Prof Carola Vinuesa; The Francis Crick Institute
Carola Vinuesa obtained a medical degree at the University Autonoma of Madrid (1993), undertook clinical training in the UK, and was awarded a PhD by the University of Birmingham (2000). As a Wellcome Trust International Research Fellow, she did postdoctoral work at the Australian National University (ANU) where she became a group leader (2006), Professor of Immunology (2010), and Head of Department (2011). In 2014 she founded and co-directed the Centre for Personalised Immunology, an NHMRC Centre of Research Excellence, as well as a sister Centre in Shanghai Renji Hospital. In late 2021 she became a Royal Society Wolfson Fellow and Assistant Research Director at The Francis Crick Institute (London, UK). She is an elected Fellow of the Royal Society of London (FRS), the Australian Academy of Science (FAA), the Australian Academy of Health and Medical Science (FAHMS) and the UK Academy of Medical Sciences (FMedSci). Carola has discovered novel T cell subsets that control B cell responses – follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr cells) – as well as the mechanisms by which they regulate antibody responses and limit autoimmunity. Her recent discoveries are connecting genetic variation in humans to autoimmune diseases like lupus and illuminating disease pathogenesis. She has been the recipient of several prestigious awards, including the Australian Academy of Science Gottschalk medal, the Australian Science Minister’s prize for Life scientist of the year, the 2023 Lupus Insight Prize (LRA) and Johann Anton Merck Award 2023.
B cells are central pathogenic drivers in autoimmunity, particularly in systemic autoimmune diseases like lupus targeting self-nucleic acids. This concept is reinforced by the remarkable efficacy of B cell–depleting chimeric antigen receptor (CAR)-T cell therapies. Although B cells contribute through multiple mechanisms, autoantibody production remains a key driver of disease initiation, amplification, and relapse. Yet the cellular origin, lifespan, and anatomical niches of autoantibody-producing cells remain incompletely defined. Long-lived plasma cells have traditionally been considered the main reservoirs of pathogenic antibodies, as autoantibodies often persist following CD20-targeted therapies. However, the profound autoantibody reduction achieved by anti-CD19 CAR-T therapy - which does not deplete terminally differentiated plasma cells - challenges this view and raises fundamental questions about how pathogenic antibody responses are maintained. To address this, we combined mouse models carrying human monogenic lupus variants with molecular immunoglobulin-tagging approaches that allow in vivo tracking of autoreactive B cell lineages. We show that individual plasma cells are short-lived and require continuous replenishment from proliferating CD19⁺ precursors that persist for a long time. The spleen serves as important reservoirs for autoantibody-producing plasma cells, with intriguing perivascular localization. Anti-CD19 CAR-T therapy efficiently eliminated both B cells and plasma cells in the spleen, and relapse was driven by newly generated autoreactive B cells rather than depletion-resistant plasma cells. These findings suggest that sustained B cell activation, rather than plasma cell longevity, underlies pathogenic autoantibody production, supporting adjunctive therapies after CAR-T, particularly in patients with strong genetic susceptibility patients.
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