DENVER—Scientists have identified a detailed cellular signature of pulmonary sarcoidosis, revealing how immune cells in the lungs change their behavior and communication during the disease. The findings, from researchers at National Jewish Health and collaborating institutions, offer a closer look at the biological events behind an inflammatory condition that can range from mild and self-limited to progressive and debilitating. By examining individual lung immune cells rather than analyzing them as a single mixture, the researchers found disease-associated changes in macrophages, B cells and CD4-positive T cells that may help explain why sarcoidosis behaves differently from one patient to another.
Sarcoidosis occurs when the immune system forms compact clusters of inflammatory cells called granulomas in tissues. The lungs are affected in most cases, although the disease can also involve the skin, eyes, lymph nodes, heart and other organs. Granulomas can remain stable for years, but persistent inflammation may scar lung tissue, restrict airflow and impair the exchange of oxygen. Despite the disease’s clinical importance, its precise cause remains unknown. Researchers believe that an abnormal immune response to one or more environmental or infectious triggers may be involved, but no single initiating agent has been established.
The new study used single-cell RNA sequencing, a molecular technique that measures gene activity in individual cells. Every cell contains largely the same DNA, but different cell types activate different sets of genes depending on their identity and surroundings. By reading these active genetic programs one cell at a time, scientists can distinguish subtle populations and states that are often obscured in conventional tissue analysis. This approach can show not only which immune cells are present, but also whether they are producing inflammatory molecules, responding to signals or changing their functional roles inside the lung.
The research team analyzed immune cells collected from the lungs of 16 people with sarcoidosis and compared them with cells from 14 healthy volunteers. The analysis revealed disease-associated patterns of gene expression in macrophages, immune cells that engulf cellular debris and pathogens and help organize inflammation. Macrophages are also central components of granulomas, where they can receive signals from T cells and release molecules that recruit or activate additional immune cells. The altered gene programs observed in these cells suggest that macrophages in sarcoidosis may occupy specialized inflammatory states rather than simply becoming uniformly more active.
The investigators also detected a reduction in B cells among the lung immune-cell populations of people with sarcoidosis. B cells are best known for producing antibodies, but they also present antigens to T cells and release signaling molecules that can shape inflammation. A lower proportion of B cells could alter the balance of immune regulation within the lung, potentially changing how other immune populations respond to persistent stimuli. The finding does not establish that B-cell loss causes sarcoidosis, but it points to a potentially important shift in the cellular environment surrounding granulomas.
In contrast, CD4-positive T cells displayed heightened inflammatory activity. These cells act as immune-system coordinators, recognizing antigen-related signals and directing other cells through chemical messengers called cytokines. In sarcoidosis, activated CD4-positive T cells have long been associated with granulomatous inflammation, but the single-cell data provide more precise information about their activity and relationships with neighboring cells. Their gene-expression patterns indicated that they may be particularly influential in maintaining an inflammatory circuit involving macrophages and other immune populations.
The study also examined cell-cell communication by analyzing ligand-receptor pairs—molecular signals released by one cell and recognized by receptors on another. Overall communication among lung immune cells appeared reduced in sarcoidosis compared with healthy tissue. Yet interactions involving CD4-positive T cells were relatively more prominent, suggesting that the immune network may not simply be broadly intensified or suppressed. Instead, it may be reorganized around a narrower set of influential cellular conversations. Such a shift could help sustain granulomas while weakening other forms of immune coordination.
“Our findings provide a more detailed picture of the immune cells involved in pulmonary sarcoidosis and how those cells communicate with one another,” said Lisa A. Maier, MD, co-senior author and a pulmonologist and researcher at National Jewish Health. She said that understanding these interactions could help identify therapeutic targets and clarify why the disease progresses in some patients but remains mild in others. Camille Moore, PhD, the study’s first author, said the results deepen understanding of the immune dysregulation underlying sarcoidosis and could guide future work on more precise diagnosis and treatment.
The findings do not yet translate into a new clinical test or therapy, and the relatively small study group means that the observed cellular patterns will need to be confirmed in larger and more diverse patient populations. Additional research will also be needed to determine whether the immune signatures change with disease stage, treatment or organ involvement, and whether they can predict which patients are likely to develop progressive lung damage. Nevertheless, the study demonstrates how single-cell analysis can turn a complex inflammatory lesion into a map of interacting cell types and molecular programs. That map may ultimately help researchers design treatments aimed at specific immune pathways rather than suppressing the immune system broadly.
Subject of Research: Pulmonary sarcoidosis and immune-cell changes in the lungs
Article Title: Single cell transcriptome signatures and cell-cell interactions associated with sarcoidosis in lung immune cell populations
Web References: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1765314/full
References: DOI: 10.3389/fimmu.2026.1765314
Keywords: Sarcoidosis, pulmonary inflammation, lungs, granulomas, single-cell RNA sequencing, macrophages, B cells, CD4-positive T cells, immune-cell communication, immunology
Tags: B cell activity in lung inflammationCD4 T cell dynamics in sarcoidosisenvironmental and infectious triggers in sarcoidosisimmune cell heterogeneity in granulomatous diseasesimmune communication in pulmonary diseaselung immune cell behavior in sarcoidosismacrophage role in sarcoidosismolecular mechanisms of sarcoidosis progressionpulmonary granulomas cellular signaturesarcoidosis immune cell profilingsingle-cell RNA sequencing in inflammatory diseasesvariability of sarcoidosis disease progression
