title: IgA class switch in I alpha exon-deficient mice. Role of germline transcription in class switch recombination.
abstract: Studies have implicated defective Ig class switch in the pathogenesis of IgA deficiency. To understand better the molecular events that regulate IgA class switch, a 1.4-kb region of the IgA locus containing the I alpha exon was replaced with a human hypoxanthine phosphoribosyltransferase minigene by gene targeting in murine embryonic stem cells. The I alpha exon-deficient mice derived from these embryonic stem cells had normal IgA levels in serum and secretions and normal numbers of IgA B cells in Peyer's patches and spleen. Further, I alpha exon-deficient B cells efficiently underwent IgA class switch in vitro, despite the absence of I alpha exon-containing germline transcripts. Notably, I alpha exon-deficient B cells did not require TGF-beta for IgA class switch since stimulation with LPS alone led to IgA expression. Nonetheless, whereas I alpha exon-deficient B cells constitutively expressed human hypoxanthine phosphoribosyltransferase transcripts, they did not produce IgA in the absence of LPS stimulation. These results demonstrate that the I alpha exon or transcripts containing the I alpha exon are not required for IgA class switch. Further, the effects of TGF-beta on I alpha locus transcription can be supplanted by expression of a heterologous minigene at that locus, but a second signal is required for the induction of IgA class switch.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Harriman
authors.forename: A
authors.initials: A
authors.lastname: Bradley
authors.forename: S
authors.initials: S
authors.lastname: Das
authors.forename: P
authors.initials: P
authors.lastname: Rogers-Fani
authors.forename: A C
authors.initials: AC
authors.lastname: Davis
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D017098:IgA Deficiency / Q000235:genetics*; D007070:Immunoglobulin A / Q000235:genetics*; D007071:Immunoglobulin A, Secretory / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D007070:Immunoglobulin A; D007071:Immunoglobulin A, Secretory; D007041:Hypoxanthine Phosphoribosyltransferase