Cargando…
Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation
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-medi...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729763/ https://www.ncbi.nlm.nih.gov/pubmed/34985329 http://dx.doi.org/10.1128/spectrum.01975-21 |
_version_ | 1784627001891487744 |
---|---|
author | Cheng, Da Luo, Zhenwu Fu, Xiaoyu Stephenson, Sophie Di Germanio, Clara Norris, Philip J. Fuchs, Dietmar Ndhlovu, Lishomwa C. Li, Quan-zhen Zetterberg, Henrik Gisslen, Magnus Price, Richard W. Peng, Shifang Jiang, Wei |
author_facet | Cheng, Da Luo, Zhenwu Fu, Xiaoyu Stephenson, Sophie Di Germanio, Clara Norris, Philip J. Fuchs, Dietmar Ndhlovu, Lishomwa C. Li, Quan-zhen Zetterberg, Henrik Gisslen, Magnus Price, Richard W. Peng, Shifang Jiang, Wei |
author_sort | Cheng, Da |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8729763 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-87297632022-01-06 Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation Cheng, Da Luo, Zhenwu Fu, Xiaoyu Stephenson, Sophie Di Germanio, Clara Norris, Philip J. Fuchs, Dietmar Ndhlovu, Lishomwa C. Li, Quan-zhen Zetterberg, Henrik Gisslen, Magnus Price, Richard W. Peng, Shifang Jiang, Wei Microbiol Spectr Research Article 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. American Society for Microbiology 2022-01-05 /pmc/articles/PMC8729763/ /pubmed/34985329 http://dx.doi.org/10.1128/spectrum.01975-21 Text en Copyright © 2022 Cheng et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Cheng, Da Luo, Zhenwu Fu, Xiaoyu Stephenson, Sophie Di Germanio, Clara Norris, Philip J. Fuchs, Dietmar Ndhlovu, Lishomwa C. Li, Quan-zhen Zetterberg, Henrik Gisslen, Magnus Price, Richard W. Peng, Shifang Jiang, Wei Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation |
title | Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation |
title_full | Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation |
title_fullStr | Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation |
title_full_unstemmed | Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation |
title_short | Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation |
title_sort | elevated cerebrospinal fluid anti-cd4 autoantibody levels in hiv associate with neuroinflammation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729763/ https://www.ncbi.nlm.nih.gov/pubmed/34985329 http://dx.doi.org/10.1128/spectrum.01975-21 |
work_keys_str_mv | AT chengda elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT luozhenwu elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT fuxiaoyu elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT stephensonsophie elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT digermanioclara elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT norrisphilipj elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT fuchsdietmar elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT ndhlovulishomwac elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT liquanzhen elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT zetterberghenrik elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT gisslenmagnus elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT pricerichardw elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT pengshifang elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation AT jiangwei elevatedcerebrospinalfluidanticd4autoantibodylevelsinhivassociatewithneuroinflammation |