1 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Am J Respir Crit Care Med. 2014 Oct 1;190(7):744-55. doi: 10.1164/rccm.201407-1226OC.
As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD).
To determine whether individuals with HIV-associated COPD exhibit dysregulated lung mucosal T-cell immunity compared with control subjects.
Using flow cytometry, we evaluated peripheral blood and lung mucosal T-cell immunity in 14 HIV(+)COPD(+), 13 HIV(+)COPD(-), and 7 HIV(-)COPD(+) individuals.
HIV(+)COPD(+) individuals demonstrated profound CD4(+) T-cell depletion with reduced CD4/CD8 T-cell ratios in bronchoalveolar lavage-derived lung mononuclear cells, not observed in peripheral blood mononuclear cells, and diminished CD4(+) T cell absolute numbers, compared with control subjects. Furthermore, HIV(+)COPD(+) individuals demonstrated decreased pulmonary HIV-specific and staphylococcal enterotoxin B-reactive CD4(+) memory responses, including loss of multifunctionality, compared with HIV(+)COPD(-) control subjects. In contrast, lung mucosal HIV-specific CD8(+) T-cell responses were preserved. Lung CD4(+) T cells from HIV(+)COPD(+) individuals expressed increased surface Fas death receptor (CD95) and programmed death-1, but similar bronchoalveolar lavage viral loads as control subjects. However, programmed death-1 expression inversely correlated with HIV-specific lung CD4(+)IFN-γ(+) T-cell responses, suggesting functional exhaustion. Moreover, lung CD4(+) T cells from HIV(+)COPD(+) patients demonstrated increased basal and HIV antigen-induced expression of the early apoptosis marker annexin V compared with control subjects, which was significantly attenuated with anti-Fas blockade. Lastly, lung mucosal, but not blood, CD4(+)/CD8(+) ratios from HIV(+) patients significantly correlated with the FEV1, but not in HIV(-)COPD(+) patients.
Together, our results provide evidence for profound lung mucosal CD4(+) T-cell depletion via a Fas-dependent activation-induced cell death mechanism, along with impaired HIV-specific CD4(+) immunity as immunologic features of HIV-associated COPD.
随着总生存时间的延长，HIV 感染者易发生其他慢性疾病，包括加速进展的慢性阻塞性肺疾病（COPD）。
确定 HIV 合并 COPD 患者与对照者相比，是否存在肺黏膜 T 细胞免疫失调。
采用流式细胞术，我们评估了 14 例 HIV（+）COPD（+）、13 例 HIV（+）COPD（-）和 7 例 HIV（-）COPD（+）患者的外周血和肺黏膜 T 细胞免疫。
HIV（+）COPD（+）患者支气管肺泡灌洗液来源的肺单核细胞中 CD4（+）T 细胞明显耗竭，CD4/CD8 T 细胞比值降低，在外周血单核细胞中未见此现象，且 CD4（+）T 细胞绝对数减少，与对照者相比。此外，HIV（+）COPD（+）患者的肺 HIV 特异性和葡萄球菌肠毒素 B 反应性 CD4（+）记忆反应下降，包括多功能性丧失，与 HIV（+）COPD（-）对照者相比。相反，肺黏膜 HIV 特异性 CD8（+）T 细胞反应得到保留。HIV（+）COPD（+）患者的肺 CD4（+）T 细胞表达增加的表面 Fas 死亡受体（CD95）和程序性死亡受体 1，但与对照者相比，支气管肺泡灌洗液中的病毒载量相似。然而，程序性死亡受体 1 的表达与 HIV 特异性肺 CD4（+）IFN-γ（+）T 细胞反应呈负相关，提示功能耗竭。此外，与对照者相比，HIV（+）COPD（+）患者的肺 CD4（+）T 细胞表现出基础和 HIV 抗原诱导的早期凋亡标志物 Annexin V 表达增加，而 Fas 阻断可显著减弱这种表达。最后，HIV 患者的肺黏膜，但不是血液，CD4（+）/CD8（+）比值与 FEV1 显著相关，但在 HIV（-）COPD（+）患者中则无相关性。
我们的结果共同提供了证据，证明 HIV 相关性 COPD 的肺黏膜 CD4（+）T 细胞耗竭是通过 Fas 依赖性激活诱导的细胞死亡机制介导的，同时存在 HIV 特异性 CD4（+）免疫受损，这是 HIV 相关性 COPD 的免疫特征。
