Increased sensitivity to IL-4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis
Increased sensitivity to IL-4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis
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DOI：
10.1046/j.1398-9995.2003.00129.x
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发表时间：
2004-01-01
期刊：
影响因子：
12.4
通讯作者：
Kurup, VP
中科院分区：
文献类型：
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作者：
Knutsen, AP;Hutchinson, PS;Kurup, VP
背景：与无ABPA的囊性纤维化患者相比，变态反应性支气管肺曲霉菌病(ABPA)的特征是Th2、CD4+T细胞对烟曲霉变应原的反应增强和高免疫球蛋白(Ig)E状态。我们推测这一反应的原因之一是ABPA对IL-4的敏感性增加，导致CD23和CD86表达增加，从而导致Th2 CD4+T细胞应答的阳性放大机制。方法：分离7例ABPA CF和19例非ABPA CF患者和16例非特应性对照的外周血单个核细胞(PBMC)，分别用rIL-4(0.1-10 ng/ml)和rIL-13(1-10 ng/ml)刺激48h，用流式细胞仪检测CD23分子的数量和CD23+B细胞的百分比。结果：ABPA CF患者外周血B细胞表面CD23分子数量在0时点显著高于非ABPA CF患者和非特应性对照组。在体外经IL-4刺激后，ABPA患者B细胞表面CD23表达的数量和百分比显著高于非ABPA患者和对照组。IL-13刺激可上调CD23的表达，但ABPA CF患者与非ABPA CF患者及对照组相比，CD23表达无明显差异。经PMA/IO刺激后，ABPA和非ABPA CF患者外周血中干扰素-γ-CD3+T细胞百分率均显著低于对照组。ABPA患者与非ABPA患者外周血中IL-4+、IL-13+CD3+T细胞水平差异无统计学意义。当检测破伤风类毒素刺激的T细胞时，ABPA和非ABPA CF患者的干扰素-γ+CD3+T细胞均显著低于对照组。在Asp f2/f3/f4刺激的T细胞中，ABPA CF患者的IL-4+CD3+T细胞明显高于非ABPA CF患者和对照组。结论：ABPA CF患者对IL-4的敏感性高于非ABPA CF患者，但对IL-13上调CD23分子的敏感性不明显。与非特应性对照组相比，CF患者外周血中干扰素-γ和IL-2+Th1T细胞的百分率均降低，而IL-4+Th2T细胞的百分率无明显变化。然而，ABPA CF患者曲霉菌刺激的Th2T细胞频率增加。提示ABPA-CF患者存在Th2T细胞的偏斜。因此，在CFABPA患者中，Th2 T细胞增加，对IL-4的敏感性增加。
Background: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a heightened Th2 CD4+ T-cell response to Aspergillus fumigatus allergens and a hyper-immunoglobulin (Ig)E state compared with cystic fibrosis patients without ABPA. We hypothesize that one reason for this response is increased sensitivity to interleukin (IL)-4 in ABPA resulting in increased expression of CD23 and CD86 and leading to a positive amplification mechanism that increases Th2 CD4+ T cell responses.Methods: Peripheral blood mononuclear cells (PBMC) were isolated from seven ABPA CF and 19 non-ABPA CF patients and 16 nonatopic controls and stimulated with rIL-4 (range 0.1-10 ng/ml) and rIL-13 (range 1-10 ng/ml) for 48 h. The number of CD23 molecules and percentages of CD23+ B cells were quantified by flow cytometry. Both phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO) and antigen stimulated, toxoid and Asp f2/f3/f4, PBMC were examined for cytoplasmic cytokine synthesis enumerated by cytokine staining using flow cytometry to measure Th2 and Th1 CD3+ T cells.Results: The numbers of CD23 molecules on B-cells were significantly elevated at time 0 in ABPA CF patients compared with both non-ABPA CF patients and nonatopic controls. Following IL-4 stimulation in vitro, the numbers and percentages of CD23 expression on B cells were significantly up-regulated in ABPA CF patients compared with non-ABPA CF patients and controls. The IL-13 stimulation up-regulated CD23 expression; however, there was no significant difference in ABPA CF patients compared with non-ABPA CF patients and controls. The percentages of interferon (IFN)-gamma+ CD3+T cells following PMA/IO stimulation were significantly decreased in both ABPA and non-ABPA CF patients compared with controls. There were no significant differences of IL-4+ and IL-13+ CD3+ T cells between ABPA and non-ABPA CF patients. When tetanus toxoid stimulated T cells were examined, both ABPA and non-ABPA CF patients had significantly decreased IFN-gamma+ CD3+ T cells compared with controls. In Asp f2/f3/f4 stimulated T cells, ABPA CF patients had significantly increased IL-4+ CD3+ T cells compared with non-ABPA CF patients and controls.Conclusions: ABPA CF patients have increased sensitivity to IL-4 but not to IL-13 up-regulation of CD23 molecules compared with non-ABPA CF patients. There were decreased percentages of IFN-gamma+ and IL-2+ Th1 T cells in CF patients compared with nonatopic controls but similar percentages of IL-4+ Th2 T cells in all three groups. However, ABPA CF patients had increased frequency of Aspergillus-stimulated Th2 T cells. This indicated that there is skewing of Th2 T cells in ABPA CF patients. Thus, in CF ABPA patients there is increased Th2 T cells and increased sensitivity to IL-4.