Bruton tyrosine kinase modulates systemic immune activation to bacterial translocation in primary antibody deficiencies
Journal of Allergy and Clinical Immunology, 2025
Ho H., Radigan L., Qi J., Roudko V., Storek M., Lee J., Fuleihan R., Sullivan K., Kim-Schulze S., Cunningham-Rundles C.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Cell Culture Supernatant Serum |  Olink Target 96 |
Abstract
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
To investigate whether the absence of functional Bruton’s 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), pro-inflammatory 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-ɣ, pro-inflammatory cytokines, and monocyte responses in XLA. Translating these findings, we showed that the use of BTK inhibitors (rilzabrutinib, PCI-29732) in inflammatory CVID PBMCs 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.