B109-25 Senescent B-cells in COPD: Insights Into Spatial Distribution, Class Switching, and At2 Cell Interactions

Purpose

The principal cell type driving the senescent state resulting in accelerated lung aging in COPD is not fully known. Previous work by our group identified the B-cell to have the highest senescence enrichment score (ES = 1.23) in lung tissue samples from COPD patients (GOLD stage III) as compared to healthy controls in humans. The current study was designed to further validate our previous findings and identify the mechanistic underpinning of our observations.

Methods

Spatial transcriptomics on age- and sex-matched fresh-frozen lung tissues (healthy and emphysematous, n = 3/group) were performed using 10X Xenium technologies to validate our findings. Additionally, antibody isotyping in blood from COPD patients and healthy individuals was performed to explore functional relevance of B-cell senescence. CellChat analysis identified interacting partners for senescent B cells.

Results

Spatial transcriptomic analyses corroborated with previous results showing significant (p = 0.034, Welch’s t-test) increase in the senescent module score for B cells in the lungs of COPD donors as compared to healthy controls. Importantly the senescent B cells were found to be spatially scattered in healthy tissues, as opposed to clustered niches occurring close to AT2 cells in COPD. Antibody isotyping showed a significant (p = 0.0105, Kruskall-Wallis test) increase in IgM concentration, but no changes in IgG1, IgG2, IgG3, IgG4 or IgA, in the blood from COPD patients thus showing defective class switching by mature B cell population. Finally, cell-cell interaction mapping of B-cells, identified loss of function between AT2 and B cells interactions, with MIF, THBS1 and Visfatin signaling being most affected in diseased lungs.

Conclusion

Overall, our results identify the mechanistic relevant of B-cell senescence in COPD. We provide evidence of altered class switching and B-cell mediated cellular networks in diseased state. The loss of function of various signaling pathways playing key role in AT2 proliferation and differentiation may point towards a possible shift in the AT2-to-AT1 transition in COPD due to the presence of senescent B-cell population in its vicinity, a speculation that is being validated using in vitro approaches.

This abstract is funded by: None