This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "cytokine_storm_hyperinflammation#IL-6-Driven Systemic Cytokine Storm"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their disease context. Key disease-specific substitutions at the trigger node: sepsis substitutes an overwhelming pathogen-associated molecular pattern load with failure of the compensatory anti-inflammatory response; CAR-T cytokine release syndrome substitutes engineered T-cell engagement of tumour antigen with consequent monocyte activation; primary haemophagocytic lymphohistiocytosis and macrophage activation syndrome substitute impaired lymphocyte cytotoxicity (PRF1, UNC13D, STX11, STXBP2), in which failure to kill antigen-presenting cells removes the normal termination signal for T-cell and macrophage activation; severe viral pneumonitis substitutes sustained viral antigen load. The distinction that makes this a single module rather than a grouping is that all of these converge on unrestrained myeloid cytokine output, not merely on a shared clinical picture. Individual cytokines and their receptors are described in prose; modules bind GO and CL terms only and do not use chemical (CHEBI) or protein term bindings.
Uncontrolled Immune Activation Trigger
trigger
An immune stimulus that is either too large to be cleared proportionately or cannot be terminated. Three routes converge here. In sepsis, a systemic pathogen load presents an overwhelming quantity of pathogen-associated molecular patterns. In cytokine release syndrome, adoptively transferred engineered T cells engage tumour antigen at high burden and activate bystander myeloid cells. In haemophagocytic lymphohistiocytosis, the trigger is a defect in the killing machinery itself: impaired perforin- or granule-mediated cytotoxicity leaves antigen-presenting cells alive, so the activating stimulus is never removed and lymphocyte-macrophage activation continues without a termination signal. What is shared is not the stimulus but the loss of proportionality between stimulus and response.
Downstream
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Unrestrained Myeloid Cytokine Amplification
Unrestrained Myeloid Cytokine Amplification
amplifier
Monocytes and macrophages are the dominant amplifying compartment. Activated through pattern-recognition receptors or by contact with activated T cells, they produce IL-6, IL-1 and TNF; these cytokines in turn recruit and activate further myeloid cells, which produce more cytokine. The loop is autoamplifying, so output rises disproportionately to the initiating signal rather than tracking it. Experimental depletion of monocytes prevents the syndrome, establishing this compartment as necessary rather than merely correlated.
Downstream
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IL-6-Driven Systemic Cytokine Storm
IL-6-Driven Systemic Cytokine Storm
central effector
Cytokine production escapes local control and becomes systemic, with IL-6 as the dominant circulating mediator acting on distant tissues through both classical and trans-signalling. At this point the cytokine response, not the inciting trigger, is the proximate cause of illness: fever, acute-phase response, and the systemic effects that follow are driven by the mediators themselves. This is the disorder-agnostic, rate-limiting step of the module - every conforming disease funnels through it whatever its trigger - and it is the step at which IL-6-axis blockade acts, making it the key conformance target.
Downstream
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Endothelial Activation and Capillary Leak
Endothelial Activation and Capillary Leak
effector
Circulating cytokines act on vascular endothelium throughout the body. The endothelium is both a target and a further source of cytokines, so its activation extends the storm. Activated endothelium loses barrier integrity, producing capillary leak with interstitial oedema and intravascular volume depletion; loses vasomotor tone, producing distributive hypotension; and loses thromboresistance, producing microvascular thrombosis and consumptive coagulopathy. This is the step that converts a circulating cytokine abnormality into distributed tissue hypoperfusion.
Downstream
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Shock and Multiorgan Dysfunction
Shock and Multiorgan Dysfunction
consequence
The clinical endpoint of the chain: vasodilatory and capillary-leak shock with tissue hypoperfusion, progressing to dysfunction of organs remote from any site of infection or tumour - acute kidney injury, acute respiratory distress, hepatic dysfunction, encephalopathy and disseminated intravascular coagulation. Organ failure here is a consequence of the host response, which is why it occurs in sterile triggers such as CAR-T cytokine release syndrome and familial haemophagocytic lymphohistiocytosis exactly as it does in sepsis.