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Immune Parameters That Distinguish Multiple Sclerosis Patients from Patients with Other Neurological Disorders at Presentation.

ABSTRACT: Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. Effector T helper cells, mainly Th1 and Th17, cytotoxic T-cells, B-cells, macrophages, microglia, and the cytokines they secrete, are implicated in the initiation and maintenance of a deregulated immune response to myelin antigens and the ensuing immune-mediated demyelination. In this study, we investigated whether signature cytokines exist in MS patients at presentation to gain an insight into the underlying immunopathogenic processes at the early stage of the disease.We collected serum and cerebrospinal fluid (CSF) samples from 123 patients at presentation, eventually diagnosed with MS or non-inflammatory (NIND) or inflammatory neurological diseases (IND) or symptomatic controls (SC). The levels of cytokines IFN-?, TNF-?, TGF-?1, IL-2, IL-4, IL-6, IL-10 and IL-17 were measured, and cytokine ratios, such as Th1/Th2, Th1/Th17, and Type-1/Type-2, were calculated. All parameters were tested for their correlations with the intrathecal IgG synthesis.Cytokine levels in CSF were lower than in serum in all the patients, with the exception of IL-6. Serum or CSF cytokine levels of MS patients did not differ significantly from NIND or SC, with the exception of serum IFN-? and TNF-? that were significantly higher in NIND. IND patients presented with the highest levels of all cytokines in serum and CSF, with the exception of serum IL-10 and CSF IL-17. MS patients had a significantly lower serum Th1/Th2 ratio compared to the NIND and IND groups, and significantly lower serum Type-1/Type-2, IFN-?/IL-10 and CSF Th1/Th17 ratios compared to IND patients. MS patients had a significantly higher CSF IL-17/IL-10 ratio compared to IND patients. The IgG index was higher in MS patients compared to the control groups; the differences reached statistical significance between the MS and the NIND and SC groups. Reiber-Felgenhauer analysis of the QIgG and QAlb indices revealed higher intrathecal IgG synthesis in MS patients, and higher blood-CSF barrier dysfunction in IND patients. The IgG index correlated with CSF IL-4 in MS patients only.We found no signature cytokines or profiles thereof in MS patients at presentation. Only IND patients presented with a clear Th1 cytokine polarization in serum and CSF. The parameters that distinguished MS patients from patients with other neurological disorders were IgG intrathecal synthesis, the IgG index and its correlation with CSF IL-4 levels.

SUBMITTER: Mouzaki A

PROVIDER: S-EPMC4552669 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Immune Parameters That Distinguish Multiple Sclerosis Patients from Patients with Other Neurological Disorders at Presentation.

Mouzaki Athanasia A Rodi Maria M Dimisianos Nikolaos N Emmanuil Andreas A Kalavrizioti Dimitra D Lagoudaki Rosa R Grigoriadis Nikolaos C NC Papathanasopoulos Panagiotis P

PloS one 20150828 8

<h4>Background/aim</h4>Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. Effector T helper cells, mainly Th1 and Th17, cytotoxic T-cells, B-cells, macrophages, microglia, and the cytokines they secrete, are implicated in the initiation and maintenance of a deregulated immune response to myelin antigens and the ensuing immune-mediated demyelination. In this study, we investigated whether signature cytokines exist in MS patients at presentation to gai ...[more]

PMID: 26317430

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Project description:Infiltrating T-lymphocytes from the peripheral blood into the central nervous system (CNS) play a dynamic role in the development of a neurological immune-mediated diseases. HAM/TSP is a chronic progressive inflammatory neurological disorder associated with human T-cell lymphotropic virus type I (HTLV-I) infection. In this chronic myelopathy, virus-infected circulating T-cells infiltrate the CNS and an immune response is initiated against the components of CNS. As the HTLV-I proviral load (PVL) has been used as the best clinical marker for patient diagnostic with HAM/TSP, we hypothesized there might be a signature on T-cell receptor (TCR) clonal repertoire in these patients, which could distinguish HAM/TSP patients from the healthy population, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease as multiple sclerosis (MS). With this in mind, we applied an innovative unbiased molecular technique – unique molecular identifier (UMI) library-strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). To address whether the clonal expansion correlates with the patient’s PVL level, analysis of longitudinal TCR repertoire was performed in 2 HAM/TSP patients. Over 5.6 million TCR sequences were generated per sample on HiSeq 2500 Illumina system and analyzed through the molecular identifier groups-based error correction pipeline (MiGEC). Bioinformatic analysis showed that clones with more than 8 reads had a lower coefficient of variation (CV) and then could be used with confidence to evaluate the TCR clonal expansion. While HAM/TSP patients showed the higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subject’s group. In addition, correlation of the PVL with TCR clonal expansion was observed in HAM/TSP patients at longitudinal time-points. Surprisingly, MS patients showed a higher diversity of TCR repertoire along with a very slight clonal T-cell expansion in comparison to either HAM/TSP patients or HC. Despite of the higher TCR clonal expansion in HAM/TSP patients, a non-shared or “private” TCR repertoire was observed in these patients. No clones that shared the same CDR3 amino acid sequences were seen in HC and MS patients. However, a cluster of related CDR3 amino acid sequences were observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. It suggestes that a TCR-repertoire signature might characterize patients with MS. Our findings suggest that even though a unique TCR-b repertoire shapes the immune response in patients with neurological immune-mediated disease, a relatedness on clonal T-cell repertoire exist in MS.

Project description:BackgroundWhile disease progression can be readily monitored in early stage relapsing multiple sclerosis (MS), it is more challenging for secondary progressive multiple sclerosis (SPMS). This advanced stage of disease has distinct pathophysiology due to compartmentalization of neuroinflammatory activity within the central nervous system, resulting in increased incidence and severity of cognitive dysfunction. The shift in the dominant disease pathways is underscored by the failure of relapsing therapies to benefit SPMS patients, highlighting the need for novel treatment strategies and clinical trial endpoints that are well-aligned with potential benefits. The Expanded Disability Status Scale (EDSS) is widely used but is weighted towards ambulatory ability, lacking sensitivity to other aspects of neurological impairment experienced in more severely disabled SPMS patients, so may not effectively capture their clinical status.To investigate the feasibility of an alternative clinical trial endpoint model for a phase 2B trial of an immune modulator for SPMS, the potential for treatment efficacy-based patient-centered outcomes was assessed within the context of a before and after, 12-week clinical trial of safety and tolerability.MethodsPatients treated with MIS416 for 12 weeks were evaluated for clinical status at baseline and end of dosing, using the established Multiple Sclerosis Functional Composite, Short Form Health Survey, and Expanded Disability Status Scale. Responder status was determined for eight outcome measures based on minimally important change, defined using published studies. To evaluate the patients' immune response to MIS416, blood plasma samples collected at baseline and pre- and 24-h post doses 1-4 were analyzed using multiplex cytokine quantification assays.ResultsUsing a combination of patient-centered outcomes, MIS416 treatment was associated with improved clinical status for 10/11 patients: eight patients showed improvement on two to five outcome measures, five of which also showed improvement by EDSS. Multi-dimensional scaling analysis of MIS416-induced factors quantified in individual patients, revealed immune response patterns which had a strong concordance with the extent of the patients' clinical response.ConclusionsThe data support the feasibility of using patient-centered outcomes as additional clinical trial endpoints, for determining the efficacy of disease-modifying therapies, in secondary progressive multiple sclerosis patients.Trial registrationClinicalTrial.gov, NCT01191996.

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Immune Parameters That Distinguish Multiple Sclerosis Patients from Patients with Other Neurological Disorders at Presentation.

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Immune Parameters That Distinguish Multiple Sclerosis Patients from Patients with Other Neurological Disorders at Presentation.

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