Elevated neuroinflammation, autoimmunity, and altered IgG glycosylation profile in the cerebral spinal fluid of severe COVID-19 patients

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2025-03-27 DOI:10.1016/j.bbi.2025.03.031

Tanner Shull , Pavan Bhimalli , Samantha Welninski , Byoung-Kyu Cho , Basil Mattamana , Jaison Arivalagan , Imad Tarhoni , Young Ah Goo , Julie A. Schneider , Sonal Agrawal , David A Bennett , Sue Leurgans , Mayur B. Patel , E.Wesley Ely , Neil L. Kelleher , Jeffrey A. Borgia , Jeffrey R. Schneider , Lena Al-Harthi

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引用次数: 0

Abstract

Background and Objectives

A spectrum of neurologic complications associated with COVID-19 are well documented. While neuroinflammation in the brain of COVID-19 patients likely contributes to these complications, the mechanisms of neuroinflammation and correlates of neurologic complications remain elusive, especially since the etiologic pathogen of COVID-19, SARS-CoV-2, minimally invades the CNS. This study aimed to evaluate markers of neuroinflammation, IgG glycosylation patterns indicative of pro- or anti-inflammatory state, and prevalence of brain auto-reactive antibodies in the CSF of COVID-19 patients and their relationship to brain neuropathology.

Methods

We evaluated the CSF of 11 deceased unvaccinated COVID-19 donors and 13 matched non-COVID-19 controls. Markers of neuroinflammation, IgG glycosylation patterns, and brain auto-reactive antibodies were assessed, along with their correlation to brain neuropathology. Statistical analyses were performed to compare groups and assess relationships between variables, using non-parametric tests and bootstrap analysis.

Results

COVID-19 CSF showed higher levels of neopterin and ANNA-1, markers of neuroinflammation and autoimmunity, respectively, and lower IFN response compared to non-COVID-19 donors. In brain regions of high microglial activation, IL4 and RANTES were significantly increased. SARS-CoV-2 was undetectable in the CSF and brain of COVID-19 donors, yet anti-SARS-CoV-2 CSF antibodies were detected. Fucosylated IgG were associated with Spike IgG, CSF protein, and soluble CD14, whereas afucosylated bisecting IgG were inversely correlated with Spike IgG. Sialic acid containing IgG were positively correlated with IL1β and TNFα. These associations were not found in non-COVID-19 donors. Inflammatory agalactosylated fucosylated IgG (G0F) were associated with infiltrating CD4 + T cells in the brains of COVID-19 donors. COVID-19 donor CSF displayed higher levels of auto-reactive antibodies to human brain antigens compared to non-COVID-19 donors and donors with positive autoantibodies showed higher levels of neopterin.

Discussion

These data describe increased neuroinflammation and autoreactive antibody markers in the CSF of COVID-19 donors and suggest that IgG glycosylation and autoimmunity may contribute to COVID-19 pathology, highlighting potential mechanisms underlying the neurologic complications associated with COVID-19.

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重症COVID-19患者脑脊液中神经炎症、自身免疫和IgG糖基化谱升高

背景和目的：与COVID-19相关的一系列神经系统并发症已得到充分记录。虽然COVID-19患者大脑中的神经炎症可能导致这些并发症，但神经炎症的机制和神经系统并发症的相关因素仍然难以捉摸，特别是因为COVID-19的病原学病原体SARS-CoV-2对中枢神经系统的侵袭最小。本研究旨在评估COVID-19患者的神经炎症标志物、促炎或抗炎状态的IgG糖基化模式、脑脊液中脑自身反应性抗体的患病率及其与脑神经病理学的关系。方法：我们评估了11例未接种COVID-19疫苗的死亡供体和13例匹配的非COVID-19对照者的CSF。评估神经炎症标志物、IgG糖基化模式和脑自身反应性抗体，以及它们与脑神经病理学的相关性。采用非参数检验和自举分析进行统计分析以比较组和评估变量之间的关系。结果：与非COVID-19供体相比，COVID-19 CSF中neopterin和ANNA-1（神经炎症和自身免疫标志物）水平分别较高，IFN反应较低。在小胶质细胞高度激活的脑区，IL4和RANTES显著升高。在COVID-19供体的脑脊液和大脑中检测不到SARS-CoV-2，但检测到抗SARS-CoV-2脑脊液抗体。聚焦的IgG与Spike IgG、CSF蛋白和可溶性CD14相关，而聚焦的平分IgG与Spike IgG呈负相关。唾液酸含IgG与il - 1β、tnf - α呈正相关。在非covid -19供体中未发现这些关联。炎症性无半胱甘肽基化聚焦IgG （G0F）与COVID-19供体大脑中CD4 + T细胞浸润有关。与非COVID-19供者相比，COVID-19供者CSF显示出更高水平的针对人脑抗原的自身反应性抗体，而自身抗体阳性的供者显示出更高水平的新蝶呤。讨论：这些数据描述了COVID-19供者脑脊液中神经炎症和自身反应性抗体标志物的增加，并表明IgG糖基化和自身免疫可能导致COVID-19病理，突出了与COVID-19相关的神经系统并发症的潜在机制。

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来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.