Regulation of B-cell Epitope migration and Autoimmunity by T follicular helper cells (BEAT), no.:796988

Project summary

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. 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 564Igi mouse is a murine model of SLE, 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 (of 564Igi and wild-type (WT) mice) 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. This model was termed ARTEMIS, to signify Autoreactive B cell driven T-cell dependent Epitope Migration toward Immunity to Self.

We now further progress on these findings by utilizing the parabiosis model and, in which 564Igi and WT mice are surgically joined and lymphocytes can subsequently exchange between the mice without need for irradiation and the subsequent slow T- and B cell reconstitution as in the ARTEMIS model. The initial kinetics of WT B cells in the 564Igi mice are investigated in an adoptive transfer model.

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Project location

2-year outgoing phase (June 2018- June 2020)
Boston Children’s hospital & Harvard Medical School
Program in Cellular and Molecular medicine, Boston, MA, USA
Supervisor: Prof. M.C. Carroll

1-year return phase (start 2022)
University medical center Utrecht (UMCU)
Center for Translational Immunology (CTI), Utrecht, the Netherlands
Supervisor: Prof. F van Wijk & Prof S.H.M. Rooijakkers

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Dissemination of the research project

– Conferences/presentation.

The American Association of Immunologists conference, Immmunology, May 2021. Follicular T Cells are Clonally and Transcriptionally Distinct in B Cell-Driven Autoimmune Disease. Elliot H Akama-Garren, T. van den Broek, L. Simoni, C. Castrillon, C.E. van der Poel, M.C Carroll [link]

The American Association of Immunologists conference, Immmunology, May 2021. Specific traits of the B cell response to self-antigens revealed by single cell transcriptomics. C. Castrillon, L. Simoni^*, T. van den Broek^*, C.E. van der Poel ^*, E. Akama-Garren,  M.C. Carroll. [link]

Program in Cellular and Molecular Medicine Retreat, North Falmouth, MA, USA. Sept 2019. The evolution of WT B-cells in the autoreactive germinal center (81). T. van den Broek, C. Castrillon, E. Akama-Garren, K. Holscher, J. O’flynn, C. van der Poel, M.C. Carroll.

Program in Cellular and Molecular Medicine Retreat, North Falmouth, MA, USA. Sept 2019. Naive cells in an autoimmune environment: a single cell level exploration. Castrillon, C., Simoni, L.*, van den Broek, T.* van der Poel, C*. Carroll, M.

FOCIS, Boston, June 2019. Autoreactivity supports the maintenance and active participation of wild-type B cells in the germinal center (W.67). T. van den Broek, C. van der Poel, J. O’flynn, E. Akama-Garren, K. Holscher, M.C. Carroll. (link)

Keystone Symposia B cell – T cell interaction (J6), Keystone, Colorado. Febr. 2019. Evolution of Self-reactive Germinal Centers and Epitope Spreading. Michael C. Carroll, Gabriel D. Victora, Søren E. Degn, T. van den Broek, C. van der Poel.

Keystone Symposia B cell – T cell interaction (J6), Keystone, Colorado (poster number 3028) Febr. 2019. Autoreactivity supports the maintenance and active participation of wild-type B cells in the germinal center. T. van den Broek, C. van der Poel, J. O’flynn, E. Akama-Garren, K. Holscher, M.C. Carroll.

Program in Cellular and Molecular Medicine Retreat, North Falmouth, MA, USA 2018. Wild-type B cell involvement in the autoreactive germinal center. T. van den Broek, J. O’flynn, E. Akama-Garren, K. Holscher, C.E. van der Poel, M.C. Carroll.

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– Articles/pre-prints

Follicular T Cells are Clonally and Transcriptionally Distinct in B Cell-Driven Autoimmune Disease. E. Akama-Garren, T. van den Broek, L.Simoni, C.Castrillom, C. van der Poel, M.C. Carroll. Cell Press [link]