Fu Xiaoyu, Cheng Da, Luo Zhenwu, Heath Sonya L, Adekunle Ruth, McKinnon John E, Martin Lisa, Sheng Zizhang, Espinosa Enrique, Jiang Wei
Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. BSB207, Charleston, SC, 29425, USA.
Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Cell Biosci. 2023 May 3;13(1):78. doi: 10.1186/s13578-023-01022-6.
. Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear.
. Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG-producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro.
. Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro.
. Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.
接受病毒学抑制抗逆转录病毒疗法（ART）的艾滋病病毒感染者（PWH）中，高达20%的人未能实现完全免疫恢复。我们最近报告称，免疫无反应者的血浆抗CD4 IgG（抗CD4IgG）自身抗体通过抗体依赖性细胞毒性特异性消耗CD4 + T细胞。然而，抗CD4IgG产生的机制仍不清楚。
采集16名健康个体和25名接受抑制性ART的PWH的血样。通过酶联免疫吸附测定法（ELISA）测量IgG亚类、血浆脂多糖（LPS）和抗CD4IgG水平。通过微阵列和定量聚合酶链反应分析B细胞中的基因谱。此外，建立了患者来源的产生抗CD4IgG的B细胞系，并在体外用LPS刺激。在体外评估C57/B6小鼠脾B细胞对LPS反应时的B细胞IgG类别转换重组（CSR）。
PWH中血浆抗CD4 IgGs增加主要为IgG1，且与体内血浆LPS水平升高以及B细胞中TLR2、TLR4和MyD88 mRNA的表达增加相关。此外，LPS刺激在体外诱导抗CD4IgG B细胞系产生抗CD4IgG。最后，LPS在体外促进CSR。
我们的研究结果表明，持续的LPS易位可能促进接受ART的PWH中抗CD4自身反应性B细胞的激活和抗CD4IgG的产生，这可能导致CD4 + T细胞逐渐耗竭。这项研究表明，逆转受损的黏膜屏障可能改善未能实现完全免疫恢复的PWH的ART治疗效果。
