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      Antibodies against CD20 or B-Cell Receptor Induce Similar Transcription Patterns in Human Lymphoma Cell Lines

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          Abstract

          Background

          CD20 is a cell surface protein exclusively expressed on B cells. It is a clinically validated target for Non-Hodgkin's lymphomas (NHL) and autoimmune diseases. The B cell receptor (BCR) plays an important role for development and proliferation of pre-B and B cells. Physical interaction of CD20 with BCR and components of the BCR signaling cascade has been reported but the consequences are not fully understood.

          Methodology

          In this study we employed antibodies against CD20 and against the BCR to trigger the respective signaling. These antibodies induced very similar expression patterns of up- and down-regulated genes in NHL cell lines indicating that CD20 may play a role in BCR signaling and vice versa. Two of the genes that were rapidly and transiently induced by both stimuli are CCL3 and CCL4. 4 hours after stimulation the concentration of these chemokines in culture medium reaches a maximum. Spleen tyrosine kinase Syk is a cytoplasmic tyrosine kinase and a key component of BCR signaling. Both siRNA mediated silencing of Syk and inhibition by selective small molecule inhibitors impaired CCL3/CCL4 protein induction after treatment with either anti-CD20 or anti-BCR antibodies.

          Conclusion

          Our results suggest that treatment with anti-CD20 antibodies triggers at least partially a BCR activation-like response in NHL cell lines.

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          Most cited references40

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          High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma.

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            Signatures of the immune response.

            A compendium of global gene expression measurements from DNA microarray analysis of immune cells identifies gene expression signatures defining various lineages, differentiation stages, and signaling pathways. Germinal center (GC) B cells represent a discrete stage of differentiation with a unique gene expression signature. This includes genes involved in proliferation, as evidenced by high expression of G2/M phase regulators and low expression of ribosomal and metabolic genes that are transcriptional targets of c-myc. GC B cells also lack expression of the NF-kappaB signature genes, which may favor apoptosis. Finally, the transcriptional repression signature of BCL-6 reveals how this factor can prevent terminal differentiation of B cells and cause B cell lymphomas.
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              Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies.

              The humoral immune response requires antigen-specific B cell activation and subsequent terminal differentiation into plasma cells. Engagement of B cell antigen receptor (BCR) on mature B cells activates an intracellular signaling cascade, including calcium mobilization, which leads to cell proliferation and differentiation. Coengagement by immune complex of BCR with the inhibitory Fc receptor FcgammaRIIb, the only IgG receptor expressed on B cells, inhibits B cell activation signals through a negative feedback loop. We now describe antibodies that mimic the inhibitory effects of immune complex by high-affinity coengagement of FcgammaRIIb and the BCR coreceptor complex on human B cells. We engineered the Fc domain of an anti-CD19 antibody to generate variants with up to approximately 430-fold greater affinity to FcgammaRIIb. Relative to native IgG1, the FcgammaRIIb binding-enhanced (IIbE) variants strongly inhibited BCR-induced calcium mobilization and viability in primary human B cells. Inhibitory effects involved phosphorylation of SH2-containing inositol polyphosphate 5-phosphatase (SHIP), which is known to be involved in FcgammaRIIb-induced negative feedback of B cell activation by immune complex. Coengagement of BCR and FcgammaRIIb by IIbE variants also overcame the anti-apoptotic effects of BCR activation. The use of a single antibody to suppress B cell functions by coengagement of BCR and FcgammaRIIb may represent a novel approach in the treatment of B cell-mediated autoimmune diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                18 February 2011
                : 6
                : 2
                : e16596
                Affiliations
                [1 ]Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany
                [2 ]Pharma Research and Early Development, Roche Glycart AG, Schlieren-Zürich, Switzerland
                University of Barcelona, Spain
                Author notes

                Conceived and designed the experiments: AF GN CK. Performed the experiments: AF. Analyzed the data: AF. Contributed reagents/materials/analysis tools: AF HB. Wrote the paper: AF GN HB.

                Article
                PONE-D-10-01597
                10.1371/journal.pone.0016596
                3041769
                21364752
                179eb6b8-97d2-4538-ad3e-13042705b069
                Franke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 1 September 2010
                : 5 January 2011
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Computational Biology
                Microarrays
                Genomics
                Genome Analysis Tools
                Gene Ontologies
                Transcriptomes
                Functional Genomics
                Genome Expression Analysis
                Immunology
                Immune Cells
                B Cells
                Immune Response
                Immunoglobulins
                Molecular Cell Biology
                Cellular Types
                Blood Cells
                Immune Cells
                Nucleic Acids
                RNA
                RNA interference
                Gene Expression
                RNA interference
                Signal Transduction
                Mechanisms of Signal Transduction
                Crosstalk
                Signal Initiation
                Signaling in Selected Disciplines
                Immunological Signaling
                Membrane Receptor Signaling
                Immunologic Receptor Signaling
                Signaling in Cellular Processes
                Transmembrane Signaling
                Cell Death
                Medicine
                Anatomy and Physiology
                Immune Physiology
                Antibodies
                Clinical Immunology
                Immune Cells
                B Cells
                Hematology
                Hematologic Cancers and Related Disorders
                Lymphomas
                Non-Hodgkin lymphoma
                Oncology
                Cancers and Neoplasms
                Hematologic Cancers and Related Disorders
                Lymphomas
                Non-Hodgkin lymphoma

                Uncategorized
                Uncategorized

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