title: Stimuli that enhance IgA class switching increase histone 3 acetylation at S alpha, but poorly stimulate sequential switching from IgG2b.
abstract: Germ-line (GL) alpha transcription can be induced in mouse splenic B cells by LPS and TGF-beta. This stimulation results in approximately 1% IgA+ cells, which can be increased by IL-4, IL-5, and anti-IgD dextran (alpha delta Dex). To determine the mechanism of this increase, we asked whether IgA class switching correlates with acetylation of histone 3 at S alpha, the switch region for IgA. In the presence of the survival factor B lymphocyte stimulator (BLyS), acetylated histone 3 (AcH3) at S alpha was changed little by TGF-beta in LPS-stimulated mouse splenic B cell cultures, despite induction of GL alpha RNA. Compared with BLyS/LPS/TGF-beta alone, treatment with BLyS/LPS/TGF-beta/IL-4/IL-5/alpha delta Dex increased AcH3 at S alpha fourfold, and also increased GL alpha RNA levels more than eightfold. By contrast, IgG2b class switching was optimal in BLyS/LPS/TGF-beta alone, and was suppressed by IL-4/IL-5/alpha delta Dex. Thus, B cell activators that increase IgA class switching do not increase IgG2b class switching. Further investigation showed that in contrast to purified IgM+ cells, IgG2b+ cells switched poorly to IgA in response to BLyS/LPS/TGF-beta/IL-4/IL-5/ +/- alpha delta Dex. These results suggest that IgA class switching is unusual among isotypes in its requirement for multiple B cell activation signals in addition to LPS and the cytokine that initiates the corresponding GL transcription.
authors.affiliation: Immunology and Virology Program, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Kaminski
authors.forename: Janet
authors.initials: J
authors.lastname: Stavnezer
mesh_terms: D000107:Acetylation; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000502:physiology; D053264:B-Cell Activating Factor / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003911:Dextrans / Q000494:pharmacology; D006657:Histones / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis* / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000378:metabolism*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000502:physiology; D015848:Interleukin-5 / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D053264:B-Cell Activating Factor; D003911:Dextrans; D006657:Histones; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D015848:Interleukin-5; C039951:anti-IgD; D015847:Interleukin-4