title: Antigen receptor cross-linking differentially regulates germ-line CH ribonucleic acid expression in murine B cells.
abstract: Cytokines are believed to regulate Ig class switching, in part, through selective modulation of germ-line constant heavy (CH) gene transcription. B cell activators such as LPS or activated T cell membranes also influence germ-line CH RNA expression in the absence of exogenous cytokines. In this report we determined whether multivalent Ag receptor cross-linking, utilizing dextran-conjugated anti-IgD Abs (alpha delta-dex), could also regulate germ-line CH RNA expression. We demonstrated that alpha delta-dex markedly inhibited germ-line epsilon RNA expression, but strongly augmented germ-line gamma 1 RNA, in LPS + IL-4-stimulated cultures. This was correlated with > 90% alpha delta-dex-mediated suppression in the secretion of IgE and generation of membrane (m)IgE+ cells, and a more modest 50% reduction in IgG1 synthesis and mIgG1+ cells. Furthermore, alpha delta-dex inhibited the LPS induction of both gamma 3 and gamma 2b germ-line RNA and the associated secretion of IgG3 and IgG2b. A similar alpha delta-dex-mediated suppression of germ-line gamma 2a RNA and IgG2a secretion in LPS + IFN-gamma-stimulated cultures was observed. By contrast, activation of resting B cells with alpha delta-dex alone led to induction of germ-line gamma 3, gamma 1, and gamma 2b RNA but did not stimulate detectable expression of RNA specific for gamma 2a or epsilon. These studies demonstrate that: 1) germ-line gamma 1 gene expression is regulated uniquely, 2) germ-line transcription and switch recombination can be dissociated, 3) the germ-line transcription of each IgG isotype has an independent pattern of regulation, and 4) cross-linking of the Ag receptor, by itself, can stimulate small amounts of germ-line CH RNA.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
authors.forename: P
authors.initials: P
authors.lastname: Zelazowski
authors.forename: J T
authors.initials: JT
authors.lastname: Collins
authors.forename: W
authors.initials: W
authors.lastname: Dunnick
authors.forename: C M
authors.initials: CM
authors.lastname: Snapper
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015152:Blotting, Northern; D002478:Cells, Cultured; D003911:Dextrans / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D015322:Gene Rearrangement, B-Lymphocyte / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007127:Immunoglobulin Constant Regions / Q000096:biosynthesis; D007072:Immunoglobulin D / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000096:biosynthesis; D015719:Single-Strand Specific DNA and RNA Endonucleases
chemical_list: D003911:Dextrans; D007127:Immunoglobulin Constant Regions; D007072:Immunoglobulin D; D007143:Immunoglobulin Heavy Chains; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D015719:Single-Strand Specific DNA and RNA Endonucleases