Enhanced Bruton\u2019s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis

Peter Heukels,Carian E Boorsma,Jelle R Miedema,Rudi W Hendriks,Marlies S Wijsenbeek,Rogier A S Hoek,Stefan F H Neys,Jan H Von Der Thusen,Barbro N Melgert,Odilia B J Corneth,Mirjam Kool,Bernt Van Den Blink,Jennifer A C Van Hulst,Menno Van Nimwegen

doi:10.1186/s12931-019-1195-7

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.

Highlights

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disorder [1, 2]
Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression
Autoreactive IgA could be useful as a biomarker for disease progression in IPF

Summary

Introduction

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disorder [1, 2]. Heukels et al Respiratory Research (2019) 20:232 organs (TLOs) have been found in lungs of IPF patients, which persist and accumulate during disease progression [10, 11]. CXCL13 was reported to be elevated in lungs and serum of patients with IPF [12, 13]. Over the past two decades several specific auto-antibodies have been identified in IPF8, likely involving local production of (auto)-antibodies in lung TLOs. Autoreactive antibodies, recognizing pulmonary proteins, may contribute to repeated lung injury [8]. Elevated serum B-cell activating factor (BAFF) was indicative for worse disease outcome in IPF patients [14]

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Conclusion