Uncoupling autoreactive B cell receptor expression from autoimmune activation identifies early checkpoints in lupus 2259295

Abstract

Abstract Introduction Systemic lupus erythematosus arises when tolerance mechanisms fail and autoreactive B cells are activated to produce pathogenic antibodies. While mechanisms sustaining chronic autoimmunity — such as germinal center (GC) persistence and epitope spreading — are well characterized, the checkpoints that link autoreactive B cell receptor (BCR) expression to the initiation of disease remain poorly defined. Methods Lupus progression can be modelled using a murine mixed bone marrow chimera system in which a single ‘rogue’ B cell clone with broad ribonuclear complex reactivity (clone 564) breaches tolerance and recruits wild-type (WT) B cells into activation. To investigate early tolerance checkpoints, we combined BCR knock-in models, adoptive transfer, and bone marrow chimera approaches to examine how antigenic context and T cell interactions influence B cell activation. Results Within mixed chimeras, WT B cells were recruited into spontaneous responses, diversified, and contributed to an expanding autoreactive repertoire. From these responses, we identified two WT-derived BCRs with lupus-associated specificities: M05, reactive to single-stranded DNA and CCL22, and G55, reactive to the Smith D2 protein. M05 and G55 knock-in mice lacked spontaneous GCs and autoantibodies, with tolerance maintained through receptor editing. However, in the presence of the 564 clone, these autoreactive B cells became activated and secreted autoantibodies, revealing that autoreactivity alone is insufficient to trigger disease. We now dissect the antigen- and T cell-dependent cues that enable tolerance breach. Conclusion This work defines the earliest antigen- and T cell-dependent checkpoints that determine whether autoreactive B cells remain silent or become pathogenic. Understanding how these tolerance barriers are breached offers new opportunities to target the initiation phase of lupus rather than its chronic sequelae. Funding Source This work was supported by grants awarded to M.C.C.: National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR074105) and National Institute of Allergy and Infectious Diseases (R01 AI130307); U.S. Department of Defense (HT9425-24-1- 0598); and the Lupus Research Alliance. Topic Categories Basic Autoimmunity (BA)