Abstract
Introduction/Aim: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterised by excessive fibrosis and the presence of lymphoid infiltrates that localise near areas of active scarring. These lymphoid aggregates, combined with the detection of circulating autoantibodies in IPF patients, suggests a significant autoimmune component to the disease. The role of B cells in IPF pathogenesis is poorly understood. The aim of this study was to characterise changes in the B cell repertoire in IPF. Specifically, analysis focused on IGHV gene usage, clonal expansion and isotype use.
Methods: B cell receptor (BCR) repertoire analysis was performed using unbiased adaptor-ligation PCR and next-generation sequencing developed by Repertoire Genesis, Inc. The BCR of individuals with IPF (n = 12) was compared to aged-matched controls (n = 6). The identification of V, D, J, and CDR3 regions was performed by aligning sequences to reference sequence data sets from the international ImMunoGeneTics information system® database. BCR repertoire network analysis was performed using the NAIR R-package.
Results: This analysis identified a number of private antibody clonotypes uniquely shared among multiple IPF patients, highlighting distinct features of the BCR repertoire in IPF. Notably, IGHV4-34 and IGHV5-51, were significantly overrepresented in IPF, particularly on IgM/IgD isotypes. Further analysis revealed the expansion of single or co-dominant B cell clones in a subset of IPF patients with evidence of extensive somatic variants, characterized by reduced isotype diversity.
Conclusion: These findings emphasise the inter-individual variability in the BCR repertoire, offering insights into the role of B cell immune repertoires in IPF. This knowledge may inform the development of more targeted diagnostic tools and therapeutic strategies for IPF, as well as inform patient selection criteria for future clinical studies.
Grant Support: The study was funded by research funds available through UNDA RFS and IRH. CMP and SEM are funded by MRFF and NHMRC.