Command Palette

Search for a command to run...

Preprint WatchModerateSeptember 2nd, 2026

Antibody-dependent priming of spontaneous germinal centers by autoreactive B cells

Kim, D.; Chiang, K.; Largent, A. D.; Pitner, R. A.; Ponnan, S. M.; McKinney, B. J.; James, R. G.; Rawlings, D. J.; Jackson, S. W.

Autoreactive B cells prime spontaneous germinal centres through autoantibody production rather than cognate T cell help, and B cell-intrinsic deletion of CD40, MHC class II or CD80/86 fails to prevent germinal centre formation.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that in the 564Igi mixed chimera model, deleting CD40 on germinal-centre-priming autoreactive B cells does not prevent spontaneous germinal centre formation, while deleting Prdm1 does, implicating autoantibody production rather than cognate T cell help as the driver. The Claidex record for CD40 contains one documented failure, gen1042-cd40-4-1bb-immunoradiotherapy-solid-tumors-phase1-2-efficacy-termination, a CD40 and 4-1BB bispecific terminated for efficacy in solid tumors. The indications differ and the direction of intervention is opposite, agonism in oncology against loss of function here. What transfers is the redundancy finding. In both settings CD40 engagement was assumed to be a controlling node and in both settings removing or engaging it did not produce the expected downstream effect. Programs that treat CD40 as a single point of control should carry an explicit test of that assumption.

Abstract excerpt

Autoreactive germinal centers (GCs) are central to autoimmune pathogenesis, yet the mechanisms by which single autoreactive B cell clones prime systemic autoimmunity remain unclear. Using the 564Igi mixed chimera model, we demonstrate that autoreactive 564Igi B cells break tolerance in wild-type B cells through an unexpected mechanism independent of cognate T cell interactions. While B cell-intrinsic TLR7 signaling was essential for spontaneous GC formation, deletion of MHC class II, CD40, or CD80/86 on GC-priming 564Igi B cells failed to prevent GCs. Instead, CRISPR-mediated deletion of Prdm1 (encoding BLIMP-1) in 564Igi B cells ablated spontaneous GCs, implicating autoantibody production as the primary driver. These findings reveal that autoantibodies can initiate feed-forward mechanisms that propagate systemic autoimmunity, independent of B cell-intrinsic antigen presentation.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.