Researchers have generated a detailed multi-omics atlas of the human oral mucosa, revealing that the gingiva is organized into distinct immune zones that remain structurally intact even during inflammatory disease.
The study, published Feb. 9 in Nature Immunology, describes a “remarkable immune zonation” at the tooth–gum interface, where a dynamic epithelium is underlined by a layer of neutrophils and a zone of antigen-presenting cell–lymphocyte aggregates.
To generate their findings, the researchers compiled an integrated dataset that included more than one million spatially mapped cells, approximately 32,000 cells with paired surface protein and transcriptomic data, and over 3.5 million CD45+ immune events analyzed by spectral flow cytometry. The samples were obtained from 28 systemically healthy adult participants — 11 who are healthy and 17 with periodontitis — recruited prospectively under an Institutional Review Board-approved protocol at the U.S. National Institutes of Health Clinical Center.
“Tooth-associated epithelium maintains a unique, pre-inflammatory state even in health,” the researchers wrote, noting that epithelial and stromal signals help organize underlying tissues into spatially distinct immune compartments.
“This preserved immune zonation meets the demands for continuous protection of this vulnerable interface and suggests unique tissue-specific wiring of immunity at the human oral mucosal barrier.”
Preserved structure, even in periodontitis
Using spatial transcriptomics and other multi-omics tools, the team compiled what it called a spatial map of the exposed mucosal microenvironment. The findings suggest that immune responsiveness at barrier surfaces is tailored to local exposure — particularly relevant in the oral cavity, where a permeable epithelium coexists with a dense and diverse microbiota.
Importantly, the study found that this immune zonation is preserved even during inflammatory disease.
During chronic periodontitis, however, inflammatory zones expand and organize into immature tertiary lymphoid structures — a process the authors say may indicate localized antibody production.
“Location-specific transcriptomes support a role for the stromal compartment in the spatial organization of immunity,” the researchers wrote, adding that this preserved architecture likely enables continuous protection of the tooth interface — one of the body’s most exposed barrier sites.
In their conclusion, the researchers said the tooth-associated epithelium represents a “healing-privileged” mucosal site, offering insights not only into tissue-specific immunity but also into mechanisms that could potentially be therapeutically leveraged to optimize barrier immune responsiveness in other tissues.