Bruton tyrosine kinase modulates systemic immune activation to bacterial translocation in primary antibody deficiencies.

BACKGROUND

Bacterial translocation is a shared phenomenon in common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). In CVID, bacterial translocation is linked to systemic immune activation and chronic inflammatory manifestations.

OBJECTIVE

We investigated whether the absence of functional Bruton tyrosine kinase (BTK) in XLA is associated with protection against systemic inflammation driven by bacterial translocation, and to assess whether BTK inhibition could modulate these inflammatory responses in CVID.

METHODS

Clinical data from the US national registry were analyzed to compare the incidence of inflammatory complications between CVID and XLA. Serum immune profiling was conducted to assess systemic immune activation associated with bacterial translocation in both disorders. In parallel, ex vivo stimulation assays were used to evaluate the effects of BTK inhibition on microbial translocation-driven inflammatory responses in CVID.

RESULTS

XLA patients, who lack BTK, were significantly protected from the inflammatory complications commonly observed in CVID. Despite comparable levels of bacterial translocation, serum cytokine profiling revealed that XLA patients exhibited markedly reduced immune activation, with lower levels of IFN-γ pathway mediators (IFN-γ, IL-12b, IL-18, CXCL9), proinflammatory cytokines (TNF-α, TNF-β, IL-6), chemokines related to host-commensal junctures (CCL19, CCL23, CCL3), and markers of monocyte and T-cell activation. XLA and CVID exhibited differential host responses to bacterial translocation stimuli in vivo and ex vivo, with reduced IFN-γ, proinflammatory cytokines, and monocyte responses in XLA. Translating these findings, we showed that the use of BTK inhibitors (rilzabrutinib, PCI-29732) in inflammatory CVID peripheral blood mononuclear cells recapitulated the in vivo differences between CVID and XLA, and effectively attenuated pathogenic immune responses to bacterial translocation stimuli.

CONCLUSIONS

These findings identify BTK as a key host modifier mediating the systemic effects of bacterial translocation. Inhibiting BTK activity in CVID may provide a novel therapeutic strategy to mitigate chronic inflammatory complications in this primary antibody deficiency.