University Medical Center of the Johannes Gutenberg University Mainz

Author Of 2 Presentations

Invited Presentations Invited Abstracts

PL02.01 - New Insights on Immunopathogenesis

Speakers
Authors
Presentation Number
PL02.01
Presentation Topic
Invited Presentations
Lecture Time
14:30 - 15:15

Abstract

Abstract

Multiple sclerosis is a complex disease in which the innate and adaptive immune systems play a fundamental role. Treatment with disease-modifying therapies reduces relapses of neurologic symptoms (Bittner and Zipp, Nat Rev Neurol 2018). However, it does not stop overall disease progression and most patients eventually develop the secondary chronic progressive form of the disease (Larochelle et al., Trends Neurosci 2016). Immune modulatory therapies have given us novel insights into disease pathology, for example, that long-neglected B cells play a relevant role or that early consequent treatment in the relapsing phase of the disease is able to prevent a later conversion into a secondary progressive disease course. Novel blood-based biomarkers such as neurofilaments might not only facilitate patient treatment stratification (Bittner et al., EBioMedicine 2020), but also illustrate the relevance of axonal damage starting from the very first phases of MS. This highlights a need for new avenues of research that address the problem of progression in a fundamentally different way. We will critically discuss current pathophysiological models of progressive disease, e.g., the involvement of the adaptive versus innate immune system, immune-independent neurodegenerative pathways, repair mechanisms and higher network alterations. A special focus will be put on CNS-intrinsic pathways, the complex interplay between immune cells, glial cells and neurons within the CNS parenchyma, and its impact on brain function in health and disease.

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Experimental Models Oral Presentation

PS06.04 - GlcNAc-signaling as a new target to reduce T cell pathogenicity in the CNS

Speakers
Presentation Number
PS06.04
Presentation Topic
Experimental Models
Lecture Time
13:27 - 13:39

Abstract

Background

Both adaptive and innate immune cells infiltrate the CNS during multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE). Pathogenic T cells are known as key drivers of the disease while treatment strategies specifically targeting inflammatory processes directly within the CNS parenchyma behind the blood-brain-barrier are still missing.

Objectives

In this project we aimed to unravel CNS-internal mechanisms to counteract the disease in both the murine and the human system by modulating T cell pathogenicity in the CNS.

Methods

We used intravital 2-photon microscopy to visualize T cells and their interactions with neurons and microglia in the CNS of EAE-diseased animals and in organotypic slice cultures. Using immunohistochemistry and flow cytometry we further analyzed surface molecules on T cells and myeloid cells to gain a deeper understanding of the molecular pathways behind the CNS-response to T cell infiltration. Human T cells isolated from blood and cerebrospinal fluid of MS patients were analyzed ex vivo to allow translation to the human system.

Results

We discovered that detrimental effects of pathogenic Th17 cells can be mediated via a cell-to-cell-interaction-dependent vesicular glutamate release pathway that induces damage in neurons. In a counteractive mechanism, microglia attempted to remove fully viable invaded pathogenic T cells from the CNS tissue during the disease. This T cell engulfment was mediated by expression of activation-dependent lectin and its T cell-binding partner, N-acetyl-D-glucosamine (GlcNAc) and enhancement of GlcNAc signaling in the CNS ameliorated disease outcome. In human subjects, we could show that GlcNAc was highly exposed on T cells in the CNS of MS patients. Of note, this GlcNAc exposure on CNS-infiltrated T cells was significantly increased as compared to peripheral T cells.

Conclusions

Myeloid cells are able to directly react to pathogenic T cell infiltration by engulfing living T cells in a GlcNAc-dependent manner. Increased GlcNAc-exposure on T cells in the human CNS reflects high susceptibility of infiltrated T cells to get eliminated by myeloid cells, suggesting that pharmacological enhancement of T cell engulfment could particularly affect T cells in the target organ of MS.

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Moderator Of 1 Session

Free Communications Sun, Sep 13, 2020
Moderators
Session Type
Free Communications
Date
Sun, Sep 13, 2020
Time (ET)
13:00 - 14:15

Author Of 2 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0159 - Serum NfL predicts disability progression in MS in a six year longitudinal cohort study (ID 1196)

Speakers
Presentation Number
P0159
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Immunomodulatory therapies are effective in controlling disability progression in patients with multiple sclerosis (MS). Nonetheless, markers are needed to predict disease progression and transition into secondary progressive MS (SPMS) in order to guide individual treatment regimens.

Objectives

Evaluating the temporal evolution of neurofilament light chain (NfL) in patients with relapsing-remitting MS (RRMS) and its ability for forecasting EDSS progression and SPMS conversion within the prospective Neurofilament and long-term outcome in MS (NaloMS) cohort.

Methods

196 patients (median age 35.0 years (interquartile range (IQR) 27.2-43.1), 69.9% (n=137) female) with relapsing-remitting MS (RRMS) or clinically isolated syndrome were followed for median six years (IQR 4-8). Serum was collected at baseline and follow-up (FU); serum NfL (sNfL) levels were measured by single molecule array.

Results

During the study period, 34 of 196 patients (17%) suffered from relapse-free EDSS-progression (RFP) one year prior to FU and 27 of 196 patients (14%) converted to SPMS at FU. sNfL at Baseline was increased in patients with RFP, which remained significant after multivariate correction. Baseline sNfL levels ≥ 7.3 pg/ml were associated with increased probability of RFP in Kaplan-Meier analysis. In addition, sNfL levels at FU were increased in SPMS-converters and temporal NfL increases were more frequent in patients transitioning to SPMS than in non-converters.

Conclusions

sNfL levels at baseline predict disability progression at median six year follow-up in a prospective longitudinal cohort study. Moreover, sNfL levels are more frequently increased at follow-up compared to baseline in patients transitioning to SPMS. Therefore, temporal evolution of sNfL might thus be an ancillary tool facilitating timely SPMS diagnosis.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0263 - Serum neurofilament predicts clinical progression and increases diagnostic accuracy in patients with early multiple sclerosis (ID 1336)

Abstract

Background

Up to date prognostic estimation in newly diagnosed patients is hardly possible while the differentiation between disabling versus more benign courses is of utmost relevance. Reliable blood-based biomarkers that are associated with diagnosis and prognosis of multiple sclerosis (MS) have not been established.

Objectives

Can serum neurofilament light chain measurements serve as a reliable biomarker for diagnostic accuracy and prognosis for multiple sclerosis patients at the time point of diagnosis?

Methods

In a multicenter prospective longitudinal observational cohort, patients with a first diagnosis of multiple sclerosis (MS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers and assessed yearly with a standardized protocol. Patients were offered standard immunotherapies according to national treatment guidelines. Serum NfL concentrations were measured using an ultrasensitive single-molecule array (Simoa).

Results

A possible association between sNfL levels and clinical diagnosis, relapses, MRI parameters and treatment decisions was tested in 814 patients classified according to current (2017) and older (2010) McDonald criteria at time point of diagnosis and two years after study inclusion sNfL levels correlated with number of T2 and Gd+ lesions and clinical relapses. After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036) and increased accuracy of distinction between CIS and RRMS, when including ≥ 90th percentile of sNfL values. Patients receiving disease-modifying treatment (DMT) during the first two years had higher sNfl baseline levels (11.8 pg/ml, 7.5-20.9 pg/ml, n = 727) than patients never receiving DMT (9.5 pg/ml, IQR 6.4-14.1 pg/ml, n = 87, p = 0.002). Longitudinal sNfL levels reflected treatment decisions within the first four years.

Conclusions

sNfL is associated with diagnosis and prognosis of MS patients at the time point of first diagnosis and may be of use for initial treatment stratification.

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