Harriman G R, Bradley A, Das S, Rogers-Fani P, Davis A C
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
J Clin Invest. 1996 Jan 15;97(2):477-85. doi: 10.1172/JCI118438.
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.
研究表明，IgA缺陷的发病机制与缺陷性Ig类别转换有关。为了更好地理解调节IgA类别转换的分子事件，通过在小鼠胚胎干细胞中进行基因打靶，将包含Iα外显子的IgA基因座的1.4kb区域替换为人次黄嘌呤磷酸核糖基转移酶小基因。源自这些胚胎干细胞的Iα外显子缺陷小鼠血清和分泌物中的IgA水平正常，派尔集合淋巴结和脾脏中IgA B细胞数量正常。此外，尽管缺乏含Iα外显子的种系转录本，但Iα外显子缺陷的B细胞在体外仍能高效地进行IgA类别转换。值得注意的是，Iα外显子缺陷的B细胞进行IgA类别转换不需要TGF-β，因为单独用LPS刺激就能导致IgA表达。然而，虽然Iα外显子缺陷的B细胞组成性表达人次黄嘌呤磷酸核糖基转移酶转录本，但在没有LPS刺激的情况下它们不产生IgA。这些结果表明，IgA类别转换不需要Iα外显子或含Iα外显子的转录本。此外，TGF-β对Iα基因座转录的影响可以被该基因座上异源小基因的表达所取代，但诱导IgA类别转换还需要第二个信号。
