We aim to determine the development, regulation and function of B and T cell populations in health and immunological diseases. This will lead us to an understanding of why certain individuals are at greater risk of developing immunological disease, as well as to identify potential therapeutic targets or improved clinical management. This is achieved through the development and application of novel experimental and computational approaches, working in partnership with a global network of clinicians, immunologists and sample cohorts.
Immunological health relies on a balance between the ability to mount an immune response against potential pathogens and tolerance to self. B and T cells are key to the immune response by producing antibodies and cytotoxic T cells. B/T cell clones selectively expand following antigen recognition by B and T cell receptors (BCR and TCR) respectively. BCRs are the membrane-form of antibodies and are generated through DNA recombination resulting in the potential to recognise a vast array of pathogens. Defects in the ability to mount effective B cell or T cell responses have been implicated in infectious susceptibility, impaired surveillance of cancer and immunodeficiencies, whereas a breakdown of immunological tolerance has been attributed to autoimmune diseases such as through autoantibody production and reduced numbers of regulatory B/T cells.
Computational and lab-based projects are available, so please do get in touch if you are interested.
30/07/2020: Great to see the review out about autoantibody-associated encephalitis by Bo Sun and colleagues:
The B cell immunobiology that underlies CNS autoantibody-mediated diseases (Nature Reviews Neurology, 2020)
29/06/2020: Well done Felicia Tucci and previous students Ibrahim Ahmed and Aure Aflaflo on a novel barcoded sequencing method:
Ultrasensitive amplicon barcoding for next-generation sequencing facilitating sequence error and amplification-bias correction (Scientific Reports, 2020) https://rdcu.be/b5iBm
How are different B cell populations developmentally linked in human health?
We are investigating the generation, function and plasticity of B cell populations in human health. In particular, we are interested in how different lymphocyte subsets are developmentally linked and differences in function, and therefore providing a platform to understand how B cell fate may be different in human disease.
Immuno-surveillance in Cancer
There is accumulating evidence for the role of both T and B cells in modulating immune responses to both solid tumours and haematological malignancies. We are investigating the contributions, function and heterogeneity of B and T cells on the immune responses to tumours and their potential role in cancer detection and treatment.
How is B cell repertoire and function different in autoimmune disease and leukaemia
B cells, and the antibodies they produce, have long been associated with autoimmune and inflammatory disease. We have developed improved technical approaches that permits increased analysis of the B cells in the context of disease. We have performed the first systematic comprehensive analysis to determine the global differences in B cell repertoire between autoimmune diseases and relationship to disease pathology in pre- and post-therapy patients. Diseases include:
- Systemic lupus erythematosus (SLE)
- IgA vascultis (formally Henoch Schönlein purpura, HSP)
- Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)
- Eosinophilic granulomatosis with polyangiitis (EGPA)
- Crohn's disease (CD)
- Behcet’s disease (BD)
- Chronic lymphocytic leukaemia (CLL)
What is the effect of genetic and environmental variation on B and T cell fate?
We are integrating genomics, transcriptomics, and metabolomics data, serological, B /T cell repertoire and viromics datasets to investigate the effect of both genetic variation and environmental factors on B cell fate, regulation, and the relationship to disease susceptibility.
How are B /T cell populations reconstitution during and after immunomodulatory therapy?
We have shown that B cell depletion therapy and/or immunosuppression therapy in patients with a range of autoimmune diseases is associated with significant changes in B cell repertoires reflecting different mechanisms of B cell modulation. However, the effect of different therapeutic interventions on B and T cell function and the resulting reconstitution is not well understood, particularly in relationship to patient prognosis. We are applying single-cell genetic technologies to investigate the determinants of B cell persistence and reconstitution during and after therapy in autoimmune disease. This information may be used to develop potential biomarkers of resistance to therapy and to determine potential therapeutic interventions that could be combined with the current standard of care that could target persistent clones in autoimmune diseases.
We aim to develop novel experimental and computational tools to investigate the function of immune responses through advances in high-throughput and genetic technologies. These technologies can be readily applied to existing cohorts to investigate the immune system from unique perspectives.
Prof. John Todd
Prof. Mark Middleton
Prof. David Mole
Dr Shivan Sivakumar
Prof. Mike Dustin
Dr Enas Abu Shah
Immune responses in pancreatic cancer may be restricted by prevalence of activated regulatory T-cells, dysfunctional CD8+ T-cells, and senescent T-cells (2020)
Shivan Sivakumar, Enas Abu-Shah, David Ahern, Edward H Arbe-Barnes, Nagina Mangal, Srikanth Reddy, Aniko Rendek, Alistair Easton, Elke Kurz, Michael Silva, Lara R Heij, Zahir Soonawalla, Rachael Bashford-Rogers, Mark R Middleton, Michael Dustin
Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures (2020)
Jacob D. Galson, Sebastian Schaetzle, Rachael J. M. Bashford-Rogers, Matthew I. J. Raybould, Aleksandr Kovaltsuk, Gavin J. Kilpatrick, Ralph Minter, Donna K. Finch, Jorge Dias, Louisa James, Gavin Thomas, Wing-Yiu Jason Lee, Jason Betley, Olivia Cavlan, Alex Leech, Charlotte M. Deane, Joan Seoane, Carlos Caldas, Dan Pennington, Paul Pfeffer, Jane Osbourn
The B cell immunobiology that underlies CNS autoantibody-mediated diseases (Nature Reviews Neurology, 2020)
Bo Sun, Melanie Ramberger, Kevin C. O’Connor, Rachael J. M. Bashford-Rogers & Sarosh R. Irani
Ultrasensitive amplicon barcoding for next-generation sequencing facilitating sequence error and amplification-bias correction (Scientific Reports, 2020)
Ibrahim Ahmed, Felicia A. Tucci, Aure Aflalo, Kenneth G. C. Smith, Rachael Bashford-Rogers
Distinctive binding properties of patient-derived LGI1-autoantibodies determine pathogenicity (Brain, 2020)
Melanie Ramberger,* Antonio Berretta,* Jeanne MM Tan,* Bo Sun, Sophia Michael, Tianrong Yeo, Jakob Theorell, Rachael Bashford-Rogers, Sofija Paneva, Victoria O’Dowd, Neesha Dedi, Sarfaraj Topia, Robert Griffin, Jorge Ramirez-Franco PhD, Oussama El Far, Stéphanie Baulac, Maria I Leite, Arjune Sen, Alexander Jeans, David McMillan,5 Diane Marshall, Daniel Anthony, Daniel Lightwood, Patrick Waters, Sarosh R Irani.
B cell receptor repertoire analysis in six immune-mediated diseases (Nature, 2019)
RJM Bashford-Rogers, L Bergamaschi, EF McKinney, DC Pombal, F Mescia, JC Lee, DC Thomas, SM Flint, P Kellam, DRW Jayne, PA Lyons, KGC Smith
Natural history and cell-of-origin of TCF3-ZNF384 & PTPN11 mutations in twins with concordant B-ALL (Blood, 2019)
Clara Bueno*, J Ramón Tejedor*, Rachael Bashford-Rogers*,Laura González-Silva*, Rafael Valdés-Mas, Antonio Agraz-Doblás, Rafael Díaz de la Guardia, Chrystele Bilhou-Nabera, Nassera Abermil, Hélène Guermouche, Mario F Fraga, Agustín F Fernández, Paola Ballerini, Ignacio Varela, Pablo Menendez.
The integrated genomic and immune landscapes of lethal metastatic breast cancer. (Cell Reports, 2019)
Leticia De Mattos-Arruda, Stephen-John Sammut, Edith M. Ross, Rachael Bashford-Rogers,Erez Greenstein, Havell Markus, Sandro Morganella, Yvonne Teng, Yosef Maruvka, Bernard Pereira, Oscar Rueda, Suet-Feung Chin, Tania Contente-Cuomo, Regina Mayor, Alexandra Arias, Raza Ali, Wei Cope, Daniel Tiezzi, Dan Reshef, Elena Martinez, Vicente Peg, Santiago Ramon y Cajal, Javier Cortes, George Vassiliou, Gad Getz, Serena Nik-Zainal, Muhammed Murtaza, Nir Friedman, Florian Markowetz, Joan Seoane and Carlos Caldas
Genetic modification of primary human B cells generates translationally-relevant models of high-grade lymphoma (Nature Communications, 2019 and bioRxiv, 2019)
Rebecca Caeser, Miriam Di Re, Joanna A Krupka, Jie Gao, Maribel Lara-Chica, João M.L Dias, Susanna L Cooke, Rachel Fenner, Zelvera Usheva, Hendrik Runge, Philip A Beer, Hesham Eldaly, Hyo-Kyung Pak, Chan-Sik Park, George Vassiliou, Brian J.P Huntly, Annalisa Mupo, Rachael JM Bashford-Rogers, Daniel J Hodson
FcgRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human. (Nature Communications, 2019)
Marion Espeli, Rachael Bashford-Rogers, John Sowerby, Nagham Alouche, Limy Wong, Alice Denton, Michelle Linterman, and Ken Smith
Unravelling The Cellular Origin And Clinical Prognostic Markers Of Infant B-Cell Acute Lymphoblastic Leukemia Using Genome-Wide Analysis (Heamatologica, 2019)
Antonio Agraz-Doblas, Clara Bueno, Rachael Bashford-Rogers, Anindita Roy, Pauline Schneider, Michela Bardini, Paola Ballerini, Gianni Cazzaniga, Thaidy Moreno, Carlos Revilla, Marta Gut, Maria G Valsecchi, Irene Roberts, Rob Pieters, Paola De Lorenzo, Ignacio Varela, Pablo Menendez, Ronald W Stam
Combined influence of B-cell receptor rearrangement and somatic hypermutation on B-cell class-switch fate in health and in chronic lymphocytic leukaemia (Frontiers Immunology, 2018)
Velislava N Petrova, Luke Muir, Paul F McKay, George S Vassiliou, Kenneth GC Smith, Paul A Lyons, Colin A Russell, Carl A Anderson, Paul Kellam, Rachael JM Bashford-Rogers
Antibody repertoire analysis in polygenic autoimmune diseases (Immunology, 2018)
Rachael J.M. Bashford-Rogers, Kenneth G.C. Smith and David C. Thomas
Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors (Nature Cell Biology, 2017)
Sarah Horton, George Giotopoulos, Haiyang Yun, Shabana Vohra, Olivia Sheppard, Rachael Bashford-Rogers, Mamunur Rashid, Alex Clipson, Wai-In Chan, Daniel Sasca, Loukia Yiangou, Hikari Osaki, Faisal Basheer, Paolo Gallipoli, Natalie Burrows, Aysegul Erdem, Anastasiya Sybirna, Sarah Förster, Wanfeng Zhao, Tonci Sustic, Anna Petrukina Harrison, Elisa Laurenti, Jessica Okosun, Daniel Hodson, Penny Wright, Kenneth Smith, Patrick Maxwell, Jude Fitzgibbon, Ming-Qing Du, David Adams, and Brian Huntly
Novel pre/pro-B cells generates macrophage populations during homeostasis and inflammation (PNAS, 2017)
Tatsiana Audzevich, Rachel Bashford-Rogers, Neil A. Mabbott, Dan Frampton, Tom C Freeman, Alexandre Potocnik, Paul Kellam, Derek W Gilroy
Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukaemia clones (Experimental Hematology, 2017)
Rachael J. M. Bashford-Rogers, Anne L. Palser, Clare Hodkinson, Joanna Baxter, George A. Follows, George S. Vassiliou, and Paul Kellam.
RNA-seq de novo assembly of clonal immunoglobulin rearrangements identifies interesting biology and uncovers prognostic features in multiple myeloma. (Blood, 2016, 128(22); 195)
Mosen-Ansorena D, Bashford-Rogers R, Bolli N, Minvielle S, Magrangeas F, Anderson KC, AveTLoiseau H, Parmigiani G, Munshi NC.
Eye on the B ALL: B cell receptor repertoires reveal persistence of numerous B lymphoblastic leukemia subclones from diagnosis to relapse. (Leukemia, 2016)
Rachael Bashford-Rogers*, Katerina A. Nicolaou*, Jack Bartram, Nicholas J. Goulden, Loizos Loizou, Laura Koumas, Jianxiang Chi, Mike Hubank, Paul Kellam, Paul A. Costeas and George S. Vassiliou.
Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in EBV-infected B cells (The Journal of Experimental Medicine, 2016)
Jens S Kalchschmidt, Rachael Bashford-Rogers, Adam CT Gillman, Kostas Paschos, Paul Kellam and Martin J Allday.
Dynamics of immunoglobulin sequence diversity in HIV-1 infected individuals (Philosophical Transactions B, 2015)
Kenneth B Hoehn, Astrid Gall, Rachael Bashford-Rogers, SJ Fidler, S Kaye, JN Weber, MO McClure, SPARTAC Trial Investigators, Paul Kellam, Oliver G Pybus.
Molecular evolution of broadly neutralizing llama antibodies to the CD4 binding site of HIV-1. (Plos Pathogens 2014)
McCoy, L. E., Rutten, L., Frampton, D., Anderson, I., Granger, L., Bashford-Rogers, R , Webb, B., Dekkers, G., Seaman, M., Koh, W., Wagner, R., Verrips, T., Kellam, P., Fassati, A., and Weiss, R. A.
Capturing needles in haystacks: comparison of B cell receptor sequencing methods. (BMC Immunology 2014).
Bashford-Rogers, R., Palser, A, Idris, S, Carter, L, Epstein, M, Callard, R, Douek, D., Vassiliou, G., Follows, G., Hubank, M. and Kellam, P.
Network properties derived from deep sequencing of the human B cell receptor repertoires delineates B cell populations. (Genome Research 2013).
Bashford-Rogers, RJM. Palser AL, Huntly BJ, Rance R, Vassiliou GS, Follows GA, Kellam P.
Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study. (LANCET, 2013).
Cotten M, Watson SJ, Kellam P, Al-Rabeeah AA, Makhdoom HQ, Assiri A, Al-Tawfiq JA, Alhakeem RF, Madani H, Alrabiah FA, Hajjar, S. A., Al-Nassir, W. N., Albarrak, A., Flemban, H., Balkhy, H. H., Alsubaie, S., Palser, A. L., Gall, A., Bashford-Rogers, R., Rambaut, A., Zumla, A. I. & Memish, Z. (2013).