Leukocyte profiles in blood and CSF distinguish neurosarcoidosis from multiple sclerosis

Heming, M.; Schulte‐Mecklenbeck, Andreas; Brix, Tobias; Groß, Catharina C.; Wiendl, Heinz; Klotz, Luisa; Hörste, Gerd Meyer zu

doi:10.1016/j.jneuroim.2020.577171

Cited by 19 publications

(15 citation statements)

References 39 publications

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“…Flow cytometry (fluorescence-activated cell sorting analysis) is an advanced method suitable for use in the CSF or PB in autoimmune brain diseases such as multiple sclerosis (MS), and it might also be well-suited for unraveling the immune mechanisms underlying a suspected LE [13,25,26]. Based on the evidence gathered from the preliminary findings first obtained from a few GAD65 antibody-positive patients [50,51] and then later on in a larger series [16,17], we hypothesized that T-and B-lymphocytes could serve as additional potential biomarkers in LE, and thereby help clarify the variance in otherwise unexplained neurocognitive symptoms.…”

Section: Introductionmentioning

confidence: 99%

Specific B- and T-cell populations are associated with cognition in patients with epilepsy and antibody positive and negative suspected limbic encephalitis

et al. 2020

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Objective Neuropsychological impairments are major symptoms of autoimmune limbic encephalitis (LE) epilepsy patients. In LE epilepsy patients with an autoimmune response against intracellular antigens as well as in antibody-negative patients, the antibody findings and magnetic resonance imaging pathology correspond poorly to the clinical features. Here, we evaluated whether T- and B-cells are linked to cognitive impairment in these groups. Methods In this cross-sectional, observational, case–controlled study, we evaluated 106 patients with adult-onset epilepsies with a suspected autoimmune etiology. We assessed verbal and visual memory, executive function, and mood in relation to the presence or absence of known auto-antibodies, and regarding T- and B-cell activity as indicated by flow cytometry (fluorescence-activated cell sorting = FACS, peripheral blood = PB and cerebrospinal fluid = CSF). Results 56% of the patients were antibody-negative. In the other patients, auto-antibodies were directed against intracellular antigens (GAD65, paraneoplastic: 38%), or cellular surface antigens (LGI1/CASPR2/NMDA-R: 6%). Excluding LGI1/CASPR2/NMDA-R, the groups with and without antibodies did not differ in disease features, cognition, or mood. CD4+ T-cells and CD8+ T-cells in blood and CD4+ T-cells in CSF were prominent in the auto-antibody positive group. Regression analyses indicated the role education, drug load, amygdala and/or hippocampal pathology, and CD4+ T-cells play in verbal memory and executive function. Depressed mood revealed no relation to flow cytometry results. Conclusion Our results indicate a link between T- and B-cell activity and cognition in epilepsy patients with suspected limbic encephalitis, thus suggesting that flow cytometry results can provide an understanding of cognitive impairment in LE patients with autoantibodies against intracellular antigens.

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Section: Introductionmentioning

confidence: 99%

Specific B- and T-cell populations are associated with cognition in patients with epilepsy and antibody positive and negative suspected limbic encephalitis

et al. 2020

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“… 43 CSF CD4 + T-cell counts in multiple sclerosis were significantly higher than those of NID controls in this study (median in multiple sclerosis and NID controls 298.9 cells/ml and 81.6 cells/ml, respectively; P = 1.4 × 10 −6 ) and this is consistent with published data. 44 Whilst increased blood–brain- or blood–CSF-barrier permeability in multiple sclerosis is likely to be contributory, increased CD4 + T-cell proliferation could also be relevant. Indeed, differences in activation responses and clonal expansion of CD4 + T-cells has been implicated in multiple sclerosis pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

CSF-resident CD4+ T-cells display a distinct gene expression profile with relevance to immune surveillance and multiple sclerosis

Hrastelj

Andrews

Loveless

et al. 2021

Brain Communications

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The CNS has traditionally been considered an immune privileged site, but is now understood to have a system of immune surveillance, predominantly involving CD4+ T-cells. Identifying functional differences between CNS and blood CD4+ T-cells, therefore, have relevance to CNS immune surveillance as well as to neurological conditions, such as multiple sclerosis, in which CD4+ T-cells play a central role. Here, CD4+ T-cells were purified from CSF and blood from 21 patients with newly diagnosed treatment-naïve multiple sclerosis and 20 individuals with non-inflammatory disorders using fluorescence-activated cell sorting, and their transcriptomes were profiled by RNA sequencing. Paired comparisons between CD4+ T-cells from CSF and blood identified 5156 differentially expressed genes in controls and 4263 differentially expressed in multiple sclerosis patients at false discovery rate <5%. Differential expression analysis of CD4+ T-cells collected from the CSF highlighted genes involved in migration, activation, cholesterol biosynthesis and signalling, including those with known relevance to multiple sclerosis pathogenesis and treatment. Expression of markers of CD4+ T-cell subtypes suggested an increased proportion of Th1 and Th17 cells in CSF. Gene ontology terms significant only in multiple sclerosis were predominantly those involved in cellular proliferation. A two-way comparison of CSF versus blood CD4+ T-cells in multiple sclerosis compared with non-inflammatory disorder controls identified four significant genes at false discovery rate <5% (CYP51A1, LRRD1, YES1 and PASK), further implicating cholesterol biosynthesis and migration mechanisms. Analysis of CSF CD4+ T-cells in an extended cohort of multiple sclerosis cases (total N = 41) compared with non-inflammatory disorder controls (total N = 38) identified 140 differentially expressed genes at false discovery rate < 5%, many of which have known relevance to multiple sclerosis, including XBP1, BHLHE40, CD40LG, DPP4 and ITGB1. This study provides the largest transcriptomic analysis of purified cell subpopulations in CSF to date and has relevance for the understanding of CNS immune surveillance, as well as multiple sclerosis pathogenesis and treatment discovery.

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“…In neurosarcoidosis, an increased CD4/CD8 T cell ratio in CSF (>5.0) has been intensely investigated as a surrogate marker, aiding in differential diagnosis for many years with inconclusive results. Of clinical relevance, however, may be recent findings reporting (i) a negative predictive value of 88%, if a CD4/CD8 T cell ratio <5.0 is combined with an absence of pleocytosis [ 58 ], (ii) that IL-6 elevations of >50 pg/mL combined with an increased CD4/CD8 T cell ratio indicate relapse in active neurosarcoidosis [ 59 ], and (iii) that activated CD4 T cells in CSF combined with plasma cells in blood differentiate neurosarcoidosis from MS [ 60 ].…”

Section: Clinical Relevance Of Immune Phenotyping Of Csf Cells By Flow Cytometrymentioning

confidence: 99%

Role and Relevance of Cerebrospinal Fluid Cells in Diagnostics and Research: State-of-the-Art and Underutilized Opportunities

et al. 2021

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Cerebrospinal fluid (CSF) has recently experienced a revival in diagnostics and research. However, little progress has been made regarding CSF cell analysis. For almost a century, CSF cell count and cytomorphological examination have been central diagnostic parameters, with CSF pleocytosis as a hallmark finding of neuroinflammation and cytology offering valuable clues regarding infectious, autoimmune, and malignant aetiologies. A great deal of information, however, remains unattended as modern immune phenotyping technologies have not yet been broadly incorporated into routine CSF analysis. This is a serious deficit considering the central role of CSF cells as effectors in central nervous system (CNS) immune defence and autoimmune CNS processes, and the diagnostic challenges posed by clinically overlapping infectious and immune-mediated CNS diseases. Here, we summarize historical, specimen-intrinsic, methodological, and technical issues determining the state-of-the-art diagnostics of CSF cells and outline future perspectives for this underutilized window into meningeal and CNS immunity.

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Leukocyte profiles in blood and CSF distinguish neurosarcoidosis from multiple sclerosis

Cited by 19 publications

References 39 publications

Specific B- and T-cell populations are associated with cognition in patients with epilepsy and antibody positive and negative suspected limbic encephalitis

Specific B- and T-cell populations are associated with cognition in patients with epilepsy and antibody positive and negative suspected limbic encephalitis

CSF-resident CD4+ T-cells display a distinct gene expression profile with relevance to immune surveillance and multiple sclerosis

Role and Relevance of Cerebrospinal Fluid Cells in Diagnostics and Research: State-of-the-Art and Underutilized Opportunities

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