1 (EDA1). Prenatal EDA1 replacement can rescue the development of skin appendages and teeth. mice, a natural animal model of EDA1 deficiency, additionally feature a striking kink of the tail, the cause of which has remained unclear. We studied the origin of this phenomenon and its response to prenatal therapy. Alterations in the distal spine could be noticed soon after birth, and kinks were present in all mice by the age of 4 months. Although their vertebral bones frequently had a disorganized epiphyseal zone possibly predisposing to fractures, cortical bone density was only reduced in vertebrae of older mice and even increased in their tibiae. Different availability of osteoclasts in the spine, which may affect bone density, was ruled out by osteoclast staining. The absence of hair follicles, a well-known niche of epidermal stem cells, and much lower bromodeoxyuridine uptake in the tail skin of 9-day-old mice rather suggest the kink being due to a skin proliferation defect that prevents the skin from growing as fast as the skeleton, so that caudal vertebrae may be squeezed and bent by a lack of skin. Early postnatal treatment with EDA1 leading to delayed hair follicle formation attenuated the kink, but did not prevent it. mice born after prenatal administration of EDA1, however, showed normal tail skin proliferation, no signs of kinking and, interestingly, a normalized vertebral bone density. Thus, our data prove the causal relationship between EDA1 deficiency and kinky tails and indicate that hair follicles are required for murine tail skin to grow fast enough. Disturbed bone development appears to be partially pre-determined and can be counteracted by timely EDA1 replacement, pointing to a role of EDA1 also in osteogenesis.
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http://dx.doi.org/10.3389/fgene.2021.709736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385758PMC
August 2021

APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.

Nature 2021 09 25;597(7874):92-96. Epub 2021 Aug 25.

Institute of Medicine, University of Gothenburg, Göteborg, Sweden.

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall. A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs, but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis.
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http://dx.doi.org/10.1038/s41586-021-03818-3DOI Listing
September 2021

Biocatalytic C3-Indole Methylation-A Useful Tool for the Natural-Product-Inspired Stereoselective Synthesis of Pyrroloindoles.

Angew Chem Int Ed Engl 2021 10 17;60(43):23412-23418. Epub 2021 Sep 17.

Institut für Bioorganische Chemie, Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich and Bioeconomy Science Center (BioSC), Stetternicher Forst, Geb. 15.8, 52426, Jülich, Germany.

Enantioselective synthesis of bioactive compounds bearing a pyrroloindole framework is often laborious. In contrast, there are several S-adenosyl methionine (SAM)-dependent methyl transferases known for stereo- and regioselective methylation at the C3 position of various indoles, directly leading to the formation of the desired pyrroloindole moiety. Herein, the SAM-dependent methyl transferase PsmD from Streptomyces griseofuscus, a key enzyme in the biosynthesis of physostigmine, is characterized in detail. The biochemical properties of PsmD and its substrate scope were demonstrated. Preparative scale enzymatic methylation including SAM regeneration was achieved for three selected substrates after a design-of-experiment optimization.
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http://dx.doi.org/10.1002/anie.202107619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596708PMC
October 2021

Mutasynthesis of Physostigmines in .

Org Lett 2021 08 6;23(16):6563-6567. Epub 2021 Aug 6.

Department of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, 44227 Nordrhein-Westfalen, Germany.

The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach that merged chemical synthesis with pathway refactoring, we produced a series of physostigmine analogues with altered specificity and toxicity profiles in the heterologous host . The compounds that were generated by applying a simple feeding strategy include the promising drug candidate phenserine, which was previously accessible only by total synthesis.
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http://dx.doi.org/10.1021/acs.orglett.1c02374DOI Listing
August 2021

Function, occurrence and inhibition of different forms of BAFF.

Curr Opin Immunol 2021 08 26;71:75-80. Epub 2021 Jun 26.

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. Electronic address:

B cell activating factor (BAFF or BLyS), an important cytokine for B cell survival and humoral immune responses, is targeted in the clinic for the treatment of systemic lupus erythematosus. This review focuses on the structure, function and inhibition profiles of membrane-bound BAFF, soluble BAFF 3-mer and soluble BAFF 60-mer, all of which have distinct properties. BAFF contains a loop region not required for receptor binding but essential for receptor activation via promotion of BAFF-to-BAFF contacts. This loop region additionally allows formation of BAFF 60-mer, in which epitopes of the BAFF inhibitor belimumab are inaccessible. If 60-mer forms in humans, it is predicted to be short-lived and to act locally because adult serum contains a BAFF 60-mer dissociating activity. Cord blood contains elevated levels of BAFF, part of which displays attributes of 60-mer, suggesting a role for this form of BAFF in the development of foetal or neonate B cells.
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http://dx.doi.org/10.1016/j.coi.2021.06.009DOI Listing
August 2021

Human primed ILCPs support endothelial activation through NF-κB signaling.

Elife 2021 Feb 8;10. Epub 2021 Feb 8.

Department of Oncology, Ludwig Institute for Cancer Research - University of Lausanne, Lausanne, Switzerland.

Innate lymphoid cells (ILCs) represent the most recently identified subset of effector lymphocytes, with key roles in the orchestration of early immune responses. Despite their established involvement in the pathogenesis of many inflammatory disorders, the role of ILCs in cancer remains poorly defined. Here we assessed whether human ILCs can actively interact with the endothelium to promote tumor growth control, favoring immune cell adhesion. We show that, among all ILC subsets, ILCPs elicited the strongest upregulation of adhesion molecules in endothelial cells (ECs) in vitro, mainly in a contact-dependent manner through the tumor necrosis factor receptor- and RANK-dependent engagement of the NF-κB pathway. Moreover, the ILCP-mediated activation of the ECs resulted to be functional by fostering the adhesion of other innate and adaptive immune cells. Interestingly, pre-exposure of ILCPs to human tumor cell lines strongly impaired this capacity. Hence, the ILCP-EC interaction might represent an attractive target to regulate the immune cell trafficking to tumor sites and, therefore, the establishment of an anti-tumor immune response.
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http://dx.doi.org/10.7554/eLife.58838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891932PMC
February 2021

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca/P2X7 Receptor Signaling Axis.

Front Cell Dev Biol 2020 12;8:592442. Epub 2021 Jan 12.

Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Cancer cell adhesion to the vascular endothelium is an important step in tumor metastasis. Thy-1 (CD90), a cell adhesion molecule expressed in activated endothelial cells, has been implicated in melanoma metastasis by binding to integrins present in cancer cells. However, the signaling pathway(s) triggered by this Thy-1-Integrin interaction in cancer cells remains to be defined. Our previously reported data indicate that Ca-dependent hemichannel opening, as well as the P2X7 receptor, are key players in Thy-1-αβ Integrin-induced migration of reactive astrocytes. Thus, we investigated whether this signaling pathway is activated in MDA-MB-231 breast cancer cells and in B16F10 melanoma cells when stimulated with Thy-1. In both cancer cell types, Thy-1 induced a rapid increase in intracellular Ca, ATP release, as well as cell migration and invasion. Connexin and Pannexin inhibitors decreased cell migration, implicating a requirement for hemichannel opening in Thy-1-induced cell migration. In addition, cell migration and invasion were precluded when the P2X7 receptor was pharmacologically blocked. Moreover, the ability of breast cancer and melanoma cells to transmigrate through an activated endothelial monolayer was significantly decreased when the β Integrin was silenced in these cancer cells. Importantly, melanoma cells with silenced β Integrin were unable to metastasize to the lung in a preclinical mouse model. Thus, our results suggest that the Ca/hemichannel/ATP/P2X7 receptor-signaling axis triggered by the Thy-1-αβ Integrin interaction is important for cancer cell migration, invasion and transvasation. These findings open up the possibility of therapeutically targeting the Thy-1-Integrin signaling pathway to prevent metastasis.
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http://dx.doi.org/10.3389/fcell.2020.592442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835543PMC
January 2021

Discovery of new acetylcholinesterase inhibitors for Alzheimer's disease: virtual screening and characterisation.

J Enzyme Inhib Med Chem 2021 Dec;36(1):491-496

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Germany, Düsseldorf.

For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer's disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening approaches to screen both ZINC15 and MolPort databases for synthetic analogs of physostigmine and donepezil, two highly potent AChE inhibitors. We characterised the inhibitory concentration of 11 compounds, ranging from 14 to 985 μM. The most potent of these compounds, S-I 26, showed a fivefold improved inhibitory concentration in comparison to rivastigmine. Moderate inhibitors carrying novel scaffolds were identified and could be improved for the development of new classes of AChE inhibitors.
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http://dx.doi.org/10.1080/14756366.2021.1876685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833026PMC
December 2021

BAFF 60-mer, and Differential BAFF 60-mer Dissociating Activities in Human Serum, Cord Blood and Cerebrospinal Fluid.

Front Cell Dev Biol 2020 6;8:577662. Epub 2020 Nov 6.

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

B cell activation factor of the TNF family (BAFF/BLyS), an essential B cell survival factor of which circulating levels are elevated in several autoimmune disorders, is targeted in the clinic for the treatment of systemic lupus erythematosus (SLE). The soluble form of BAFF can exist as 3-mer, or as 60-mer that results from the ordered assembly of twenty 3-mers and that can be obtained from naturally cleaved membrane-bound BAFF or made as a recombinant protein. However, which forms of soluble BAFF exist and act in humans is unclear. In this study, BAFF 3-mer and 60-mer in biological fluids were characterized for size, activity and response to specific stimulators or inhibitors of BAFF. Human cerebrospinal fluids (CSF) from patients with multiple sclerosis and adult human sera contained exclusively BAFF 3-mer in these assays, also when BAFF concentrations were moderately SLE or highly (BAFFR-deficient individual) increased. Human sera, but not CSF, contained a high molecular weight, saturable activity that dissociated preformed recombinant BAFF 60-mer into 3-mer. This activity was lower in cord blood. Cord blood displayed BAFF levels 10-fold higher than in adults and consistently contained a fair proportion of active high molecular weight BAFF able to dissociate into 3-mer but not endowed with all properties of recombinant BAFF 60-mer. If BAFF 60-mer is produced in humans, it is dissociated, or at least attenuated in the circulation.
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http://dx.doi.org/10.3389/fcell.2020.577662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677505PMC
November 2020

Methods for the Administration of EDAR Pathway Modulators in Mice.

Methods Mol Biol 2021 ;2248:167-183

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia, a congenital condition characterized by the absence or abnormal formation of sweat glands, teeth, and several skin appendages. Stimulation of the EDA receptor (EDAR) with agonists in the form of recombinant EDA or anti-EDAR antibodies can compensate for the absence of Eda in a mouse model of Eda deficiency, provided that agonists are administered in a timely manner during fetal development. Here we provide detailed protocols for the administration of EDAR agonists or antagonists, or other proteins, by the intravenous, intraperitoneal, and intra-amniotic routes as well as protocols to collect blood, to visualize sweat gland function, and to prepare skulls in mice.
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http://dx.doi.org/10.1007/978-1-0716-1130-2_12DOI Listing
April 2021

A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS.

J Exp Med 2021 02;218(2)

Department of General Paediatrics, Clinic Oldenburg, Oldenburg, Germany.

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.
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http://dx.doi.org/10.1084/jem.20192191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658692PMC
February 2021

Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia.

Cancers (Basel) 2020 Sep 23;12(10). Epub 2020 Sep 23.

Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Department of Internal Medicine, University Hospital Tuebingen, 72076 Tuebingen, Germany.

The introduction of idelalisib, ibrutinib and venetoclax for treatment of chronic lymphocytic leukemia (CLL) has greatly improved long term survival of patients. However, many patients do not achieve complete remission and suffer from development of resistance upon treatment with these small molecule inhibitors. Here we report that the TNF family member B-cell activating factor (BAFF) mediates resistance of CLL cells to idelalisib, ibrutinib and venetoclax by sustaining survival and preventing apoptosis of the malignant B cells as revealed by analysis of cellular ATP levels and mitochondrial membrane integrity as well as caspase activation, respectively. As BAFF also plays a prominent role in autoimmune diseases, the BAFF-neutralizing antibody belimumab was developed and approved for treatment of systemic lupus erythematosus (SLE). When we employed belimumab in the context of CLL treatment with idelalisib, ibrutinib and venetoclax, BAFF neutralization was found to significantly increase the sensitivity of the leukemic cells to all three small molecule inhibitors. Notably, BAFF neutralization proved to be beneficial independently of clinical stage according to Binet and Rai or IgVH mutational status. Our results identify drug repurposing of belimumab for neutralization of BAFF to complement small molecule inhibitor treatment as a promising therapeutic approach in CLL that is presently undergoing clinical evaluation.
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http://dx.doi.org/10.3390/cancers12102725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598196PMC
September 2020

B-Cell Activating Factor Secreted by Neutrophils Is a Critical Player in Lung Inflammation to Cigarette Smoke Exposure.

Front Immunol 2020 29;11:1622. Epub 2020 Jul 29.

University of Orleans and CNRS, INEM-UMR7355, Orléans, France.

Cigarette smoke (CS) is the major cause of chronic lung injuries, such as chronic obstructive pulmonary disease (COPD). In patients with severe COPD, tertiary lymphoid follicles containing B lymphocytes and B cell-activating factor (BAFF) overexpression are associated with disease severity. In addition, BAFF promotes adaptive immunity in smokers and mice chronically exposed to CS. However, the role of BAFF in the early phase of innate immunity has never been investigated. We acutely exposed C57BL/6J mice to CS and show early BAFF expression in the bronchoalveolar space and lung tissue that correlates to airway neutrophil and macrophage influx. Immunostaining analysis revealed that neutrophils are the major source of BAFF. We confirmed that neutrophils secrete BAFF in response to cigarette smoke extract (CSE) stimulation. Antibody-mediated neutrophil depletion significantly dampens lung inflammation to CS exposure but only partially decreases BAFF expression in lung tissue and bronchoalveolar space suggesting additional sources of BAFF. Importantly, BAFF deficient mice displayed decreased airway neutrophil recruiting chemokines and neutrophil influx while the addition of exogenous BAFF significantly enhanced this CS-induced neutrophilic inflammation. This demonstrates that BAFF is a key proinflammatory cytokine and that innate immune cells in particular neutrophils, are an unconsidered source of BAFF in early stages of CS-induced innate immunity.
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http://dx.doi.org/10.3389/fimmu.2020.01622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405926PMC
April 2021

Syndecan-4/PAR-3 signaling regulates focal adhesion dynamics in mesenchymal cells.

Cell Commun Signal 2020 08 18;18(1):129. Epub 2020 Aug 18.

Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Independencia, 838-0453, Santiago, Chile.

Background: Syndecans regulate cell migration thus having key roles in scarring and wound healing processes. Our previous results have shown that Thy-1/CD90 can engage both αvβ3 integrin and Syndecan-4 expressed on the surface of astrocytes to induce cell migration. Despite a well-described role of Syndecan-4 during cell movement, information is scarce regarding specific Syndecan-4 partners involved in Thy-1/CD90-stimulated cell migration.

Methods: Mass spectrometry (MS) analysis of complexes precipitated with the Syndecan-4 cytoplasmic tail peptide was used to identify potential Syndecan-4-binding partners. The interactions found by MS were validated by immunoprecipitation and proximity ligation assays. The conducted research employed an array of genetic, biochemical and pharmacological approaches, including: PAR-3, Syndecan-4 and Tiam1 silencing, active Rac1 GEFs affinity precipitation, and video microscopy.

Results: We identified PAR-3 as a Syndecan-4-binding protein. Its interaction depended on the carboxy-terminal EFYA sequence present on Syndecan-4. In astrocytes where PAR-3 expression was reduced, Thy-1-induced cell migration and focal adhesion disassembly was impaired. This effect was associated with a sustained Focal Adhesion Kinase activation in the siRNA-PAR-3 treated cells. Our data also show that Thy-1/CD90 activates Tiam1, a PAR-3 effector. Additionally, we found that after Syndecan-4 silencing, Tiam1 activation was decreased and it was no longer recruited to the membrane. Syndecan-4/PAR-3 interaction and the alteration in focal adhesion dynamics were validated in mouse embryonic fibroblast (MEF) cells, thereby identifying this novel Syndecan-4/PAR-3 signaling complex as a general mechanism for mesenchymal cell migration involved in Thy-1/CD90 stimulation.

Conclusions: The newly identified Syndecan-4/PAR-3 signaling complex participates in Thy-1/CD90-induced focal adhesion disassembly in mesenchymal cells. The mechanism involves focal adhesion kinase dephosphorylation and Tiam1 activation downstream of Syndecan-4/PAR-3 signaling complex formation. Additionally, PAR-3 is defined here as a novel adhesome-associated component with an essential role in focal adhesion disassembly during polarized cell migration. These novel findings uncover signaling mechanisms regulating cell migration, thereby opening up new avenues for future research on Syndecan-4/PAR-3 signaling in processes such as wound healing and scarring.
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http://dx.doi.org/10.1186/s12964-020-00629-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433185PMC
August 2020

The Role of TNFR2 and DR3 in the In Vivo Expansion of Tregs in T Cell Depleting Transplantation Regimens.

Int J Mol Sci 2020 May 9;21(9). Epub 2020 May 9.

Transplantation Immunobiology, School of Biology and Biotechnology, Institute of Molecular Biology, Genomics and Proteomics, University of Leon, 24071 Leon, Spain.

Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.
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http://dx.doi.org/10.3390/ijms21093347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247540PMC
May 2020

Novel strategies for expansion of tooth epithelial stem cells and ameloblast generation.

Sci Rep 2020 03 18;10(1):4963. Epub 2020 Mar 18.

Research Program in Developmental Biology, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Enamel is secreted by ameloblasts derived from tooth epithelial stem cells (SCs). Humans cannot repair or regenerate enamel, due to early loss of tooth epithelial SCs. Contrarily in the mouse incisors, epithelial SCs are maintained throughout life and endlessly generate ameloblasts, and thus enamel. Here we isolated Sox2-GFP+ tooth epithelial SCs which generated highly cellular spheres following a novel in vitro strategy. This system enabled analysis of SC regulation by various signaling molecules, and supported the stimulatory and inhibitory roles of Shh and Bmp, respectively; providing better insight into the heterogeneity of the SCs. Further, we generated a novel mouse reporter, Enamelin-tdTomato for identification of ameloblasts in live tissues and cells, and used it to demonstrate presence of ameloblasts in the new 3D co-culture system of dental SCs. Collectively, our results provide means of generating 3D tooth epithelium from adult SCs which can be utilized toward future generation of enamel.
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http://dx.doi.org/10.1038/s41598-020-60708-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080756PMC
March 2020

Analysis of Complex Molecules and Their Reactions on Surfaces by Means of Cluster-Induced Desorption/Ionization Mass Spectrometry.

J Vis Exp 2020 03 1(157). Epub 2020 Mar 1.

Institute of Applied Physics and Center for Materials Research (LaMa), Justus Liebig University Giessen;

Desorption/Ionization Induced by Neutral SO2 Clusters (DINeC) is employed as a very soft and efficient desorption/ionization technique for mass spectrometry (MS) of complex molecules and their reactions on surfaces. DINeC is based on a beam of SO2 clusters impacting on the sample surface at low cluster energy. During cluster-surface impact, some of the surface molecules are desorbed and ionized via dissolvation in the impacting cluster; as a result of this dissolvation-mediated desorption mechanism, low cluster energy is sufficient and the desorption process is extremely soft. Both surface adsorbates and molecules of which the surface is composed of can be analyzed. Clear and fragmentation-free spectra from complex molecules such as peptides and proteins are obtained. DINeC does not require any special sample preparation, in particular no matrix has to be applied. The method yields quantitative information on the composition of the samples; molecules at a surface coverage as low as 0.1 % of a monolayer can be detected. Surface reactions such as H/D exchange or thermal decomposition can be observed in real-time and the kinetics of the reactions can be deduced. Using a pulsed nozzle for cluster beam generation, DINeC can be efficiently combined with ion trap mass spectrometry. The matrix-free and soft nature of the DINeC process in combination with the MS capabilities of the ion trap allows for very detailed and unambiguous analysis of the chemical composition of complex organic samples and organic adsorbates on surfaces.
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http://dx.doi.org/10.3791/60487DOI Listing
March 2020

Soft cluster-induced desorption/ionization mass spectrometry: How soft is soft?

Biointerphases 2020 03 12;15(2):021001. Epub 2020 Mar 12.

Institut für Angewandte Physik and Zentrum für Materialforschung, Justus-Liebig-Universität Giessen, Heinrich-Buff-Ring 16, D-35392 Giessen, Germany.

Desorption/ionization induced by neutral clusters (DINeC) is used as an ultrasoft desorption/ionization method for the analysis of fragile biomolecules by means of mass spectrometry (MS). As a test molecule, the glycopeptide vancomycin was measured with DINeC-MS, and resulting mass spectra were compared to the results obtained with electrospray ionization (ESI), matrix assisted laser desorption ionization, and time-of-flight secondary ion MS. Of the desorption-based techniques, DINeC spectra show the lowest abundance of fragments comparable to ESI spectra. The soft desorption nature of DINeC was further demonstrated when applied to MS analysis of teicoplanin.
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http://dx.doi.org/10.1116/6.0000046DOI Listing
March 2020

No interactions between heparin and atacicept, an antagonist of B cell survival cytokines.

Br J Pharmacol 2019 10 15;176(20):4019-4033. Epub 2019 Oct 15.

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

Background And Purpose: The TNF family ligands, B cell activating factor of the TNF family (BAFF, also known as B lymphocyte stimulator, BLyS) and a proliferation-inducing ligand (APRIL), share the transmembrane activator and calcium-modulator and cyclophilin ligand (CAML)-interactor (TACI) as one of their common receptors. Atacicept, a chimeric recombinant TACI/IgG1-Fc fusion protein, inhibits both ligands. TACI and APRIL also bind to proteoglycans and to heparin that is structurally related to proteoglycans. It is unknown whether the portion of TACI contained in atacicept can bind directly to proteoglycans, or indirectly via APRIL, and whether this could interfere with the anti-coagulant properties of heparin.

Experimental Approach: Binding of atacicept and APRIL to proteoglycan-positive cells was measured by FACS. Activities of heparin and atacicept were measured with activated factor Xa inhibition and cell-based assays. Effects of heparin on circulating atacicept was monitored in mice.

Key Results: Atacicept did not bind to proteoglycan-positive cells, but when complexed to APRIL could do so indirectly via APRIL. Multimers of atacicept obtained after exposure to cysteine or BAFF 60-mer bound directly to proteoglycans. Atacicept alone, or in complex with APRIL, or in a multimeric form did not interfere with heparin activity in vitro. Conversely, heparin did not influence inhibition of BAFF and APRIL by atacicept and did not change circulating levels of atacicept.

Conclusions And Implications: Lack of detectable interference of APRIL-bound or free atacicept on heparin activity makes it unlikely that atacicept at therapeutic doses will interfere with the function of heparin in vivo.
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http://dx.doi.org/10.1111/bph.14811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811742PMC
October 2019

HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT.

Cell Mol Immunol 2019 07 3;16(7):679-682. Epub 2019 Jun 3.

Transplantation Immunobiology Section, Research Institutes of the University of Leon, Campus of Vegazana s/n, 24071, Leon, Spain.

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http://dx.doi.org/10.1038/s41423-019-0241-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804897PMC
July 2019

TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes.

Front Immunol 2019 30;10:951. Epub 2019 Apr 30.

Clinic for Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.

The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.
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http://dx.doi.org/10.3389/fimmu.2019.00951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503035PMC
September 2020

Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia.

Dis Model Mech 2019 04 25;12(4). Epub 2019 Apr 25.

Developmental Biology Division, Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK

Patients with mutations in the ectodysplasin receptor signalling pathway genes - the X-linked ligand ectodysplasin-A (), the receptor or the receptor adapter - have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains ( ) and ( ) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired () rat strain carries a mutation in the gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant than those in unaffected heterozygous rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children.
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http://dx.doi.org/10.1242/dmm.037804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505480PMC
April 2019

Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia using Recombinant Ectodysplasin in a Canine Model.

J Pharmacol Exp Ther 2019 09 18;370(3):806-813. Epub 2019 Apr 18.

University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)

X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.
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http://dx.doi.org/10.1124/jpet.118.256040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812859PMC
September 2019

Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL.

Cancers (Basel) 2019 Feb 26;11(3). Epub 2019 Feb 26.

Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tuebingen 72076, Germany.

NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface receptors, which include several members of the TNF/TNF receptor family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors.
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http://dx.doi.org/10.3390/cancers11030277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468810PMC
February 2019

Feather arrays are patterned by interacting signalling and cell density waves.

PLoS Biol 2019 02 21;17(2):e3000132. Epub 2019 Feb 21.

Roslin Institute Chicken Embryology, Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.
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http://dx.doi.org/10.1371/journal.pbio.3000132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383868PMC
February 2019

Modeling Edar expression reveals the hidden dynamics of tooth signaling center patterning.

PLoS Biol 2019 02 7;17(2):e3000064. Epub 2019 Feb 7.

Laboratoire de Biologie et Modélisation de la Cellule, Université de Lyon, ENS de Lyon, Univ Claude Bernard, CNRS UMR 5239, INSERM U1210, Lyon, France.

When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that broad activation of Edar expression precedes its spatial restriction to tooth signaling centers. This reveals a hidden two-step patterning process for tooth signaling centers, which was modeled with a single activator-inhibitor pair subject to reaction-diffusion (RD). The study of Edar expression also unveiled successive phases of signaling center formation, erasing, recovering, and fusion. Our model, in which R2 signaling center is not intrinsically defective but erased by the broad activation preceding M1 signaling center formation, predicted the surprising rescue of R2 in Edar mutant mice, where activation is reduced. The importance of this R2-M1 interaction was confirmed by ex vivo cultures showing that R2 is capable of forming a tooth. Finally, by introducing chemotaxis as a secondary process to RD, we recapitulated in silico different conditions in which R2 and M1 centers fuse or not. In conclusion, pattern formation in the mouse molar field relies on basic mechanisms whose dynamics produce embryonic patterns that are plastic objects rather than fixed end points.
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http://dx.doi.org/10.1371/journal.pbio.3000064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382175PMC
February 2019

A proliferation-inducing ligand-mediated anti-inflammatory response of astrocytes in multiple sclerosis.

Ann Neurol 2019 03 4;85(3):406-420. Epub 2019 Feb 4.

Institute for Advanced Biosciences, Grenoble Alpes University/National Institute of Health and Medical Research U1209/National Center for Scientific Research UMR5309, La Tronche, France.

Objective: The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.

Methods: APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.

Results: APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.

Interpretation: Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.
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http://dx.doi.org/10.1002/ana.25415DOI Listing
March 2019

Inhibition of Membrane-Bound BAFF by the Anti-BAFF Antibody Belimumab.

Front Immunol 2018 20;9:2698. Epub 2018 Nov 20.

Department of Biochemistry, University of Lausanne, Lausanne, Switzerland.

B cell activating factor of the TNF family (BAFF, also known as BLyS), a cytokine that regulates homeostasis of peripheral B cells, is elevated in the circulation of patients with autoimmune diseases such as systemic lupus erythematosus (SLE). BAFF is synthetized as a membrane-bound protein that can be processed to a soluble form after cleavage at a furin consensus sequence, a site that in principle can be recognized by any of the several proteases of the pro-protein convertase family. Belimumab is a human antibody approved for the treatment of SLE, often cited as specific for the soluble form of BAFF. Here we show in different experimental systems, including in a monocytic cell line (U937) that naturally expresses BAFF, that belimumab binds to membrane-bound BAFF with similar EC50 as the positive control atacicept, which is a decoy receptor for both BAFF and the related cytokine APRIL (a proliferation inducing ligand). In U937 cells, binding of both reagents was only detectable in furin-deficient U937 cells, showing that furin is the main BAFF processing protease in these cells. In CHO cells expressing membrane-bound BAFF lacking the stalk region, belimumab inhibited the activity of membrane-bound BAFF less efficiently than atacicept, while in furin-deficient U937 cells, belimumab inhibited membrane-bound BAFF and residual soluble BAFF as efficiently as atacicept. These reagents did not activate complement or antibody-dependent cell cytotoxicity upon binding to membrane-bound BAFF . In conclusion, our data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin.
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http://dx.doi.org/10.3389/fimmu.2018.02698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256835PMC
October 2019

Correction to: CART cells are prone to Fas- and DR5-mediated cell death.

J Immunother Cancer 2018 09 25;6(1):92. Epub 2018 Sep 25.

Department of Fundamental Oncology, Translational Tumor Immunology Group, Lausanne, Switzerland.

After publication of this article [1], it was noticed that 3 authors were missed from the author list.
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http://dx.doi.org/10.1186/s40425-018-0410-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154881PMC
September 2018
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