title: B cells genetically deficient in the c-Rel transactivation domain have selective defects in germline CH transcription and Ig class switching.
abstract: The Ig heavy chain locus contains a number of binding sites for the transcriptional activator, c-Rel. In this study, we evaluated the capacity of B cells from mice made genetically deficient in the C-terminal, transactivation domain of the c-Rel protein (delta c-Rel) to undergo Ig class switching. Flow-cytometric and digestion circularization PCR analyses revealed that delta c-Rel B cells failed to switch to IgG3 in response to LPS alone, or to IgG1 or IgE in response to LPS + IL-4. This failure to switch to IgG3 or IgG1 was associated with a corresponding loss of germline CH gamma 3 or CH gamma 1 RNA. However, the defective switching to IgE in delta c-Rel B cells was associated with normal levels of germline CH epsilon RNA relative to control B cells. The ability of delta c-Rel B cells to switch to IgG1, in response to LPS + IL-4, could be restored through the action(s) of additional stimuli, and this was associated with induction of normal levels of germline CH gamma 1 RNA relative to controls. In contrast, LPS-activated B cells from delta c-Rel mice underwent normal switching to IgA in the presence of TGF-beta, relative to control B cells. This was associated with equivalent steady state levels of germline CH alpha RNA between the two B cell populations. These data are the first to demonstrate a key and selective role for c-Rel in the regulation of Ig class switching. Furthermore, distinct differences are revealed in the Ig isotype induction profiles of B cells lacking c-Rel activity vs those deficient in p50/nuclear factor-kappa B.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zelazowski
authors.forename: D
authors.initials: D
authors.lastname: Carrasco
authors.forename: F R
authors.initials: FR
authors.lastname: Rosas
authors.forename: M A
authors.initials: MA
authors.lastname: Moorman
authors.forename: R
authors.initials: R
authors.lastname: Bravo
authors.forename: C M
authors.initials: CM
authors.lastname: Snapper
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D005854:Germ Cells / Q000276:immunology; D007070:Immunoglobulin A / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching; D007127:Immunoglobulin Constant Regions / Q000235:genetics*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007137:Immunoglobulin alpha-Chains / Q000096:biosynthesis; D007139:Immunoglobulin epsilon-Chains / Q000096:biosynthesis / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D020569:Proto-Oncogene Proteins c-rel; D012313:RNA / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology*
chemical_list: D007070:Immunoglobulin A; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007137:Immunoglobulin alpha-Chains; D007139:Immunoglobulin epsilon-Chains; D007142:Immunoglobulin gamma-Chains; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D007073:Immunoglobulin E; D012313:RNA