KU Leuven

Author 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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