This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "complement_dysregulation#C5 Convertase Activation and Terminal Pathway Assembly"). 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: atypical haemolytic uraemic syndrome substitutes germline loss of fluid-phase or membrane regulators (CFH, CFI, CD46) or gain-of-function C3/CFB variants; paroxysmal nocturnal haemoglobinuria substitutes somatic PIGA mutation with consequent absence of GPI-anchored CD55 and CD59; C3 glomerulopathy substitutes acquired convertase-stabilising autoantibodies. Anti-AChR myasthenia gravis is **not** a trigger-node conformer - it has no regulator lesion, and its autoantibody initiates the classical pathway - so it attaches at the terminal node, whose `GO:0001905` / `GO:0005579` binding its own curated node carries. Substitutions at the effector node follow the injured cell: erythrocyte (PNH), glomerular endothelium (aHUS, C3G), post-synaptic muscle membrane (MG). Complement component chemistry and the individual complement proteins are described in prose only; modules bind GO and CL terms only and do not use chemical (CHEBI) or protein term bindings.
Loss of Complement Regulatory Control
trigger
The complement alternative pathway is constitutively active at a low level and is restrained, rather than switched on, by a dedicated set of regulators acting both in the fluid phase (factor H, factor I) and on host membranes (CD46/MCP, CD55, CD59, thrombomodulin). Disease begins when that restraint is lost. The lesion may be a germline loss-of-function variant in a regulator, a gain-of-function variant in C3 or factor B that renders the convertase resistant to regulation, somatic loss of the GPI anchor that displays CD55 and CD59 on the cell surface, or an acquired autoantibody that stabilises the convertase or neutralises factor H. These are mechanistically distinct lesions with one shared consequence, and it is that shared consequence, not the lesion, that the rest of this chain models.
Downstream
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Unrestrained Alternative Pathway Amplification
Show evidence (3 references)
"Genetically-determined or acquired dysregulation of the complement is frequently identified in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS."
Establishes that the upstream lesion is dysregulation of complement, and that it may be either genetically determined or acquired - the two alternative trigger routes this node models. Evidence source is OTHER because this is a review.
"The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations."
Supports loss of membrane-bound complement regulators (CD55, CD59) as a trigger lesion producing uncontrolled complement activation, the substitution a conforming paroxysmal nocturnal haemoglobinuria node makes at this node. Evidence source is OTHER because this is a review.
"Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes."
Supports the acquired autoantibody route to loss of regulatory control, and specifies the mechanism (convertase stabilisation), the substitution a conforming C3 glomerulopathy node makes. Evidence source is OTHER because this is a review.
Unrestrained Alternative Pathway Amplification
amplifier
Freed from regulation, the alternative pathway C3 convertase (C3bBb) runs as a positive-feedback amplification loop: each C3b generated recruits factor B to form further convertase, depositing more C3b on the surface. Because the loop is self-amplifying, a modest failure of restraint produces a large, sustained increase in surface-bound C3b rather than a proportionate one. This node is also the point of entry for classical- and lectin-pathway initiated disease, in which an immune complex or a carbohydrate ligand supplies the initiating C3b that the alternative pathway then amplifies.
Downstream
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C5 Convertase Activation and Terminal Pathway Assembly
Show evidence (3 references)
"Overactivation of the complement alternative pathway drives the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS)."
Establishes overactivation of the alternative pathway as the driving amplification step downstream of lost regulation. Evidence source is OTHER because this is a review.
"The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage."
States the regulated-cascade principle whose failure defines this node: regulation exists to confine complement activation and thereby avoid host tissue damage, so loss of it produces host injury. Evidence source is OTHER because this is a review.
"Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common."
Confirms alternative-pathway dysregulation as the fundamental amplifying mechanism in a second, independent conforming disease, and links it onward to terminal-pathway dysregulation. Evidence source is OTHER because this is a review.
C5 Convertase Activation and Terminal Pathway Assembly
central effector
Dense C3b deposition converts the C3 convertase into a C5 convertase, which cleaves C5 into C5a and C5b. C5a is a potent anaphylatoxin and neutrophil chemoattractant; C5b nucleates the sequential assembly of C6, C7, C8 and multiple C9 molecules into the lytic C5b-9 membrane attack complex in the target membrane. This is the disorder-agnostic, rate-limiting step of the module: every conforming disease funnels through it regardless of which regulator failed upstream, and it is the step at which terminal complement inhibitors act. It is therefore the key conformance target.
Downstream
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Complement-Mediated Cell Injury and Endothelial Activation
Show evidence (3 references)
"Complement plays an important role in innate and antibody-mediated immunity, and activation and amplification of complement results in the formation of membrane attack complexes (MACs), lipophilic proteins that damage cell membranes."
States the conserved terminal step this node models - activation and amplification culminating in membrane attack complex formation that damages cell membranes. Evidence source is OTHER because this is a review spanning animal-model and patient data.
"Studies in animals lacking specific complement proteins have confirmed that MAC formation is required to induce experimental autoimmune MG (EAMG) and NMJ damage."
Genetic dissection in animals establishes MAC formation as required for injury, supporting this node as the rate-limiting step rather than an incidental correlate. Evidence source is MODEL_ORGANISM because the requirement was demonstrated in complement-deficient animals.
"We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH)."
Identifies C5 and terminal complement activation as the druggable step, supporting this node as the drug-target anchor for the module's target_mechanisms pattern. Evidence source is HUMAN_CLINICAL because this is a randomized controlled trial in patients.
Terminal Complement Inhibition (Eculizumab)
Platform:
Monoclonal antibody
Anti-C5 monoclonal antibodies bind complement component C5 and prevent its cleavage into C5a and C5b, blocking both anaphylatoxin generation and assembly of the C5b-9 membrane attack complex while leaving upstream C3 functions - opsonisation and immune-complex clearance - intact. Eculizumab is the first-in-class agent; ravulizumab is the long-acting successor. Because the block is at the shared terminal step rather than at any disease-specific upstream lesion, one agent treats mechanistically distinct conforming disorders, which is the therapeutic expression of this module. Terminal blockade abolishes serum bactericidal activity against Neisseria, so meningococcal vaccination and prophylaxis are mandatory. Represents the terminal-complement-inhibitor drug-target design pattern for conforming disorders.
Evidence: 4