Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis

Abstract

RationaleIdiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice.MethodsB-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis.ResultsMore IgA+ memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = − 0.50). Bruton’s tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA+ germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88).ConclusionOur study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.

In silico immune infiltration profiling combined with functional enrichment analysis reveals a potential role for naïve B cells as a trigger for severe immune responses in the lungs of COVID-19 patients

“…Correlative studies have shown significantly increased expression of memory B cells, plasmablast and BAFF (B cell-activating factor of the TNF family) in lung tissue and peripheral blood of IPF patients [ 39 , 40 ], where BAFF is considered important for the survival of plasma cells [ 41 ]. In addition, the proportion of T follicular helper cells in the peripheral blood of IPF patients increased significantly [ 42 , 43 ].…”

“…Correlative studies have shown significantly increased expression of memory B cells, plasmablast and BAFF (B cell-activating factor of the TNF family) in lung tissue and peripheral blood of IPF patients [39,40], where BAFF is considered important for the survival of plasma…”

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

“…Perhaps as a compensatory mechanism, aberrant expansion of ectopic inducible bronchus-associated tissues (iBALT) independently supports the maturation and selection of B cells (CD5 + and CD20 + ) in aged, COPD, and IPF clinical cohorts, in particular those with cigarette smoking history (294)(295)(296). Single cell sequencing and proteomic analysis of lungs and peripheral blood cells from IPF individuals shows strong evidence of B1 and CD38 + CD138 + plasma cells accumulation, while experimental modeling of fibrosis generated strong correlation between the degree of pulmonary fibrosis and B-cell numbers in the germinal center (297)(298)(299)(300). The involvement of B cells in sterile (environmental) injury is not as well-established, aside from allergen induced IgE production in aging asthma cohorts (301).…”

Targeting Bruton’s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies

“…Increased BTK expression was found in circulating B cells in a fraction of patients with idiopathic pulmonary fibrosis (IPF; Heukels et al, 2019). However, BTKi showed divergent effects in bleomycin mouse models for pulmonary fibrosis, likely due to off-target effects and multi-kinase inhibition (Gu et al, 2018;Sun et al, 2020).…”