O4‐09‐06: Clonally Expanded Cd8 T Cells Patrol Alzheimer's Cerebrospinal Fluid

Gate, David; Saligrama, Naresha; Yang, Andrew; Middeldorp, Jinte; Levanthal, Olivia; Chen, Kelly; Lehallier, Benoit; McBride, Alisha A.; Channappa, Divya; Tam, Grace; Kim, Yongha; Greicius, Michael D.; Wagner, Anthony D.; Davis, Mark M.; Wyss‐Coray, Tony

doi:10.1016/j.jalz.2019.06.4793

Cited by 11 publications

(21 citation statements)

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“…Moreover, a recent report identi ed α-synuclein-speci c T cells in peripheral blood of Parkinson's disease (PD) patients (17), but whether these cells enter the CSF is unknown. Finally, our group reported the presence of clonally expanded T cells in the CSF of AD patients and granzyme-A + CD8 + T cells in the parenchyma of AD brains (18). Cumulatively, these advances provide evidence that T cells may be involved in the pathobiology of several neurodegenerative diseases and emphasize the value of CSF cells to study the role of adaptive immunity in neurodegenerative disease.…”

Section: Introductionmentioning

confidence: 79%

“…Interestingly, the largest clusters contained TCR sequences exclusively from patients with neurodegenerative diseases, even though healthy control TCRs were also included in the analysis (Figure 3c), and were expressed by CD8 + T cells (Figure 3d). Moreover, three of the TCRb sequences in Cluster 1 were identical ( Supplementary Figure 3b) (CASSLGQAYEQYF) and have been shown to be speci c for Epstein-Barr virus (EBV) epitope EBNA3A (18).…”

Section: Resultsmentioning

confidence: 99%

“…CSF cells, on the other hand, provide a way to directly study immunology in the central nervous system. Indeed, recent studies of intrathecal immunity by us and others have shown this understudied immune compartment to be relevant to the pathobiology of neurodegenerative diseases (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)22). Yet, CSF cells have been widely understudied because of the invasive method of CSF extraction (typically lumbar puncture), and because cells are often discarded for proteomic analysis.…”

Section: Discussionmentioning

confidence: 99%

“…It will be important to continue to expand our knowledge of TCR antigen speci city in neurodegenerative diseases, especially in diseases where infection is not thought to be the primary cause. This is especially important given the growing evidence that T cells may negatively contribute to the pathobiology of several neurodegenerative diseases, including AD and PD (17,18). Utilizing these methods to identify candidate disease-associated TCRs will aid in the identi cation of self/non-self antigen targets of clonally expanded T cells in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

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Methods to investigate intrathecal adaptive immunity in neurodegeneration

Leventhal

Channappa

et al. 2021

Preprint

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Background: Cerebrospinal fluid (CSF) provides basic mechanical and immunological protection to the brain. Historically, analysis of CSF has focused on protein changes, yet recent studies have shed light on cellular alterations. Evidence now exists for involvement of intrathecal T cells in the pathobiology of neurodegenerative diseases. However, a standardized method for long-term preservation of CSF immune cells is lacking. Further, the functional role of CSF T cells and their cognate antigens in neurodegenerative diseases are largely unknown.Results: We present a method for long-term cryopreservation of CSF immune cells for downstream single cell RNA and T cell receptor sequencing (scRNA-TCRseq) analysis. We observe preservation of CSF immune cells, consisting primarily of memory CD4+ and CD8+ T cells. We then utilize unbiased bioinformatics approaches to quantify and visualize TCR sequence similarity within and between disease groups. By this method, we identify clusters of disease-associated, antigen-specific TCRs from clonally expanded CSF T cells of patients with neurodegenerative diseases.Conclusions: Here, we provide a standardized approach for long-term storage of CSF immune cells. Additionally, we present unbiased bioinformatic approaches that will facilitate the discovery of target antigens of clonally expanded T cells in neurodegenerative diseases. These novel methods will help improve our understanding of adaptive immunity in the central nervous system.

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Section: Introductionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Methods to investigate intrathecal adaptive immunity in neurodegeneration

Leventhal

Channappa

et al. 2021

Preprint

Self Cite

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“…Researches also provided a nuanced comparison of the human brain's immune states during homeostasis, aging, and disease through the integration of CyTOF and other omic techniques and demonstrated that microglia subsets exhibited disease‐specific transformations in the brain (Table 4). 159–163 Another interesting study focused on the impact of immune response to stroke on long‐term cognitive disability 164 . With the approach of CyTOF, serial blood sample from patients was collected and analyzed over the course of a year to functionally and comprehensively characterize the immune response to stroke and its correlation with cognitive functioning between 90 and 365 days poststroke.…”

Section: Applicationsmentioning

confidence: 99%

Progress and applications of mass cytometry in sketching immune landscapes

Zhang

Warden

2020

Clinical & Translational Med

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Recently emerged mass cytometry (cytometry by time-of-flight [CyTOF]) technology permits the identification and quantification of inherently diverse cellular systems, and the simultaneous measurement of functional attributes at the single-cell resolution. By virtue of its multiplex ability with limited need for compensation, CyTOF has led a critical role in immunological research fields. Here, we present an overview of CyTOF, including the introduction of CyTOF principle and advantages that make it a standalone tool in deciphering immune mysteries. We then discuss the functional assays, introduce the bioinformatics to interpret the data yield via CyTOF, and depict the emerging clinical and research applications of CyTOF technology in sketching immune landscape in a wide variety of diseases.

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Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms

Song

Bartley

Chow

et al. 2021

Cell Reports Medicine

150

130

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COVID-19 patients frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single cell RNA-seq and cytokine analyses of CSF and blood from COVID-19 patients with neurological symptoms, we find compartmentalized, CNS specific T cell activation and B cell responses. All COVID-19 cases had CSF anti-SARS-CoV-2 antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are found only during brain infection, and are not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from a COVID-19 patient, and find that these mAbs target both anti-viral and anti-neural antigens—including one mAb that reacted to both spike protein and neural tissue. Overall, CSF IgG from 5/7 patients contains anti-neural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of COVID-19 patients and suggests a role for autoimmunity in neurologic sequelae of COVID-19.

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O4‐09‐06: Clonally Expanded Cd8 T Cells Patrol Alzheimer's Cerebrospinal Fluid

Cited by 11 publications

References 0 publications

Methods to investigate intrathecal adaptive immunity in neurodegeneration

Methods to investigate intrathecal adaptive immunity in neurodegeneration

Progress and applications of mass cytometry in sketching immune landscapes

Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms

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