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regulation of B-cell Epitope migration and Autoimmunity by T follicular helper cells

Objective

The detection of autoantibodies typically appear a few years prior to clinical autoimmune disease and their reactivity can drift at or after disease onset. The laboratory of M.C. Carroll (outgoing institute) has developed a murine model (ARTEMIS; Autoreactive B-cell driven T-dependent Epitope Migration towards Immunity to Self) where the presence of a single autoreactive B cell clone drives activation, expansion and differentiation of other autoreactive B-cells in spontaneous germinal centers (GC) followed by autoantibody deposition in the kidney. These autoreactive B-cells target multiple other self-antigens (also known as epitope spreading) and are independent of the initial trigger once tolerance is broken. Follicular T helper (Tfh) cells play a prominent role in the selection of B-cells in the GC and have been linked to excessive GC formation, high-level production of pathogenic autoantibodies and end-organ damage in murine and human autoimmune disease. With this project I will address the role of Tfh cells in the maturation process of the self-reactive B-cell response and epitope spreading as observed in human autoimmune disease. Preliminary results show dependence of T cells, the extent and nature of T-cell involvement is however not yet addressed. I will utilize the mixed bone-marrow chimera model (ARTEMIS) in combination with selected strains altered in important factors for Tfh function and differentiation. As the GC reaction is a highly dynamic process we will visualize this utilizing multi-photon intravital microscopy and analyze important interactions of Tfh cells in the developing autoreactive GC. The development of autoreactivity from WT B-cells in the ARTEMIS model better reflects natural autoreactive GC behavior and human autoimmune disease and could therefore favor the transition of potential therapeutic targets from murine to human disease.

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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2017

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Coordinator

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 260 929,80
Address
HEIDELBERGLAAN 100
3584 CX Utrecht
Netherlands

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Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 260 929,80

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