BAFF-APRIL blockade reveals isotype-specific pathogenic autoantibody remodelling in antiphospholipid syndrome.

Objectives

Durable suppression of pathogenic autoantibodies remains a central challenge in antibody-mediated autoimmune diseases. We aimed to examine pathogenic autoantibody remodelling under targeted humoral immunotherapy using antiphospholipid syndrome (APS) as a tractable human model.

Methods

In this study, we used dual blockade of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) with telitacicept as an immune perturbation in a high-risk triple-positive antiphospholipid antibody (aPL) cohort including primary APS and asymptomatic aPL carriers, integrating longitudinal serology with paired pretreatment and posttreatment peripheral-blood and bone marrow single-cell and B-cell receptor repertoire profiling.

Results

Telitacicept induced broad B-lineage contraction but remodelled aPL responses nonuniformly, with consistent immunoglobulin (Ig) M- and IgA-class reductions and heterogeneous IgG-class suppression. This pattern coincided with extensive peripheral B-cell and plasmablast turnover, but greater clonal continuity within class-switched marrow plasma cells. In an exploratory post-hoc analysis of baseline IgG aPL-positive patients, incomplete IgG suppression was associated with greater persistence of pretreatment immunoglobulin heavy constant gamma positive (IGHG⁺) clonotypes and associated secretory programmes, whereas residual marrow IGHG⁺ plasma-cell abundance did not clearly distinguish response groups.

Conclusions

Together, these findings define compartment- and isotype-selective remodelling of pathogenic autoantibody responses in APS and identify persistent marrow IGHG⁺ plasma-cell clonotypes as a cellular correlate of incomplete suppression of IgG aPL.