Conley M E, Larché M, Bonagura V R, Lawton A R, Buckley R H, Fu S M, Coustan-Smith E, Herrod H G, Campana D
Department of Pediatrics, University of Tennessee College of Medicine, Memphis.
J Clin Invest. 1994 Oct;94(4):1404-9. doi: 10.1172/JCI117476.
Recent studies show that most patients with X-linked hyper IgM syndrome have defects in the gene for CD40 ligand. We evaluated 17 unrelated males suspected of having X-linked hyper IgM syndrome. Activated T cells from 13 of the 17 patients failed to bind a soluble CD40 construct. In these patients, the sequence of CD40 ligand demonstrated mutations. By contrast, T cells from the remaining four patients exhibited normal binding to the CD40 construct. Sequencing of the cDNA for CD40 ligand from these patients did not show mutations. The possibility that hyper IgM syndrome in these four patients was due to abnormalities in the B cell response to CD40-mediated signals was examined. Peripheral blood lymphocytes were stimulated with anti-CD40 alone, IL4 alone or anti-CD40 plus IL4. In comparison with B cells from controls or patients with hyper IgM syndrome and mutant CD40 ligand, B cells from the patients with hyper IgM syndrome and normal CD40 ligand were defective in their ability to secrete IgE (P < 0.02) or express activation markers, CD25 and CD23 (P < 0.02) in response to stimulation with anti-CD40. The failure of these B cells to respond to CD40-mediated activation could not be attributed to a generalized deficiency in B cell activation because IL4 induced normal up-regulation of CD23 and CD25 expression. These findings indicate that hyper IgM syndrome may result from defects in expression of CD40 ligand by activated T cells or defects in CD40-mediated signal transduction in B cells.
近期研究表明，大多数X连锁高IgM综合征患者的CD40配体基因存在缺陷。我们评估了17名疑似患有X连锁高IgM综合征的无亲缘关系男性。17名患者中有13名患者的活化T细胞无法结合可溶性CD40构建体。在这些患者中，CD40配体序列显示出突变。相比之下，其余4名患者的T细胞与CD40构建体的结合表现正常。对这些患者的CD40配体cDNA进行测序未发现突变。我们研究了这4名患者的高IgM综合征是否是由于B细胞对CD40介导信号的反应异常所致。分别用抗CD40、IL4或抗CD40加IL4刺激外周血淋巴细胞。与来自对照组或患有高IgM综合征且CD40配体突变的患者的B细胞相比，患有高IgM综合征且CD40配体正常的患者的B细胞在受到抗CD40刺激时，分泌IgE的能力（P < 0.02）或表达活化标志物CD25和CD23的能力（P < 0.02）存在缺陷。这些B细胞对CD40介导的活化无反应不能归因于B细胞活化的普遍缺陷，因为IL4可正常诱导CD23和CD25表达上调。这些发现表明，高IgM综合征可能是由于活化T细胞中CD40配体表达缺陷或B细胞中CD40介导的信号转导缺陷所致。
