Postdoctoral Fellow Boston Children's Hosp., Harvard Med. Sch., United States
Disclosure(s):
Kristine Oleinika, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
