Fluid In Multiple Sclerosis Research Articles

Fibrinolysis associated proteins and lipopolysaccharide bioactivity in plasma and cerebrospinal fluid in multiple sclerosis

The coagulation cascade and fibrinolysis have links with neuroinflammation and increased activation of the coagulation system has been reported in MS patients. We quantified levels of D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and the bioactivity of bacterial lipopolysaccharide (LPS) in cerebrospinal fluid (CSF) and plasma from newly diagnosed untreated MS patients and controls. These molecules showed multiple correlations with each other as well as with age, HLA-DRB1*15:01, body-mass-index and CSF IgG. Our results confirm previous findings of increased plasma PAI-1 and LPS in MS patients compared to controls indicating changes in platelet function and gut permeability in MS.

ScNAT: a deep learning method for integrating paired single-cell RNA and T cell receptor sequencing profiles

Many deep learning-based methods have been proposed to handle complex single-cell data. Deep learning approaches may also prove useful to jointly analyze single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) data for novel discoveries. We developed scNAT, a deep learning method that integrates paired scRNA-seq and scTCR-seq data to represent data in a unified latent space for downstream analysis. We demonstrate that scNAT is capable of removing batch effects, and identifying cell clusters and a T cell migration trajectory from blood to cerebrospinal fluid in multiple sclerosis.

Alemtuzumab treatment exemplifies discordant immune effects of blood and cerebrospinal fluid in multiple sclerosis

Background and objectivesImmune responses in the central nervous system (CNS) are highly compartmentalized and cerebrospinal fluid (CSF) in particular often reflects CNS pathology better than peripheral blood. While CSF leukocytes are known to be distinct from blood, the immediate effects of peripheral leukocyte depletion on CSF leukocytes have not been studied in humans. MethodsWe here analyzed CSF and blood from two relapsing-remitting multiple sclerosis (RRMS) patients early after peripheral leukocyte depletion with the anti-CD52 antibody alemtuzumab compared to untreated RRMS and control patients using single cell RNA-sequencing. ResultsAs expected for alemtuzumab, most leukocyte lineages including T cells were synchronously depleted from CSF and blood, while - surprisingly - pDCs were maintained in CSF but depleted from blood by alemtuzumab. Transcriptionally, genes associated with migration were elevated only in the CSF after alemtuzumab. Predicted cellular interactions indicated a central role of pDCs and enhanced migration signaling in the CSF after alemtuzumab. DiscussionThe CSF and blood compartments are thus partially uncoupled, emphasizing that the CNS is only partially accessible even for treatments profoundly affecting the blood.

Metabolomics of Cerebrospinal Fluid in Multiple Sclerosis Compared With Healthy Controls: A Pilot Study.

BackgroundMultiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) leading to the loss of myelin and axons. Diagnosis is based on clinical findings, MRI, and analysis of cerebrospinal fluid (CSF). CSF is an ultrafiltrate of plasma and reflects inflammatory processes in the CNS. The aim of this study was to perform metabolomics analysis of CSF in patients after the first attack of MS and healthy controls and try to find new specific analytes for MS including those potentially predicting disease activities at the onset.MethodsWe collected CSF from 19 patients (16 females, aged 19–55 years) after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS and CSF of 19 controls (16 females, aged 19–50 years). Analyses of CSF samples were provided using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector (TripleTOF 5600, AB Sciex, Canada).ResultsApproximately 130 selected analytes were identified, and 30 of them were verified. During the targeted analysis, a significant decrease in arginine and histidine and a less significant decrease in the levels of asparagine, leucine/isoleucine, and tryptophan, together with a significant increase of palmitic acid in the patient group, were found.ConclusionWe observed significant differences in amino and fatty acids in the CSF of newly diagnosed patients with MS in comparison with controls. The most significant changes were observed in levels of arginine, histidine, and palmitic acid that may predict inflammatory disease activity. Further studies are necessary to support these findings as potential biomarkers of MS.

Diffusion tensor imaging reveals greater microstructure damage in lesional tissue that shrinks into cerebrospinal fluid in multiple sclerosis.

Atrophied T2 lesion volume (LV), reflecting the complete transformation of lesions into cerebrospinal fluid (CSF), has been associated with disease progression in multiple sclerosis (MS). The underlying damage leading to lesion destruction remains poorly understood. The objective of this study was to use diffusion tensor imaging (DTI) to investigate the extent of microstructural tissue damage at baseline in lesions that subsequently transform into CSF. Ninety-nine MS patients (67 relapsing-remitting MS [RRMS] and 32 progressive PMS [PMS]) were imaged at baseline and after an average of 5.3 ± 0.6 years of follow-up. Assessments included T2 LV and DTI at baseline and atrophied T2 LV over follow-up. Lesioned areas that became atrophied T2 LV were compared to those that did not. Baseline lesional DTI metrics were compared between RRMS versus PMS patients and between patients with disability progression (DP, n = 35) versus non-DP (n = 64), using ANCOVA models. Lesion tissue that developed into atrophied T2 LV had significantly different baseline DTI parameters compared to nonatrophied T2-LV tissue (p<0.001), with the largest effect for free-water (d = 2.739). Baseline tissue characteristics of future atrophied T2 LV were not significantly different between groups. However, DP patients developed greater atrophied T2 LV (377 vs. 83 mm3 , p < 0.001). Extensive microstructural damage characterizes lesions replaced by CSF, independently of disease phenotype or future DP. Greater atrophied T2 LV predicts DP.

Molecular Biomarkers in the Cerebrospinal Fluid in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the spinal cord and brain. Detection of the disease at its initial stages is a difficult task as the causes and mechanisms of the manifestations of the disease remain unclear. Diagnosis of MS is a complex process. Studies of the molecular mechanisms of the disease and the search for biomarkers are among the key directions in the diagnosis of the disease. This review addresses potential biomarkers for multiple sclerosis detected in the cerebrospinal fluid.

Determination of chitinase 3-like 1 in cerebrospinal fluid in multiple sclerosis and other neurological diseases

ObjectivesChitinase 3-like 1 (CHI3L1) is an extracellular monomeric single-chain glycoprotein expressed by many types of cells. Its elevated levels were found in cerebrospinal fluid in central nervous system (CNS) inflammatory diseases patients. The aim of the study was 1) to validate the reference interval of cerebrospinal fluid (CSF) CHI3L1 in a control group; 2) to measure the CHI3L1 concentration in different diagnosis groups .including multiple sclerosis (MS); and 3) to correlate those values with other biomarkers of axonal damage or neuroinflammation in different grous.MethodsThe study included 132 CSF samples sent to the Department of Clinical Biochemistry, Institute of Laboratory Diagnostics, University Hospital Ostrava. Concentrations of CHI3L1, CXCL13 chemokine, neurofilament light chains, and phosphorylated neurofilament heavy chains were determined by enzyme-linked immunosorbent assays. IgG oligoclonal bands were detected by isoelectric focusing in agarose gels followed by immunofixation. IgM and FLC oligoclonal bands were analyzed by IEF followed by affinity immunoblotting. The group consisted of 42 patients with multiple sclerosis, 14 with clinically isolated syndrome, 11 with other central nervous system inflammatory diseases, 46 with non-inflammatory diseases of the central nervous system, 4 with inflammatory diseases of the peripheral nervous system, and 15 controls.ResultsThe estimated reference values of CHI3L1 were 28.6–182.5 μg.L-1. Statistically significant differences of CSF CHI3L1 concentrations were found among diagnosis groups (p < 0.0001), after age adjustment (p = 0.002). There was a statistically significant relationship between CHI3L1 and NFL in the MS group (rs = 0.460; P = 0.002), and between CHI3L1 and pNFH in the MS group (rs = 0.691; P < 0.001). No statistically significant difference was found in the categorical comparison of CHI3L1 in the MS group and other diagnostic groups as well as when using the Mann-Whitney U test for CHI3L1 with additional parameters with and without oligoclonal bands present.ConclusionsCSF CHI3L1 values differ depending on diagnosis and correlate significantly with concentrations of the axonal damage markers CSF neurofilament light chains, and CSF phosphorylated neurofilament heavy chains, but not with CSF concentrations of the inflammatory marker CXCL13. Thus, CSF CHI3L1 could be another promising prognostic, albeit probably etiologically nonspecific, biomarker of MS.

Serum and synovial survivin in rheumatoid arthritis: Relation to disease activity and severity

BackgroundRheumatoid arthritis (RA) is a progressive debilitating autoimmune disease, affecting 1% of the world population, leading to cartilage and bone destruction caused by insufficient apoptosis in the inflamed RA synovium. Survivin is a proto-oncogene biomarker known for its anti-apoptotic and cell cycle-regulating properties. Overexpression of survivin in non-cancerous processes has been linked to inflammation, presumably contributing to the decreased apoptosis in the T cells of the cerebrospinal fluid in multiple sclerosis, in skin lesions of patients with psoriasis and in synovial tissue of patients with RA.Aim of the workThe aim of this study is to measure the serum and synovial levels of survivin and clarify their relations to disease activity, functional capacity, and radiographic damage in patients with RA.Patients and methodsThis study was carried outon50patients with RA who hada mean ageof46.4±10.94 years.Theywere39femalesand11males.Thecontrolgroupwasofmatchedageand sex,withameanageof46.03±10.53yearsandfemale:maleratioof23:7.Allpatients were subjected to full history taking, thorough clinical examination, assessment of disease activity by disease activity score 28 activity score, and assessment of functional capacity and disability using Health Assessment Questionnaire. Plain radiographs of both hands of feet were done, scored and graded by Larsen score. Serum survivin from all the studied participants and survivin levelsinthe synovial fluid aspirated from 18 patients with RA who presented with knee effusion at the time of examination were measuredbyenzyme-linked immunosorbent assay, usingapair of matched anti bodies (R&D systems, Abingdon, Uk).ResultsThe mean serum survivin level was highly statistically significantly elevated (P<0.001) in the sera of patients with RA than in the controls, being 239.1 ±115.15 and 77.03±30.20 pg/ml, respectively. Synovial survivin levels ranged between 420 and 575 pg/ml, with a mean of 479.61±52.68 pg/ml, which was statistically significantly higher than the mean serum survivin level in patients with RA (P<0.001). Patients were divided into survivin -ve group, which included 21 (42%) of 50 patients with serum survivin less than 167.63 pg/ml, and survivin +ve group, which included 29 (58%) of 50 patients with RA with serum survivin more than or equal to 167.63 pg/ml. Survivin +ve RA patients group had significantly longer mean disease duration (P<0.001), Higher Health Assessment Questionnaire SCORE, and higher mean Larsen score (P<0.001) than survivin -ve RA patients group. Overall, nine (69.2%) of 13 RA patients with Sjogren’s syndrome, eight (80%) of 10 of the patients with pleural effusion, three (50%) of six patients with Raynaud’s phenomenon, and all patients with SC nodules (five, 100%), episcleritis (two, 100%), and vasculitis (one, 100%) were survivin +ve. Larsen score in the patients with RA ranged from 0 to 65, with a mean of 23.6 ±18.98. Patients with RA who had Larsen score grading more than or equal to 2 (27/ 50, 52%) were considered to have an erosive RA disease. There were no statistically significant differences between patients with RA according to the presence of erosion regarding age, sex, visual analog scale values, disease activity score values, the presence of rheumatoid factor antibodies or anti-cyclic citrullinated peptides antibodies, the mean of hemoglobin %, white blood cells count, platelets count, erythrocyte sedimentation rate first hour value, or the C-reactive protein level. All patients with RA with erosive disease were survivin +ve and had statistically significantly elevated mean serum and synovial survivin levels than those patients with non erosive disease (337.37±55.19 vs. 126.78±24.33 pg/ ml and 422.5±3.53 vs. 486.75±51.52 pg/ml, respectively).ConclusionsHigh levels of survivin are detected in the sera and synovial fluid of patients with RA and are associated with erosive joint damage and poor functional outcomes. Our findings support the role of survivin in the pathogenesis of RA. Further studies are needed on a larger group of RA patients follow-up to ascertain the erosive effect of survivin. Conduction of studies on survivin antagonist to evaluate their effect on ameliorating RA disease progression is recommended.

Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses.

The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS-associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis.

The cerebrospinal fluid in multiple sclerosis: far beyond the bands.

ABSTRACTThe cerebrospinal fluid analysis has been employed for supporting multiple sclerosis diagnosis and ruling out the differential diagnoses. The most classical findings reflect the inflammatory nature of the disease, including mild pleocytosis, mild protein increase, intrathecal synthesis of immunoglobulin G, and, most typically, the presence of oligoclonal bands. In recent years, new biomarkers have emerged in the context of multiple sclerosis. The search for new biomarkers reflect the need of a better evaluation of disease activity, disease progression, and treatment efficiency. A more refined evaluation of disease and therapy status can contribute to better therapeutic choices, particularly in escalation of therapies. This is very relevant taking into account the availability of a greater number of drugs for multiple sclerosis treatment in recent years. In this review, we critically evaluate the current literature regarding the most important cerebrospinal fluid biomarkers in multiple sclerosis. The determination of biomarkers levels, such as chemokine ligand 13, fetuin A, and mainly light neurofilament has shown promising results in the evaluation of this disease, providing information that along with clinical and neuroimaging data may contribute to better therapeutic decisions.

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.

Exome sequencing in single cells from the cerebrospinal fluid in multiple sclerosis

Background: Genome-wide association studies (GWAS) have identified over 100 germline variants that influence susceptibility to multiple sclerosis, most of which map within or near to genes with immunological function. However, the role of somatic mutations in multiple sclerosis has not been investigated. Objective: The objective of this paper is to explore the role that somatic mutations might play in the development of multiple sclerosis. Methods: We exome-sequenced in total 21 individual CD4+ lymphocytes isolated from cerebrospinal fluid of two patients. In addition we sequenced DNA from the patients’ peripheral blood to serve as germline reference. Results: In comparison with the respective germline sequence, each cell differed at an average of 1784 positions, but as anticipated subsequent analysis confirms that most, if not all, of these potential mutations are likely to represent artefacts generated during the amplification of a single genome and/or by sequencing. Fifty-six of the potential mutations were predicted to have likely functional effects on genes that have previously been implicated by GWAS, including three in the CD6 gene. Conclusion: More robust methods applied to larger numbers of cells will be needed to define the role of somatic mutations.

Proteomic analysis of the cerebrospinal fluid in multiple sclerosis and neuromyelitis optica patients

The present study aimed to compare the 2-dimensional (2D) electrophoresis pattern of the cerebrospinal fluid (CSF) in multiple sclerosis (MS), neuromyelitis optica (NMO) and control individuals, to identify the proteins with differential expression and to examine their significance. CSF samples from the three groups were collected and total protein was isolated and quantified using the Bradford method. 2D electrophoresis of the samples was conducted using equal amounts of CSF. In the CSF 2D gel electrophoresis map, 118points were obtained from the MS group, 155points from the NMO group and 350points from the normal control group. Non-matching proteins appeared in 14spots in the MS group and in 45spots in the NMO group, and were also expressed in the 2D electrophoresis pattern of the normal control group. Four differential proteins were identified through the HD-MS/MS and MASCOT network search. Pre-albumin (PA) was found only in the CSF 2D gel electrophoresis map of the MS patients. Keratin1 was expressed in the normal control group, but not in the MS group. The difference in the expression of keratin9 in the MS group was twice that in the normal control group. The expression of keratin1, keratin9 and transferrin in the NMO group was twice that in the normal control group. The expression of PA was found only in the CSF 2D gel electrophoresis map of the MS patients, and not in the NMO group. Keratin1 was expressed in the NMO group, but not in the MS group. The expression of a variety of proteins in the 2D electrophoresis pattern of CSF was significantly different in the MS, NMO and control groups. PA, keratin1, transferrin and keratin9 are identified as significantly differentially expressed proteins.

The prognostic significance of cerebrospinal fluid in multiple sclerosis

Background Multiple Sclerosis (MS) patients lacking CSF oligoclonal bands are purported to have a milder course of disease. We reviewed the natural history of oligoclonal band (OCB) — negative (OCB−) compared to OCB positive (OCB+) patients. Method A retrospective study of 451 MS patients. Results Only 48/451 patients (10.6%) were CSF OCB−. The mean age at onset was 37.1 ± 8.8 years with female:male ratio = 2. First CNS location presentation was less well defined in OCB− vs. OCB+ patients with significantly more supratentorial presentation. The clinical course of OCB− vs OCB+ was somewhat different; 22.9 vs 15.1% PPMS; 18.8 vs 12.4% SPMS; and 56.3 vs 71% RRMS, respectively. There were significantly fewer WBC, less IgG and a lower IgG index in OCB− cases. Fewer OCB− cases fulfilled McDonald MRI criteria. There were no discernable differences in disease severity between the two groups as determined by the EDSS, progression index, MSSS, number of relapses or annualized relapse rate. Conclusion The presence of OCB correlates better with other indications of acute inflammatory MS, especially an RR course. This study suggests that the simple lack of OCB positivity does not necessarily insure a more benign disease course.

Growth‐associated protein 43 in lesions and cerebrospinal fluid in multiple sclerosis

Axonal damage in multiple sclerosis (MS) is correlated to disease progression. Early axonal damage may be compensated for by regenerative processes. Growth-associated protein 43 (GAP-43) is a marker for axonal growth and synaptogenesis in various neurodegenerative diseases. We investigated the expression of GAP-43 in 48 MS grey and white matter lesions of different stages. Decreased GAP-43 expression was found in 74% of the white matter lesions, independent of the lesion stage. In 19 out of 35 white matter lesions, areas of increased GAP-43 expression were present immediately adjacent to the lesions. Increased or unaltered expression was observed in remyelinated lesions. GAP-43 was expressed in neurofilament-positive structures. GAP-43 expression appeared unchanged in grey matter lesions. Macrophages were present in the areas of changed GAP-43 expression. cerebrospinal fluid GAP-43 levels were negatively correlated with magnetic resonance imaging measures of whole-brain atrophy (r = -0.30). In conclusion, these results indicate that decreased GAP-43 immunopositivity reflects axonal damage in MS lesions, which may again be reflected in decreased cerebrospinal fluid levels. The increased levels of GAP-43 in remyelinated or nondemyelinated white matter close to MS lesions may reflect regenerative attempts by damaged axons.

Level of sFas/APO 1 in serum and cerebrospinal fluid in multiple sclerosis

The aim of the study was to measure sFas/APO 1 serum and cerebrospinal fluid (CSF) levels in patients with relapsing–remitting multiple sclerosis (MS) during relapses, as an index of inhibition of apoptosis of activated lymphocytes in eight patients with clinically definite multiple sclerosis, and 12 healthy controls. The level of serum and CSF sFas/APO 1 was determined by commercially available enzyme-linked immunosorbent assay (ELISA) kits. No significant differences were detected in the sFas/APO 1 serum level between patients and controls, but the levels in CSF was lower in the former. Our results suggest the possibility of Fas mediated apoptosis as a contributing factor in the pathogenesis of multiple sclerosis.

The small sodium-channel blocking factor in the cerebrospinal fluid of multiple sclerosis patients is probably an oligopeptide.

An endogenous factor that is able to reduce the fast transient sodium current of excitable cells has been reported to exist in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. This was confirmed with nine clinically definite MS patients in the acute relapse. In order to purify and chemically identify the factor, microconcentration and gel filtration high-performance liquid chromatography (HPLC) were applied. After each purification step the activity-containing fraction was determined using a biological assay. With all CSFs the activity was contained in the fraction corresponding to 600-800 Da molecular weight, indicating that the factor is chemically homogeneous. The biological activity of the CSF specimens was not correlated to the laboratory CSF data; however, it was correlated to the area under the 210 nm UV light absorption peak in the corresponding chromatogram, i.e. the 600-800 Da MW fraction. As the factor was degradable by acid hydrolysis and a carboxypeptidase, it is suggested that it might be a small peptide.

Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis.

The cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is characterized by increased concentrations of immunoglobulin (Ig), which on electrophoretic analysis shows restricted heterogeneity (oligoclonal bands). CSF Ig is composed of both serum and intrathecally produced components. To examine the properties of intrathecal antibody-producing B cells, we analyzed Ig heavy-chain variable (V(H)) region genes of B cells recovered from the CSF of 12 MS patients and 15 patients with other neurological diseases (OND). Using a PCR technique, we could detect rearrangements of Ig V(H) genes in all samples. Sequence analysis of complementarity-determining region 3 (CDR3) of rearranged VDJ genes revealed expansion of a dominant clone or clones in 10 of the 12 MS patients. B cell clonal expansion was identified in 3 of 15 OND. The nucleotide sequences of V(H) genes from clonally expanded CSF B cells in MS patients demonstrated the preferential usage of the V(H) IV family. There were numerous somatic mutations, mainly in the CDRs, with a high replacement-to-silent ratio; the mutations were distributed in a way suggesting that these B cells had been positively selected through their antigen receptor. Our results demonstrate that in MS CSF, there is a high frequency of clonally expanded B cells that have properties of postgerminal center memory or antibody-forming lymphocytes.

Clonal expansion and somatic mutation of VH genes of B cells from the cerebrospinal fluid of multiple sclerosis

Clonal expansion and somatic mutation of VH genes of B cells from the cerebrospinal fluid of multiple sclerosis

Cortisol and interleukin (IL)-6 in post-mortem cerebrospinal fluid of multiple sclerosis (MS) patients and controls

Cortisol and interleukin (IL)-6 in post-mortem cerebrospinal fluid of multiple sclerosis (MS) patients and controls