Multi-omics comparison of periodontitis and peri-implantitis identifies plasma cell enrichment as a shared feature and a periodontitis-associated endothelial-plasma cell APP-CD74 axis.

OBJECTIVE

To define the shared and divergent immune architecture of periodontitis (PD) and peri-implantitis (PI) and to identify intercellular communication programs linked to plasma cell accumulation.

METHODS

Differentially expressed genes (DEGs) in PD and PI versus healthy controls were identified from two bulk datasets (GSE223924, GSE106090); robust cross-dataset common DEGs underwent functional enrichment and protein-protein interaction analysis. A single-cell atlas (GSE171213) supported dual deconvolution (BisqueRNA, CIBERSORTx) and CellChat-based, plasma cell-centered communication inference. Key findings were independently validated in two additional periodontitis bulk cohorts (GSE10334, GSE16134) and an independent periodontitis single-cell dataset (GSE164241). Candidate ligand-receptor interactions were evaluated by spatial transcriptomics (GSE206621) and multiplex immunofluorescence in a rat periodontitis model.

RESULTS

PI showed broader transcriptomic perturbation than PD (1,832 PI-specific and 820 PD-specific cross-validated DEGs). A total of 693 robust common DEGs with 99.0% directional concordance defined a shared inflammatory core enriched in cytokine signaling, B-cell activation, and osteoclast differentiation. Single-cell analysis resolved 15 cell populations and marked immune remodeling in periodontitis. Dual deconvolution identified plasma cell enrichment as the most reproducible infiltration feature across datasets and methods. CellChat revealed disease-associated remodeling of the plasma cell communication network, with endothelial cells as dominant senders and APP-CD74 as the strongest candidate incoming axis. Spatial transcriptomics showed a 14.43-fold increase in spot-level APP-CD74 co-enrichment in periodontitis-affected tissue, and multiplex immunofluorescence supported enhanced protein-level coupling between APP+CD31+ endothelial and CD74+CD138+ plasma cell domains.

CONCLUSIONS

Plasma cell enrichment is the most robust shared immune feature of PD and PI. In periodontitis, convergent multi-omics and tissue-level evidence supports a candidate endothelial-plasma cell communication program centered on APP-CD74, suggesting that endothelial-plasma cell niche remodeling may sustain periodontal inflammation and inform host-modulatory strategies. Importantly, this axis was established only in periodontitis; its relevance to peri-implantitis remains inferential and will require direct single-cell and spatial validation in peri-implant tissue.