Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
Front Immunol. 2018 Aug 10;9:1826. doi: 10.3389/fimmu.2018.01826. eCollection 2018.
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase () mutation. Patients are susceptible to severe enterovirus infections. The underlying mechanism remains unknown. BTK is involved in toll-like receptors pathway, which initiates antiviral responses including interferon (IFN) productions.
To demonstrate type I and III IFN productions in dendritic cells of XLA patients is decreased in response to oral poliovirus vaccine (OPV) but not H1N1 virus.
Monocyte-derived dendritic cells (MoDCs) were derived from nine XLA patients aged 22-32 years old and 23 buffy coats from Hong Kong Red Cross blood donors. LFM-A13 was used to inhibit BTK. OPV Sabin type 1 and H1N1 influenza virus were used to stimulate MoDCs with RPMI as mock stimulation. The antiviral cytokine productions and phenotypic maturation of MoDCs were determined 24 h post-stimulation. OPV RNA was determined at 0, 6, 12, and 24 h post-stimulation.
Upon OPV stimulation, IFN-α2, IFN-β, and IFN-λ1 productions in MoDCs from XLA patients and BTK-inhibited MoDCs of healthy controls were significantly lower than that from healthy controls. Whereas upon H1N1 stimulation, the IFN-α2, IFN-β, and IFN-λ1 productions were similar in MoDCs from XLA patients, BTK-inhibited MoDCs of healthy controls and healthy controls. The mean fluorescent intensities (MFI) of CD83, CD86, and MHC-II in MoDCs from XLA patients in response to OPV was similar to that in response to mock stimulation, while the MFI of CD83, CD86, and MHC-II were significantly higher in response to H1N1 stimulation than that in response to mock stimulation. Whereas, the MFI of CD83, CD86, and MHC-II in MoDCs of healthy controls were significantly higher in response to both OPV and H1N1 stimulation compared to that in response to mock stimulation.
Production of type I and III IFN in response to OPV was deficient in MoDCs from XLA patients, but was normal in response to H1N1 due to deficient BTK function. Moreover, phenotypic maturation of MoDCs from XLA patients was impaired in response to OPV but not to H1N1. These selective impairments may account for the unique susceptibility of XLA patients toward severe enterovirus infections.
X 连锁无丙种球蛋白血症（XLA）是一种由 Bruton 酪氨酸激酶（BTK）突变引起的原发性免疫缺陷病。患者易发生严重的肠道病毒感染。其潜在机制尚不清楚。BTK 参与 Toll 样受体途径，该途径启动抗病毒反应，包括干扰素（IFN）的产生。
证明 XLA 患者的树突状细胞（DC）对口服脊髓灰质炎疫苗（OPV）的反应中，I 型和 III 型 IFN 的产生减少，但对 H1N1 病毒无此反应。
从 9 名年龄在 22-32 岁的 XLA 患者和 23 份香港红十字会献血者的外周血单核细胞中分离出单核细胞来源的树突状细胞（MoDCs）。用 LFM-A13 抑制 BTK。用 OPV Sabin 1 型和 H1N1 流感病毒刺激 MoDCs，RPMI 作为模拟刺激。刺激后 24 小时测定抗病毒细胞因子的产生和 MoDC 的表型成熟。在刺激后 0、6、12 和 24 小时测定 OPV RNA。
OPV 刺激时，XLA 患者和健康对照组 BTK 抑制剂 MoDC 产生的 IFN-α2、IFN-β 和 IFN-λ1 明显低于健康对照组。而 H1N1 刺激时，XLA 患者 MoDC 产生的 IFN-α2、IFN-β 和 IFN-λ1 与健康对照组 BTK 抑制剂 MoDC 和健康对照组相似。XLA 患者 MoDC 对 OPV 的反应中 CD83、CD86 和 MHC-II 的平均荧光强度（MFI）与对模拟刺激的反应相似，而对 H1N1 的反应中 CD83、CD86 和 MHC-II 的 MFI 明显高于对模拟刺激的反应。然而，健康对照组 MoDC 对 OPV 和 H1N1 的反应中 CD83、CD86 和 MHC-II 的 MFI 明显高于对模拟刺激的反应。
XLA 患者 MoDC 对 OPV 的 I 型和 III 型 IFN 产生反应缺陷，但由于 BTK 功能缺陷，对 H1N1 的反应正常。此外，XLA 患者 MoDC 对 OPV 的表型成熟反应受损，但对 H1N1 无此反应。这些选择性缺陷可能解释了 XLA 患者对严重肠道病毒感染的独特易感性。
