Integrin β3 deficiency unleashes spontaneous pulmonary inflammation by promoting B cell hyperactivation via the CD40-CD40L axis

Background Pulmonary immune homeostasis requires tight control of adaptive responses. Integrin β3 is a well-known mediator of cell adhesion and platelet function. However, its role in adaptive immunity, especially in B cell responses, remains unclear. Methods We defined the pulmonary phenotype of constitutive β3-deficient (β3 −/− ) mice by histopathology. We performed integrated transcriptomic and proteomic profiling of lung tissue to map the molecular signature of spontaneous pulmonary inflammation. We further probed the underlying mechanisms with additional histology and functional assays and tested for biological significance using transcriptomics data from auto-immune disease patients. Results β3 −/− mice developed spontaneous pulmonary inflammation marked by B cell activation and in situ immune-complex deposition within alveoli. Multi-omics integration implicated the CD40-CD40 Ligand (CD40L) axis as a central driver of this pathology. Mechanistically, loss of β3 enhanced CD40L–CD40 engagement on B cells, resulting in NF-κB pathway hyperactivation. Consistent with our murine data, reduced ITGB3 expression in patients with autoimmune disease correlated with transcriptional signatures of B cell activation and inflammation. Conclusions These results reframe integrin β3 as a threshold regulator of B cell activation. The β3–CD40L–CD40 axis therefore represents a potential therapeutic target for B cell–mediated autoimmune diseases.