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
Show evidence (3 references)
"Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders."
Establishes the multiplicity of triggers converging on one systemic syndrome, which is precisely what this trigger node abstracts over. Evidence source is OTHER because this is a narrative review.
"Functional impairment or absence of 1 or more of several proteins that participate in lymphocyte cytotoxicity underlies the disease."
Supports the impaired-cytotoxicity route into this node, the substitution a conforming familial haemophagocytic lymphohistiocytosis entry makes at the trigger. Evidence source is OTHER because this is a review.
"Sepsis is a severe clinical syndrome related to the host response to infection."
Frames sepsis as a disorder of the host response rather than of the pathogen directly, supporting its entry at this trigger node. Evidence source is OTHER because this is a review.
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
Show evidence (2 references)
"The severity of infections is due to an activation cascade that will lead to an autoamplifying cytokine production: the cytokine storm."
States the autoamplifying character of cytokine production that defines this node, and attributes severity to it rather than to the pathogen. Evidence source is OTHER because this is a review.
"Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab."
Causal evidence that monocytes are the amplifying source and that removing them prevents the syndrome, supporting this node as necessary to the chain. Evidence source is MODEL_ORGANISM because the depletion experiments were performed in humanized mice.
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
Show evidence (2 references)
"In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS."
Identifies elevated systemic IL-6 with fever as the hallmark of the storm state modelled at this node. Evidence source is MODEL_ORGANISM because these are humanized mouse experiments.
"Recognition that the immune response to the pathogen, but not the pathogen itself, can contribute to multiorgan dysfunction and that similar cytokine storm syndromes could occur with no obvious infection led to the investigation of immunomodulators and cytokine-directed therapies."
Supports the defining claim of this node - that the immune response rather than the trigger causes organ dysfunction - and the therapeutic logic of targeting it. Evidence source is OTHER because this is a narrative review.
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
Show evidence (2 references)
"New promising therapeutic strategies focusing on the endothelium, as a source and a target of cytokines, are described."
Supports the endothelium's dual role as both target and source of cytokines, the amplifying property that makes this a distinct effector node rather than a passive downstream consequence. Evidence source is OTHER because this is a review.
"Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone."
Consensus definition establishing profound circulatory and cellular abnormality as the distinguishing, high-mortality step downstream of the systemic response, corresponding to this node. Evidence source is OTHER because this is an expert consensus task force report.
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.
Show evidence (2 references)
"Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection."
The consensus definition places life-threatening organ dysfunction as the consequence of a dysregulated host response, exactly the terminal node of this module. Evidence source is OTHER because this is an expert consensus task force report.
"Familial hemophagocytic lymphohistiocytosis (FHL) is a rare heritable disorder of immune regulation that is typically characterized by sudden onset of severe systemic illness."
Documents severe systemic illness as the consequence in a sterile, genetically triggered conforming disorder, supporting that this endpoint is driven by immune dysregulation rather than by infection. Evidence source is OTHER because this is a review.
IL-6 Axis Blockade (Tocilizumab)
Platform:
Monoclonal antibody
Tocilizumab is a humanized monoclonal antibody against the IL-6 receptor that blocks both classical and trans IL-6 signalling, interrupting the storm at its dominant systemic mediator. It is the established treatment for CAR-T-associated cytokine release syndrome. Its limits are as informative as its successes and should be preserved by conforming entries rather than smoothed over: IL-6 blockade does not address the IL-1-driven component, and in the humanized-mouse model it failed to prevent delayed neurotoxicity that IL-1 receptor antagonism did prevent - evidence that the storm has parallel arms and that this module's IL-6 arm is one of them. Represents the IL-6-axis-blockade drug-target design pattern for conforming disorders.
Evidence: 3