The Danger Theory
Understanding how the immune system really decides what to attack
Core Principles
The Danger Theory revolutionized immunology by shifting focus from "foreign" to "dangerous."
The Problem with "Self vs Non-Self"
The old way of thinking said our immune system attacks anything "foreign." But this couldn't explain why pregnant women don't reject their babies, or why we don't attack helpful bacteria in our gut.
The traditional self/non-self model failed to explain maternal-fetal tolerance, beneficial microbiota coexistence, transplant scenarios, and the context-dependent nature of autoimmune responses.
The "Danger" Solution
Polly proposed that our immune system is like a smart security system - it doesn't just look for strangers, it looks for actual trouble or damage.
Danger Theory proposes that immune activation requires both antigen recognition AND danger signals (DAMPs) from stressed or damaged tissues, providing essential context for appropriate immune responses.
Danger Signals (DAMPs)
When cells are damaged or stressed, they release special "alarm" molecules. These signals tell the immune system that something is wrong and needs attention.
DAMPs include molecules like HMGB1, ATP, heat shock proteins, and nucleic acid fragments. These endogenous danger signals are recognized by pattern recognition receptors and activate innate immune responses.
Clinical Implications
This new understanding helps doctors develop better treatments for diseases where the immune system attacks the body, like rheumatoid arthritis or Type 1 diabetes.
Danger Theory has informed therapeutic strategies including DAMP inhibition, tolerance induction protocols, and context-dependent immunomodulation for autoimmune diseases, transplantation, and cancer immunotherapy.
Traditional vs Danger Model
3D Cell Visualization
See how cells send danger signals when they're damaged
Healthy Cell
A healthy cell keeps its danger signals inside, like keeping the alarm system off when everything is safe.
Healthy cells maintain membrane integrity and do not release DAMPs, preventing unnecessary immune activation.
Damaged Cell
When a cell is damaged, it releases danger signals like a fire alarm, calling for help from the immune system.
Damaged cells release DAMPs (Damage-Associated Molecular Patterns) that activate dendritic cells and initiate immune responses.
Real-World Applications
Autoimmune Diseases
Understanding that tissue damage triggers immune responses helps explain why autoimmune diseases often start after infections or injuries.
Molecular mimicry combined with danger signals can break tolerance, leading to autoimmune pathology. This explains the temporal relationship between infections and autoimmune disease onset.
Transplant Medicine
Reducing "danger signals" during transplant surgery helps prevent the immune system from attacking the new organ.
Minimizing ischemia-reperfusion injury and DAMP release during transplantation, combined with appropriate immunosuppression timing, improves graft survival and reduces rejection rates.
Cancer Immunotherapy
Cancer treatments work better when they create "danger signals" that alert the immune system to attack cancer cells.
Immunogenic cell death induced by chemotherapy or radiation releases DAMPs that enhance tumor antigen presentation and promote anti-tumor immune responses.