Dataset Information

CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation.

ABSTRACT:

Background

The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels.

Methods

Cytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n?=?20), clinically isolated syndrome (CIS, n?=?30), multiple sclerosis (MS, n?=?20), Lyme neuroborreliosis (LNB, n?=?8) and patients with other inflammatory neurological diseases (OIND, n?=?30). Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry.

Results

CXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in the CSF of all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with CSF B cells, plasmablasts and intrathecal Ig synthesis.

Conclusions

CXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity.

SUBMITTER: Kowarik MC

PROVIDER: S-EPMC3418196 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Publications

CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation.

Kowarik Markus C MC Cepok Sabine S Sellner Johann J Grummel Verena V Weber Martin S MS Korn Thomas T Berthele Achim A Hemmer Bernhard B

Journal of neuroinflammation 20120516

<h4>Background</h4>The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels.<h4>Methods</h4>Cytokine/chemo ...[more]

PMID: 22591862

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Project description:BackgroundC-X-C chemokine ligand 13 (CXCL13) is frequently elevated in cerebrospinal fluid (CSF) in a variety of inflammatory central nervous system (CNS) diseases, has been detected in meningeal B cell aggregates in brain tissues of multiple sclerosis patients, and proposedly recruits B cells into the inflamed CNS. Besides B cells also follicular helper T (Tfh) cells express the cognate receptor C-X-C chemokine receptor type 5 (CXCR5) and follow CXCL13 gradients in lymphoid tissues. These highly specialized B cell helper T cells are indispensable for B cell responses to infection and vaccination and involved in autoimmune diseases. Phenotypically and functionally related circulating CXCR5+CD4 T cells occur in blood. Their co-recruitment to the inflamed CSF is feasible but unresolved.MethodsWe approached this question with a retrospective study including data of all patients between 2017 and 2019 of whom immune phenotyping data of CXCR5 expression and CSF CXCL13 concentrations were available. Discharge diagnoses and CSF laboratory parameters were retrieved from records. Patients were categorized as pyogenic/aseptic meningoencephalitis (ME, n = 29), neuroimmunological diseases (NIMM, n = 22), and non-inflammatory neurological diseases (NIND, n = 6). ANOVA models and Spearman's Rank-Order correlation were used for group comparisons and associations of CXCL13 levels with immune phenotyping data.ResultsIn fact, intrathecal CXCL13 elevations strongly correlated with CXCR5+CD4 T cell frequencies in the total cohort (p < 0.0001, r = 0.59), and ME (p = 0.003, r = 0.54) and NIMM (p = 0.043, r = 0.44) patients. Moreover, the ratio of CSF-to-peripheral blood (CSF/PB) frequencies of CXCR5+CD4 T cells strongly correlated with CXCL13 levels both in the total cohort (p = 0.001, r = 0.45) and ME subgroup (p = 0.005, r = 0.50), indicating selective accumulation. ME, NIMM and NIND groups differed with regard to CSF cell counts, albumin quotient, intrathecal IgG, CXCL13 elevations and CXCR5+CD4 T cells, which were higher in inflammatory subgroups.ConclusionThe observed link between intrathecal CXCL13 elevations and CXCR5+CD4 T cell frequencies does not prove but suggests recruitment of possible professional B cell helpers to the inflamed CSF. This highlights CSF CXCR5+CD4 T cells a key target and potential missing link to the poorly understood phenomenon of intrathecal B cell and antibody responses with relevance for infection control, chronic inflammation and CNS autoimmunity.

Project description:Purpose: To determine global gene expression changes following siRNA knockdown of Myc, Kcnk1, and Snta1 compared to non-targeting siRNAs or mock-transfected cells Methods: Total RNA was processed using the Illumina TruSeq Stranded mRNA Sample Preparation Kit according to manufacturer’s protocol. Generated cDNA libraries were sequenced using an Illumina HiSeq 2000 sequencer with four biological replicates sequenced per condition using single read, 50 cycle runs. Quality of sequencing reads were assessed using FastQC (Babraham Bioinformatics) and then aligned to a reference genome (hg19, UCSC Genome Browser) using TopHat. Sequencing yielded, on average, 23.7 million unique reads per sample with a 60.7 - 65.7% mapping rate. Cufflinks was used to generate transcript abundance for each annotated protein-coding gene as Fragments Per Kilobase of transcript per Million mapped reads (FPKM), and statistical analysis and comparison of FPKM values was calculated using R (Bioconductor). Results: Fold changes comparing mock and a non-targeting siRNA were highly congruent. Myc RNAi induced numerous changes, with 955 downregulated genes and 1214 upregulated genes. The effect on Myc itself was relatively modest, possibly reflecting its ability to negatively auto-regulate its own expression. Gene ontology analysis highlighted ribosome biogenesis, metabolism, gene expression, cell cycle, and apoptosis pathways, consistent with known Myc functions. The Kcnk1 siRNA affected 424 genes, with KCNK1 itself one of the most repressed. While gene ontology analysis also highlighted metabolism and biosynthesis pathways, the p-values and fold enrichment scores were substantially lower, indicating that DiM can be suppressed without major effects on metabolism and biosynthesis pathways. The Snta1 siRNA deregulated 575 genes, with SNTA1 itself the most repressed gene. Cell cycle and mitosis-related gene ontology terms feature heavily, consistent with this siRNA accelerating mitotic exit. Interestingly, FoxM1, which drives G2/M gene expression was reduced 1.75-fold, indicating that this siRNA may disrupt mitotic controls by deregulating FoxM1. Conclusions: Global gene expression profiling identifies Egr1 as regulator of mitotic cell fate. Total RNA was extracted from at least four replicates of siRNA-transfected cells and libraries for sequencing was prepared for each replicate.

Dataset Information

CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation.

Background

Methods

Results

Conclusions

Publications

CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation.

Similar Datasets

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