Department of Molecular Biology and Microbiology.
Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine.
AIDS. 2020 May 1;34(6):815-826. doi: 10.1097/QAD.0000000000002499.
Since intestinal immunity and the microbiome are disrupted in HIV disease, we studied the abundance of innate immune sensors, Toll-like receptors (TLRs), in the mucosa of participants with viremia, prior to antiretroviral therapy (ART), immune success (>500 CD4 T cells/μl after 2 years of ART; suppressed viremia), and immune failure (<350 CD4 T cells/μl after 2 years of ART; suppressed viremia). We hypothesized that disruption of intestinal TLR abundance and location provides a mechanism behind persistent inflammation.
Immunofluorescence for TLR3, TLR4, and TLR9 on paraffin embedded biopsies from uninfected, viremic, immune success, and immune failure colons was imaged by deconvolution microscopy and quantified with MetaMorph software. Plasma levels of C-reactive protein, IL-6, and intestinal fatty-acid binding protein (I-FABP) were correlated with TLR expression.
Viremic participants have significantly higher levels of TLR3 and TLR9 on surface epithelium and in crypts when compared with uninfected controls. TLR3 is further elevated in immune failure and immune success. TLR9 abundance remains elevated in immune failure and is normalized in immune success. TLR9 expression in the crypt and lamina propria positively associates with C-reactive protein and IL-6 and negatively with I-FABP. TLR4 is significantly lower on surface epithelium and higher in crypts in viremic. Its expression in the lamina propria positively correlates with IL-6 and negatively correlates with I-FABP.
Mucosal TLR imbalance and deregulation, and the resulting mucosal TLR desensitization and hypervigilance, remain after suppressive ART, in the presence or absence of T-cell recovery, likely contributing to chronic systemic inflammation.
由于 HIV 疾病会破坏肠道免疫和微生物组，我们研究了携带病毒血症的参与者的粘膜中固有免疫传感器，即 Toll 样受体（TLR）的丰度，这些参与者在接受抗逆转录病毒治疗（ART）之前、免疫成功（接受 2 年 ART 后 CD4 T 细胞>500/μl；病毒血症受抑制）和免疫失败（接受 2 年 ART 后 CD4 T 细胞<350/μl；病毒血症受抑制）。我们假设，肠道 TLR 丰度和位置的破坏为持续炎症提供了一种机制。
对未感染、携带病毒血症、免疫成功和免疫失败结肠的石蜡包埋活检进行 TLR3、TLR4 和 TLR9 的免疫荧光染色，使用反卷积显微镜进行成像，并使用 MetaMorph 软件进行定量。血浆 C 反应蛋白、IL-6 和肠脂肪酸结合蛋白（I-FABP）的水平与 TLR 表达相关。
与未感染对照组相比，携带病毒血症的参与者的表面上皮和隐窝中 TLR3 和 TLR9 的水平显著升高。TLR3 在免疫失败和免疫成功中进一步升高。TLR9 的丰度在免疫失败中仍然升高，在免疫成功中恢复正常。TLR9 在隐窝和固有层中的表达与 C 反应蛋白和 IL-6 呈正相关，与 I-FABP 呈负相关。TLR4 在表面上皮上显著降低，在隐窝中升高。其在固有层中的表达与 IL-6 呈正相关，与 I-FABP 呈负相关。
在抑制性 ART 后，即使存在 T 细胞恢复，黏膜 TLR 失衡和失调，以及由此产生的黏膜 TLR 脱敏和过度敏感，仍可能导致慢性全身炎症。
