Abstract
Systemic lupus erythematosus (SLE) is driven by pathogenic B cells. Yet, why some patients receiving B cell depletion achieve durable remission, whilst others fail remains unclear. Here we use CD19-directed chimeric antigen receptor (CAR) T cell therapy as a mechanistic probe in 18 patients with refractory SLE1,2, with longitudinal follow-up extending up to 40 months. We show that durable, drug-free remission is defined not by the depth of B cell depletion alone, but by the elimination of the extrafollicular (EF) B cell differentiation trajectory – specifically, activated naïve B cell precursors and CD11c+ T-bet+ double-negative type 2 B cells. In long-term responders, B cell reconstitution recapitulated healthy ontogeny, while the EF pathway remained truncated, coinciding with collapse of the interferon-rich milieu and contraction of PD1hi T peripheral helper cells. In contrast, in relapse, persistently elevated CXCL13, interferons and expanded PD1hi T cells preceded the B cell return, and nascent B cells immediately followed the EF differentiation trajectory in the confirmed absence of germinal centers in the lymph node, shortly followed by clinical symptoms. These findings indicate that CAR-T cell therapy achieves remission by breaking a feed-forward loop between the sy
Authors and Affiliations
Danae-Mona Nöthling¹˒²*, Kirill Anoshkin¹˒²*, Patrick G. Gavin³, Tobias Rothe¹˒², Laura Bucci¹˒², Futoshi Iwata¹˒², Panagiotis Garantziotis¹˒², Nicola Ferrari⁴, Sarah L.N. Clarke⁵, Melanie Hagen¹˒², Andreas Wirsching¹˒², Jule Bachl¹˒², Carlo Tur¹˒², Sebastian Böltz¹˒², Sascha Kretschmann²˒⁶, Michael Aigner²˒⁶, Simon Völkl²˒⁶, Luis Munoz¹˒², Fabian Müller²˒⁶, Andreas Mackensen²˒⁶, Markus Eckstein⁷, Maria Gabriella Raimondo¹˒², Aline Bozec¹˒², Georg Schett¹˒²†, and Ricardo Grieshaber-Bouyer¹˒²#†
¹ Department of Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
² Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany
³ Translational Science and Experimental Medicine, Respiratory and Immunology, BioPharmaceuticals, AstraZeneca, Gaithersburg, MD, USA
⁴ Translational Science and Experimental Medicine, Respiratory and Immunology, BioPharmaceuticals, AstraZeneca, Cambridge, UK
⁵ Translational Science, Immunology Cell Therapy, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
⁶ Department of Medicine 5 – Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
⁷ Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
* Danae-Mona Nöthling and Kirill Anoshkin contributed equally to this work.
† Georg Schett and Ricardo Grieshaber-Bouyer contributed equally to this work.
Corresponding author: Ricardo Grieshaber-Bouyer