Periodic Reporting for period 2 - BEAT (regulation of B-cell Epitope migration and Autoimmunity by T follicular helper cells)
Período documentado: 2020-07-01 hasta 2021-06-30
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.).
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.).
The acquisition of new distinct autoreactivities, epitope spreading, is thought to be driven by chronic immune responses causing inclusion of new autoreactive B cell clones, but the underlying mechanisms involved are ill understood.
The Researcher utilized the 564Igi mouse as a murine model of SLE, which is generated by knock-in of a B cell receptor of an autoreactive B-cell clone. We have previously shown (S.Degn et al. Cell 2017) in a mixed bone marrow chimera model that we can induce and reproduce the spontaneous development of self-reactive B cells from the WT-repertoire (epitope spreading). Once tolerance was broken, WT B-cells acquired new targets of auto-reactivity and became independent of the initial trigger, although still dependent on T cell stimulation.
The Researcher now further progresses on these findings and specifically addresses the requirements needed to start and maintain epitope spreading. In this project, the Researcher was able to show that naïve wild-type (WT) B cells induce epitope spreading by active entry, participation and differentiation in pre-existing autoreactive germinal centers (aGC). Entry of the WT B cell into the aGC is an active process that depends on primary signals via antigen presentation and recognition as well as secondary signals via Toll-like receptor 7 and Interferon alpha, among others. Moreover, entered WT B cells clonally evolved towards dominance of individual clonal lineages, persisted for extended periods and differentiated into autoantibody producing plasma cells. Collectively, the Researcher has setup a new model for epitope spreading that identified a distinct mechanistic insight of the initial phase of epitope spreading and that could have clinical implications for developing targets for early immunotherapeutic strategies.
These results have been presented at (inter)national conferences and is currently submitted for publication.
The Researcher utilized the 564Igi mouse as a murine model of SLE, which is generated by knock-in of a B cell receptor of an autoreactive B-cell clone. We have previously shown (S.Degn et al. Cell 2017) in a mixed bone marrow chimera model that we can induce and reproduce the spontaneous development of self-reactive B cells from the WT-repertoire (epitope spreading). Once tolerance was broken, WT B-cells acquired new targets of auto-reactivity and became independent of the initial trigger, although still dependent on T cell stimulation.
The Researcher now further progresses on these findings and specifically addresses the requirements needed to start and maintain epitope spreading. In this project, the Researcher was able to show that naïve wild-type (WT) B cells induce epitope spreading by active entry, participation and differentiation in pre-existing autoreactive germinal centers (aGC). Entry of the WT B cell into the aGC is an active process that depends on primary signals via antigen presentation and recognition as well as secondary signals via Toll-like receptor 7 and Interferon alpha, among others. Moreover, entered WT B cells clonally evolved towards dominance of individual clonal lineages, persisted for extended periods and differentiated into autoantibody producing plasma cells. Collectively, the Researcher has setup a new model for epitope spreading that identified a distinct mechanistic insight of the initial phase of epitope spreading and that could have clinical implications for developing targets for early immunotherapeutic strategies.
These results have been presented at (inter)national conferences and is currently submitted for publication.
The Researcher provides a new model to study epitope spreading in autoimmune disease and has resulted in new insights in the disease process of patients with auto-immunity, such as systemic lupus erythematosus (SLE). These insights provide potential targets for intervention that could halt disease progression in patients with autoimmune diseases and hereby has a major impact on their personal health and consequently their impact on society. In contrast to halting the immune response, these targets could also be used to enhance the immune response and could for instance be beneficial to boost vaccination responses. Currently, some of the targets the Researcher identified are being used in COVID-19 vaccination trials and has also opened avenues for innovative therapeutic strategies. Overall, the generation of the new model could further help identify targets that block or enhance the immune response, hereby playing a role in generating therapeutic targets that dampen or enhance the immune response when necessary.