Marie Curie project – Beat

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.

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 (2022-2023)
University Medical Center Utrecht (UMCU)
Center for Translational Immunology (CTI), Utrecht, the Netherlands
Supervisor: Prof. F van Wijk & Prof S.H.M. Rooijakkers

Dissemination of the research project

– Conferences/presentations.

The Dutch Society of Immunology (NVvI), Annual Conference Dec. 2022. Rapid and persistent break of tolerance of B cells in spontaneous germinal centres. T. van den Broek, K.Oleinika, S.Rahmayanti, C.Castrillon, CE van der Poel, MC Carroll.

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.

– Articles

van den Broek T *, Oleinika K *, Rahmayanti S, Castrillon C, van der Poel CE, Carroll MC. (* contributed equally) Invasion of spontaneous germinal centers by naive B cells is rapid and persistent
Sci Immunol. 2024 Mar 22;9(93):eadi8150. PMID: 38517953

Castrillon C, Simoni L *, van den Broek T *, van der Poel CE *, Akama-Garren EH, Ma M , Carroll MC. (* contributed equally) Complex subsets but redundant clonality after B cells egress from spontaneous germinal centers.
Elife. 2023 Jun 21:12:e81012. PMID: 37341394

Akama-Garren EH, van den Broek T, Simoni L, Castrillon C, van der Poel CE, Carroll MC. Follicular T cells are clonally and transcriptionally distinct in B cell-driven mouse autoimmune disease.
Nat Commun. 2021 Nov 18;12(1):6687 PMID: 34795279

Van der Poel CE, Bajic G , Macaulay CW , van den Broek T, Ellson CD, Bouma G, Victora GD , Degn SE, Carroll MC. Follicular Dendritic Cells Modulate Germinal Center B Cell Diversity through FcγRIIB.
Cell Rep. 2019 Nov 26;29(9):2745-2755.e4. PMID: 31775042