KU Leuven

Author Of 2 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0038 - CHIT1 at Diagnosis Reflects Long-Term Multiple Sclerosis Disease Activity (ID 783)

Speakers
Presentation Number
P0038
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Evidence for a role of innate immune cells such as the CNS-resident macrophages or microglia in MS pathogenesis is growing, and the heterogeneity of microglial subsets is increasingly recognized. Several biomarkers directly reflect the neurodegenerative and inflammatory processes in MS. Macrophage and microglia-related biomarkers in CSF have been reported in other neurological diseases.

Objectives

We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity
(relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.

Methods

In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia-related proteins, chitotriosidase (CHIT1), chitinase-3–like protein 1 (CHI3L1 or YKL-40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme-linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia-related markers in publicly available RNA expression data from postmortem brain tissue.

Results

CHIT1 levels at diagnostic LP correlated with 2 aspects of long-term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E-04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E-04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL.

Conclusions

CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0412 - Treatment-induced BAFF expression alters B cell biology in multiple sclerosis (ID 767)

Speakers
Presentation Number
P0412
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Although fingolimod and interferon-β are two mechanistically different MS treatments, they both induce B cell activating factor (BAFF), and shift the B cell pool towards a regulatory phenotype.

Objectives

To investigate whether there is a shared mechanism between both treatments in how they influence the B cell compartment.

Methods

We collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod). We determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels.

Results

Interferon-β and fingolimod induced BAFF protein and mRNA expression (P≤3.15x10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P=5.70x10-6) and reduction in B cell-surface BAFF-R expression (P=2.70x10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels.

Conclusions

Treatment-induced BAFF prompts a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

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Presenter Of 1 Presentation

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0412 - Treatment-induced BAFF expression alters B cell biology in multiple sclerosis (ID 767)

Speakers
Presentation Number
P0412
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Although fingolimod and interferon-β are two mechanistically different MS treatments, they both induce B cell activating factor (BAFF), and shift the B cell pool towards a regulatory phenotype.

Objectives

To investigate whether there is a shared mechanism between both treatments in how they influence the B cell compartment.

Methods

We collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod). We determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels.

Results

Interferon-β and fingolimod induced BAFF protein and mRNA expression (P≤3.15x10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P=5.70x10-6) and reduction in B cell-surface BAFF-R expression (P=2.70x10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels.

Conclusions

Treatment-induced BAFF prompts a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

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