IL-6-inducedhuman B cell differentiation.
Item
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Title
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IL-6-inducedhuman B cell differentiation.
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Identifier
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AAI9405564
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identifier
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9405564
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Creator
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Natkunam, Yasodha.
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Contributor
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Adviser: Selina Chen-Kiang
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Date
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1993
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular | Health Sciences, Immunology
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Abstract
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Terminal differentiation of B cells has been studied in an (Interleukin-6) IL-6-inducible system. We demonstrate that the hallmarks of terminal B cell differentiation are recapitulated in an Epstein Barr Virus-immortalized human lymphoblastoid cell line, CESS, induced by IL-6. IL-6 signaling leads to marked enhancement of synthesis of immunoglobulin (Ig) mRNAs encoding the secreted form-specific Ig heavy-chain. The enhanced mRNA synthesis leads to the increased synthesis and secretion of IgG. The regulation of Ig synthesis in CESS cells is subject to feedback control upon long term stimulation by IL-6. The IL-6-induced cells exhibit dramatic and stage-specific alterations in cell morphology which are characteristic of plasma cells in vivo. This implies that IL-6 not only regulates the molecular and biochemical markers of B cell differentiation, but also the architecture of the cell.;The mRNA encoding transcription factor, Oct-2, is temporally regulated by IL-6 in CESS cells, and is subject to feedback control upon long term IL-6 stimulation, suggesting a role for Oct-2 in mediating the IL-6-signals in the activation of Ig gene transcription. The steady state levels of mRNAs encoding the ligand binding (gp80) and the signal transducing (gp130) subunits of the IL-6 receptor are also regulated and subject to feedback control upon long term IL-6 induction. This regulation suggests a possible mechanism for modulating IL-6 signaling in B cells during terminal differentiation. Induction of differentiation by IL-6 occurs in freshly isolated human tonsillar B cells after Epstein-Barr virus immortalization, and is not restricted to an Ig isotype. Thus, the IL-6-inducible CESS cell system provides a model to study the molecular mechanisms which underlie terminal B cell differentiation.;IL-6 regulates the expression of major histocompatibility complex (MHC) class II molecules in human B cells. IL-6-differentiated cells decrease the expression of MHC class II on the cell surface, which reflects another hallmark of plasma cells. This reduction in the surface expression of MHC class II is not restricted to a MHC class II locus. The reduction of surface MHC class II expression on differentiated cells is inversely correlated with the enhanced synthesis of IgG, as assessed by intracellular immunofluorescence. The mechanisms which regulate the reduction of MHC class II in differentiating B cells is primarily downstream of mRNA synthesis. The diminution of MHC class II on the cell surface corresponds to the enhanced synthesis of an endoplasmic reticulum-resident stress protein, GRP94, which is thought to bind MHC class II molecules in the endoplasmic reticulum. Our results suggest that the synthesis of GRP 94 may be preferentially induced by IL-6, and may be involved in the regulation of MHC class II expression during terminal B cell differentiation.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
