Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation.
Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation.
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HIV患者脑脊液抗CD4自身抗体水平升高与神经炎症相关
DOI：
10.1128/spectrum.01975-21
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发表时间：
2022-02-23
影响因子：
3.7
通讯作者：
Jiang W
中科院分区：
文献类型：
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作者：
Cheng D;Luo Z;Fu X;Stephenson S;Di Germanio C;Norris PJ;Fuchs D;Ndhlovu LC;Li QZ;Zetterberg H;Gisslen M;Price RW;Peng S;Jiang W
尽管抗逆转录病毒治疗（ART）有效，但HIV感染者（PWH）中枢神经系统（CNS）持续炎症的机制尚不完全清楚。我们最近的研究表明，在抑制性抗逆转录病毒治疗期间，血浆抗CD4 IgG通过抗体介导的细胞毒性（ADCC）作用于CD4+ T细胞，导致CD4+ T细胞恢复不良，血浆抗CD4 IgG水平与认知能力下降和特异性脑区萎缩有关。然而，抗cd4 igg在神经炎症中的作用尚不清楚。在目前的研究中，研究人员对31例未经art治疗和26例病毒学抑制的PWH患者的血浆和脑脊液（CSF）样本以及16例hiv血清阴性对照进行了CSF抗cd4 IgG、白细胞（WBC）计数、神经炎症可溶性生物标志物和神经丝轻链（NfL）水平的评估。我们发现37%的PWH表现出CSF抗cd4 IgG水平升高，但很少或没有PWH观察到CSF抗cd4 IgM，抗cd8 IgG或抗双链DNA IgG升高。PWH患者脑脊液抗cd4 IgG水平与神经炎症（白细胞计数、新蝶呤和髓细胞活化标志物）直接相关，但与脑脊液NfL水平无关。利用一种对ART无应答的细胞，我们产生了一种具有ADCC活性的致病性抗cd4单克隆IgG (JF19)；JF19通过体外CD4结合诱导人原代单核细胞源性巨噬细胞产生可溶性CD14 （sCD14）和白细胞介素-8 （IL-8）。本研究首次证明脑脊液抗cd4 IgG水平升高存在于PWH亚组中，这可能在HIV的神经炎症中起作用。这项研究报告了HIV患者中枢神经系统中存在一种自身抗体，其在脑脊液中的水平与一些神经炎症标志物相关。
The mechanisms of persistent central nervous system (CNS) inflammation in people with HIV (PWH) despite effective antiretroviral therapy (ART) are not fully understood. We have recently shown that plasma anti-CD4 IgGs contribute to poor CD4+ T cell recovery during suppressive ART via antibody-mediated cytotoxicity (ADCC) against CD4+ T cells, and that plasma anti-CD4 IgG levels are associated with worse cognitive performance and specific brain area atrophy. However, the role of anti-CD4 IgGs in neuroinflammation remains unclear. In the current study, plasma and cerebrospinal fluid (CSF) samples from 31 ART-naive and 26 treated, virologically suppressed PWH, along with 16 HIV-seronegative controls, were evaluated for CSF levels of anti-CD4 IgG, white blood cell (WBC) counts, soluble biomarkers of neuroinflammation, and neurofilament light chain (NfL). We found that 37% of the PWH exhibited elevated CSF anti-CD4 IgG levels, but few or none of the PWH were observed with elevated CSF anti-CD4 IgM, anti-CD8 IgG, or anti-double-strand DNA IgG. CSF anti-CD4 IgG levels in PWH were directly correlated with neuroinflammation (WBC counts, neopterin, and markers of myeloid cell activation), but not with CSF NfL levels. Using cells from one immune nonresponder to ART, we generated a pathogenic anti-CD4 monoclonal IgG (JF19) presenting with ADCC activity; JF19 induced the production of soluble CD14 (sCD14) and interleukin-8 (IL-8) in human primary monocyte-derived macrophages via CD4 binding in vitro. This study demonstrates for the first time that elevated CSF anti-CD4 IgG levels present in a subgroup of PWH which may play a role in neuroinflammation in HIV. IMPORTANCE This study reports that an autoantibody presents in the CNS of HIV patients and that its levels in the CSF correlate with some markers of neuroinflammation.
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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