Classification of neurological diseases using multi-dimensional CSF analysis

Groß, Catharina C.; Schulte‐Mecklenbeck, Andreas; Madireddy, Lohith; Pawlitzki, Marc; Strippel, Christine; Räuber, Saskia; Krämer, Julia; Rolfes, Leoni; Ruck, Tobias; Beuker, Carolin; Schmidt‐Pogoda, Antje; Schneider‐Hohendorf, Tilman; Hahn, Tim; Schwab, Nicholas; Minnerup, Jens; Melzer, Nico; Klotz, Luisa; Meuth, Sven G.; Hörste, Gerd Meyer zu; Baranzini, Sergio E.; Wiendl, Heinz

doi:10.1093/brain/awab147

Cited by 31 publications

(30 citation statements)

References 55 publications

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“…On the other hand, the proportion of plasma cells shows more promise, as plasma cells appear to be almost absent from non-MS CSF (Figure 5a). Interestingly, our finding on this cell type aligns well with results from the few flow cytometry studies [26][27][28] that have assessed plasma cells or plasmablasts in MS CSF compared to other neurological diseases. Consistent with a recent observation 26 , a cut-off of 0.25% for plasma cells showed 100% specificity and 70% sensitivity for distinguishing RRMS from ONID and IIH in our samples.…”

Section: Can Csf Cell Composition Distinguish Rrms From Other Neuroinflammatory Disorders?supporting

confidence: 87%

Defining the architecture of cerebrospinal fluid cellular communities in neuroinflammatory diseases

Roostaei

Diaconu

Touil

et al. 2021

Preprint

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Cerebrospinal fluid (CSF) biomarkers are important for multiple sclerosis (MS) diagnosis. Moreover, absent of autopsy or biopsy tissue, CSF is the most relevant source for studying the immune cells involved in MS pathophysiology. Single-cell RNA sequencing (scRNA-seq) provides new opportunities to advance our understanding of disease-associated changes in CSF immune cells. Here, using scRNA-seq data generated from 58 CSF and 10 PBMC samples, we provide an updated atlas of the immune cells present in human CSF in MS and other neuroinflammatory conditions, including novel lymphoid and myeloid cell clusters. Our atlas can thus serve as a reference for future studies of immune cells in neuroinflammation. Our further characterization of CSF myeloid cells suggests that most CSF microglia-like cells resemble two of the previously-described brain microglia signatures. Additionally, our data from a sex-mismatched bone marrow transplant recipient suggest that CSF microglia-like cells are of peripheral origin. Our comparisons between MS and other neuroinflammatory disorders show a highly-specific increase in plasma cells, along with reductions in the proportion of microglia-like cells in MS CSF. Furthermore, our analyses on MS patients receiving anti-CD20 therapy ocrelizumab suggest that the treatment effects are not limited to B cell depletion, and ocrelizumab appears to reverse some MS-associated T and myeloid changes in CSF. Finally, we utilized our atlas to prioritize (1) CSF cell types expressing genes associated with MS susceptibility, and (2) ligand-receptor gene pairs that are differentially expressed in MS CSF, providing targets for further mechanistic and causal investigations in pathophysiology and treatment of MS.

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Section: Can Csf Cell Composition Distinguish Rrms From Other Neuroinflammatory Disorders?supporting

confidence: 87%

Defining the architecture of cerebrospinal fluid cellular communities in neuroinflammatory diseases

Roostaei

Diaconu

Touil

et al. 2021

Preprint

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“…While EDTA–blood and CSF cells were analysed within 1 h of withdrawal, serum, CSF supernatant and peripheral blood mononuclear cells (PBMCs) were cryopreserved following standardized processes as described previously. 36 …”

Section: Methodsmentioning

confidence: 99%

“…Flow-cytometric analyses of EDTA blood and CSF cells were performed as a part of routine clinical prectice and for therapy surveillance, as described previously. 36 , 37 In addition, PBMCs from a subcohort of ALEM patients were analysed according to a flow-cytometric functional immune phenotyping matrix as described before. 37 For this purpose, cryopreserved PBMCs were thawed and stained with distinct sets of fluorochrome-conjugated antibodies ( Supplementary material ).…”

Section: Methodsmentioning

confidence: 99%

Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity

Ruck

Barman

Schulte‐Mecklenbeck

et al. 2022

Brain

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Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing–remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.

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“…NICs comprised patients with somatoform disorders or patients who donated CSF during the course of spinal anesthesia as described previously. 19 Groups in each cohort were subdivided into young (≤50 years) and old (>50 years) participants. One rationale behind the 50-year cutoff is that the DMT efficacy for RRMS has mostly been tested only in clinical trials with patients up to 50–55 years 3 , 4 Furthermore, a recent meta-analysis shows that there is a lower efficacy of DMTs for the average of patients with MS beyond 53 years.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis

Eschborn

Pawlitzki

Wirth

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesIn MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation.MethodsTo evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85).ResultsAnalysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS. However, HDs displayed a strong age-dependent decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells, whereas this age-dependent reduction was completely abrogated in patients with MS. An age-dependent increase in the expression of the costimulatory molecule CD226 on memory CD8 T cells was absent in patients with MS. CD226 expression correlated with disability in younger (≤50 years) patients with MS. CSF analysis revealed a significant age-dependent decline in various immune cell populations in PPMS but not RRMS, suggesting a differential effect of aging on the intrathecal compartment in PPMS.DiscussionOur data illustrate that aging in MS is associated with a dysbalance between costimulatory and immunoregulatory signals provided by CD8 T cells favoring a proinflammatory phenotype and, more importantly, a pattern of premature immune aging in the CD8 T-cell compartment of young patients with MS with potential implications for disease severity.

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Classification of neurological diseases using multi-dimensional CSF analysis

Cited by 31 publications

References 55 publications

Defining the architecture of cerebrospinal fluid cellular communities in neuroinflammatory diseases

Defining the architecture of cerebrospinal fluid cellular communities in neuroinflammatory diseases

Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity

Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis

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