Inflammation is an immune response that maintains internal homeostasis and protects against infection or tissue damage. In response to external and internal signals, immune cells become activated and initiate protective programs. This response is beneficial when it eliminates the source of threat; however, excessive or prolonged activation can itself drive disease. Molecules and cells involved in inflammatory processes contribute to the pathogenesis of the most common disorders.
The process begins with the release of proinflammatory cytokines – signaling proteins that coordinate immune cell activity. These cytokines activate the endothelium – the inner lining of blood vessels – and increase vascular permeability, facilitating immune cell extravasation into tissues. Chemokines then direct these cells to sites of inflammation. Such mechanisms underlie cardiovascular, autoimmune, infectious, and oncological diseases. Understanding these pathways is essential for effective anti-inflammatory therapy.
The Spanish team analyzed peripheral blood immune cells, refining their classification and functional states. They identified disease-specific cellular states reflecting distinct inflammatory responses. In addition, they modeled inflammatory gene expression profiles and defined genes associated with activation, migration, cytotoxic responses, and antigen presentation. The proposed classification framework may support personalized therapeutic strategies for acute and chronic inflammatory conditions.
Atlas Of Circulating Immune Cells Across Inflammatory Diseases
The investigators analyzed more than 6.3 million peripheral blood mononuclear cells from 1,047 patients with 19 inflammatory diseases and from healthy donors.
Diseases were categorized into five groups:
- Immune-mediated inflammatory diseases: systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn’s disease, and multiple sclerosis.
- Chronic inflammatory conditions: chronic obstructive pulmonary disease, asthma, and cirrhosis.
- Infections – influenza, COVID-19, hepatitis B, and HIV infection.
- Solid tumors – breast cancer, colorectal cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma.
All data were compared with samples from healthy donors.
The resulting unified atlas of circulating immune cells revealed significant differences in immune cell distribution across diseases and confirmed established clinical patterns:
- In systemic lupus erythematosus, levels of unconventional T cells (UTC), innate lymphoid cells (ILC), and naïve CD4 T cells were reduced, whereas B cells and monocytes were increased.
- In inflammatory bowel diseases, UTC and ILC levels were decreased.
- In rheumatoid arthritis, UTC were reduced, while monocytes and B cells were increased.
- Sepsis was associated with lymphopenia.
- HIV infection was associated with lymphocytosis.
Inflammatory Programs Across Diseases And Immune Cell Types
Inflammatory molecules were grouped into 21 gene signatures reflecting key processes: immune cell adhesion and activation, migration, antigen presentation, and cytokine signalling. After refinement within specific cellular contexts, 119 cell–type–specific factors were defined and their activity quantified across diseases. In most pathologies, inflammatory signature activity was increased compared with healthy donors.
Immune-Mediated Inflammatory Diseases
- Increased activity of adhesion molecules.
- Enhanced TNF signaling through the NFκB pathway.
- Activation of antigen presentation programs, including cross-presentation.
- Type I and II interferon (IFN) signatures were reduced in most cell types but elevated in non-naïve CD8 T cells, indicating cell-specific regulation.
- IFN-stimulated signatures were broadly increased across immune cells.
- In systemic lupus erythematosus, chemokine and chemokine receptor expression was additionally elevated.
- In multiple sclerosis, IFN-stimulated signatures were reduced, while chemokine receptor activity was increased, consistent with enhanced migratory capacity of circulating immune cells into the central nervous system.
Sepsis
- Elevated TNF and TNF receptor activity, predominantly in non-naïve CD8 T cells.
- Increased IFN-γ responses in monocytes.
- Concurrent reduction in other inflammatory signals, including adhesion molecules and cytokines.
Chronic Inflammatory Diseases
- Increased expression of antigen-presenting molecules.
- Enhanced IFN signaling.
Viral Infections
- Influenza and COVID-19 showed increased IFN signaling.
- In contrast, IFN signaling was reduced in HIV and hepatitis B infection.
Solid Tumors
- Colorectal and nasopharyngeal cancers exhibited pronounced TNF–NFκB pathway activity.
T Cell–Specific Programs
- Only rheumatoid arthritis, psoriasis, and inflammatory bowel disease showed increased follicular T helper (Tfh) signatures in non-naïve CD4 T cells, suggesting that circulating Tfh cells are involved in these conditions.
- In immune-mediated inflammatory diseases, both naïve and non-naïve CD4 T cells displayed enhanced T helper signatures, indicating early skewing toward inflammatory CD4 T cell responses.
Cellular Sources Of Interferon Signatures And Their Regulation
In immune-mediated inflammatory diseases, increased type I and II IFN activity was primarily concentrated in non-naïve CD8 T cells. IFN activity was elevated across nearly all CD8 subtypes, though the magnitude varied between diseases.
At the single-gene level, FGFBP2 and GZMB made major contributions. Their expression increased predominantly in effector memory CD8 T cells, particularly in ulcerative colitis. These genes have previously been associated with T cells localized to sites of epithelial damage. Blood-based analyses suggest that their activation occurs in circulation before tissue migration.
Two principal transcription factors driving IFN signatures were identified: STAT1 and SP1. STAT1 primarily regulated canonical IFN signaling genes, whereas SP1 controlled a broader set of targets. Their activity differed across cell types, diseases, and disease stages.
Machine Learning Identifies Disease-Discriminating Genes
Severe influenza displayed a molecular profile similar to severe COVID-19, indicating shared inflammatory programs in severe respiratory infections.
CYBA emerged as a key marker of barrier tissue inflammatory diseases. Increased CYBA expression in monocytes supported classification of inflammatory bowel diseases, whereas reduced expression characterized skin disorders such as psoriasis and psoriatic arthritis. Mutations in CYBA cause chronic granulomatous disease, marked by impaired phagocyte activation and defective superoxide production. Patients develop recurrent bacterial and fungal infections affecting barrier tissues, including the skin.
Another significant gene was IFITM1, which is important for the classification of chronic lung diseases. High expression in lymphoid cells – particularly non-naïve CD4 T cells and innate lymphoid cells – was associated with chronic obstructive pulmonary disease, whereas lower expression was linked to asthma.
Conclusion
The researchers established an atlas of circulating immune cells across inflammatory diseases. Using machine learning models, they identified genes that distinguish inflammatory conditions and developed a classifier based on blood immune cell profiles. These findings may provide the foundation for a diagnostic tool in inflammatory diseases. However, larger training datasets are required for clinical implementation.
Reference
Interpretable inflammation landscape of circulating immune cells
