BEAT · regulation of B-cell Epitope migration and Autoimmunity by T follicular helper cells
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-07-01 → 2023-07-01
- EU contribution
- €260,930
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
regulation of B-cell Epitope migration and Autoimmunity by T follicular helper cells
Systemic Lupus Erythematosus (SLE) is a severe and heterogeneous systemic autoimmune disease characterized by the production of antibodies to nucleic acid antigens. More than 75% of patients have serum autoantibodies to double-stranded DNA, which typically appear a few years before SLE is diagnosed. The trigger for this and may other auto-immune disease are unknown and are likely multi factorial. At or during disease onset the autoantibody repertoire drifts towards a wider variety of nuclear, nucleolar, and protein-DNA complexes: a process known as epitope spreading. The mechanism is not well understood, but the chronic inflammatory environment in SLE could drive inclusion of new autoreactive B cell clones. The acquisition of new reactivities is correlated with disease severity, and while the initial trigger of autoimmunity has been elusive mechanistic insight in epitope spreading could provide an interesting opportunity to dampen or even halt disease progression. The Researcher aims to identify and functionally characterize requirements of the early phase of epitope spreading. State-of-the-art mouse models and cutting-edge immunological and imaging methods are applied. This study provides an opportunity to identify targets at the initiation of epitope spreading that could be used for therapeutic intervention in autoimmunity and as a result alter disease severity. The period reported here spans the Outgoing Phase, during which work was performed at the Program of Cellular and Molecular Medicine at Bston Children's Hospital and Harvard medical School (Boston, U.S.A.).
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITAIR MEDISCH CENTRUM UTRECHT · UtrechtCoordinatorNetherlands
- CHILDREN'S HOSPITAL CORPORATION · BostonUnited States
Links
Data: CORDIS, © European Union