Characterization of Immunologic Defects in Patients with Common Variable Immunodeficiency (CVID) with Intestinal Disease
Characterization of Immunologic Defects in Patients with Common Variable Immunodeficiency (CVID) with Intestinal Disease
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DOI：
10.1002/ibd.21376
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发表时间：
2011-01-01
影响因子：
4.9
通讯作者：
Mayer, Lloyd
中科院分区：
文献类型：
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作者：
Agarwal, Shradha;Smereka, Paul;Mayer, Lloyd
背景：共同变量免疫缺陷(CVID)是一种异质性疾病，通常表现为反复的鼻肺感染。总体而言，6%-10%的CVID患者发展为炎症性肠病(IBD)样疾病，使这些患者成为研究免疫介导的胃肠道疾病的独特人群。方法：用抗CD3+CD28或植物血凝素(PHA)+佛波酯(PMA)刺激CVID合并IBD患者外周血(PB)T细胞，用酶联免疫吸附试验(ELISA)检测细胞因子的产生。用实时定量聚合酶链式反应(PCR)比较未经刺激的固有层淋巴细胞(LPLs)细胞因子的表达。采用免疫组织化学方法检测胃粘膜活检组织学改变。结果：抗CD3+CD28刺激的CVID/IBD外周血T细胞较对照组有降低IL-2、IL-10、干扰素-γ和肿瘤坏死因子-α的趋势。经PHA/PMA刺激后，上述差异不明显。未检测到LPL产生的炎性细胞因子。组织学上，CVID患者血浆细胞减少/缺失，肠道IgM和IgA减少。与正常对照组和IBD对照组相比，合并胃肠道疾病的CVID患者结肠内CD3+T细胞尤其是CD8+T细胞明显增加，提示肠道免疫功能紊乱。结论：CVID合并IBD样病患者的肠道炎症可能是通过T细胞受体介导的细胞因子异常产生而介导的。然而，观察到的可变性表明，这涉及到多种机制，而不是单一的机制。组织学特征，如肠道浆细胞减少和肠道免疫球蛋白缺乏，可能是诊断常规治疗无效的胃肠道疾病患者CVID的有用标记物。
Background: Common variable immunodeficiency (CVID) is a heterogeneous disorder commonly presenting with recurrent sinopulmonary infections. In all, 6%-10% of CVID patients develop an inflammatory bowel disease (IBD)-like disorder, making these patients a unique population to investigate immune-mediated gastrointestinal disease. This study examined whether defects in peripheral and/or intestinal lymphocytes are involved in disruption of the intestinal mucosa in CVID patients with inflammatory intestinal diseases.Methods: Peripheral blood (PB) T cells from healthy controls; CD or UC; CVID; and CVID with IBD were stimulated for 48 hours with anti-CD3+CD28 or phytohemagglutinin (PHA) + phorbol 12-myristate 13-acetate (PMA); cytokine production was measured by enzyme-linked immunosorbent assay (ELISA). Cytokine expression from unstimulated lamina propria lymphocytes (LPLs) was compared by real-time polymerase chain reaction (PCR). Immunohistochemistry of mucosal biopsies was performed. Cell populations were quantified by morphometry.Results: CVID/IBD PB T cells stimulated by anti-CD3+CD28 had trends for reduced IL-2, IL-10, IFN-gamma, and TNF-alpha compared to controls. These differences were not apparent following stimulation by PHA/PMA. Constitutive production of inflammatory cytokines by LPLs was not detected. Histologically, CVID patients had reduced/absent plasma cells with reductions in intestinal IgM and IgA. CVID patients with and without gastrointestinal (GI) disease exhibited increased CD3+ T cells, specifically CD8+, in the colon compared to normal and IBD controls, suggesting immune dysregulation.Conclusions: Intestinal inflammation in CVID patients with IBD-like disease may be mediated by abnormal cytokine production through a T-cell receptor-mediated pathway. However, the variability observed suggests multiple, rather than singular, mechanisms are involved. Histologic features such as reduced intestinal plasma cells and lack of intestinal immunoglobulins may be useful markers in diagnosing CVID in a patient with GI disease refractory to conventional therapies.