This is a mechanism module, not a disease. Do NOT create a "Necrotizing Vasculitis" Disease entry - MONDO:0800113 is definitionally a class over other diseases and is already modelled in dismech as the Grouping kb/groupings/Necrotizing_Vasculitides.yaml (issue #8754, PR #8860). This module supplies the shared effector mechanism that the Grouping asserts in prose in its second membership criterion but could not encode as a machine-checkable leaf, because no single shared GO process was annotated across the members. Disorder entries reach it via conforms_to (for example, "necrotizing_vasculitis#Fibrinoid Necrosis of the Vessel Wall").
Xogenesis anchor, with a caveat. The terminal output is not a new discrete structure but a canonical one made pathological, so the process genus is OGMS:0000061 pathological bodily process, sub-typed as OGMS:0000080 pathological transformation (the vessel wall becomes pathological), at site UBERON:0035965 wall of blood vessel. The species term MPATH:9 fibrinoid necrosis sits in MPATH's *process* branch (under MPATH:596 pathological process / MPATH:597 cell and tissue damage process), NOT in the MPATH:603 pathological anatomical entity subtree that the Xogenesis convention normally draws from, and there is no MPATH continuant for "fibrinoid-necrotic vessel wall". That is recorded here as an OBO gap rather than papered over by binding a continuant term that does not mean this. SNOMED CT "Morphologically abnormal structure" (49755003) is a census/gap guide only and is not bound. No CURIE in this stanza is bound in a term slot; the nodes bind GO, CL and UBERON only.
Key disease-specific substitutions at the trigger node: GPA and MPA substitute PR3-ANCA and MPO-ANCA bound to cytokine-primed neutrophils, with GPA carrying an additional extravascular granulomatous arm that belongs to granuloma_formation, not here; EGPA substitutes a Th2/eosinophil-dominant milieu in which ANCA is present in only a minority (its eosinophil arm is discussed under the exclusions below, and CL:0000771 is deliberately NOT bound at the central effector: the available sources call eosinophils a hallmark and a main effector of organ damage in EGPA without placing their degranulation inside the vessel wall, which is the one thing that node is defined by); polyarteritis nodosa substitutes an ANCA-negative medium-artery lesion whose consequence node is microaneurysm and infarction rather than glomerulonephritis; IgA vasculitis substitutes galactose-deficient IgA1 immune complexes; cryoglobulinaemic vasculitis substitutes cold-precipitable immunoglobulin complexes, usually HCV-driven; cutaneous leukocytoclastic angiitis substitutes a drug or infectious hapten with the consequence node restricted to dermal postcapillary venules; rheumatoid vasculitis substitutes rheumatoid-factor-containing complexes in long-standing seropositive RA.
A note on Primary Polyarteritis Nodosa before the exclusions, because the two look similar and are not. PAN is wired here at the effector and consequence nodes only: its dismech entry has no neutrophil or complement node to wire further upstream, and its own cited evidence says the pathogenesis of idiopathic PAN remains enigmatic. That is a NOT-YET-CURATED mechanism, not a different one - the Chapel Hill definition of PAN is necrotizing arteritis with mural leukocyte infiltration, so it belongs on this chain and the missing upstream nodes are a curation gap to close. The exclusions below are the opposite case: diseases whose effector is KNOWN and is not this one. Reaching the lesion is not what qualifies a conformer; having no contrary mechanism yet is not the same as having a contrary one.
DO NOT conform these, even though they reach a necrotizing lesion. The boundary is the C5a/neutrophil hub, not the lesion. (a) Deficiency of Adenosine Deaminase 2 (kb/disorders/Deficiency_of_Adenosine_Deaminase_2.yaml) is a monogenic medium-vessel necrotizing vasculitis, but ADA2 loss skews macrophages to a pro-inflammatory M1 subset (PMID:30565235) and the disease responds to TNF-alpha inhibition rather than to complement- or neutrophil-directed therapy (PMID:32845415), so it reaches the terminal nodes by a different effector and is deliberately not wired here. (b) Lymphocyte-dominant vasculitides, where the effector is lymphocytic or direct viral endothelial injury, are out of scope even when fibrinoid necrosis is present. (c) Angiotensin- and pressure-driven fibrinoid vasculopathy (malignant hypertension) and thrombotic microangiopathy are haemodynamic or thrombotic, not leukocyte-and-complement mediated, and are out of scope - the Necrotizing Vasculitides Grouping makes the same exclusion. (d) In EGPA, wire the NEUTROPHIL node to the central effector; the eosinophil-infiltrative arm (cardiomyopathy, neuropathy) runs to its own consequences and is an adjunct sub-branch, not a replacement for the hub, so the eosinophil node is left unwired.
Scope caveat: the strongest experimental evidence for the amplifier node (complement knockout and C5aR-deficient bone marrow protecting mice from anti-MPO glomerulonephritis) comes from the ANCA arm. The immune-complex members are placed on the same chain on histopathologic and clinical grounds - the same neutrophil-with-fibrinoid-necrosis lesion, the same C5a-generating complement activation - and a conformer in that arm should cite its own complement evidence rather than inheriting the ANCA-model citations. Modules bind GO and CL terms only, with UBERON locations; no CHEBI or MONDO bindings in nodes, except in the treatments block where the therapeutic agent carries an ontology identifier per the treatment schema.
Is the C5a-C5aR1 amplification step actually required in the immune-complex vasculitides, as it is demonstrably required in the ANCA-associated ones, or do the two arms converge on the shared lesion through partly distinct effector programs?
KNOWLEDGE GAP
nv_c5a_dependence_untested_in_immune_complex_arm
Attached to:
Complement C5a Amplification and Neutrophil Recruitment
This module places all eight members on one chain through the amplifier node, but the evidence behind that node is asymmetric and the asymmetry is not incidental. The pauci-immune arm has genetic dissection (factor B and C5 knockouts protected, C4 knockouts not), a compartment-specific bone-marrow C5aR requirement, and an interventional RCT. The immune-complex arm rests on histopathology and review-level statements that deposited complexes activate complement and recruit neutrophils, with no branch-specific complement blockade trial. The two arms also enter complement by different routes - alternative versus classical - so convergence on an identical C5a-dependent step is a plausible inference from the shared lesion rather than a demonstrated fact. This matters practically: it determines whether avacopan, the node-specific agent modelled in this module, should be expected to work in cryoglobulinaemic or IgA vasculitis at all, and it is the single assumption most likely to be wrong in the module as curated.
Proposed experiments:
C5aR1 blockade in biopsy-proven immune-complex small-vessel vasculitis
Vessel Wall Immune Stimulus Deposition and Endothelial Activation
trigger
The proximal trigger is the localization of an immune stimulus to the wall of a small or medium vessel together with activation of the overlying endothelium. Two upstream routes converge here and are mutually exclusive in any one disease. In the pauci-immune route, a cytokine-primed neutrophil translocates its granule autoantigens (proteinase 3, myeloperoxidase) to the cell surface where circulating ANCA can bind them, engaging Fc-gamma receptors and converting a circulating cell into an adherent, activated one at the vessel wall. In the immune-complex route, preformed or in-situ immune complexes (galactose-deficient IgA1 in IgA vasculitis, cold-precipitable cryoglobulins in cryoglobulinaemic vasculitis, rheumatoid-factor complexes in rheumatoid vasculitis, drug- or infection-driven complexes in cutaneous leukocytoclastic angiitis) deposit in the wall. Either way the endothelium upregulates adhesion molecules and the vessel becomes a site of leukocyte arrest. The requirement for a priming inflammatory milieu is why neutrophil activation alone is not sufficient and why infection so often precedes onset.
Used by disorders
IgA Vasculitis
as Systemic IgA Immune Complex Deposition in Small Vessels
Downstream
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Complement C5a Amplification and Neutrophil Recruitment
Factors released by the ANCA-activated neutrophil at the wall activate the alternative complement pathway, initiating the amplification loop.
Complement C5a Amplification and Neutrophil Recruitment
amplifier
Complement is engaged in the vessel wall and generates the anaphylatoxin C5a. C5a acting through the neutrophil C5a receptor (C5aR1) both chemoattracts further neutrophils to the segment and primes them for a stronger response to the same stimulus, so a local activation event becomes a self-sustaining inflammatory amplification loop confined to the vessel wall. This is the step that converts a focal, potentially self-limited insult into destructive disease.
The ENTRY ROUTE into complement differs between the two arms and is the one place where conformers should not copy this node verbatim. In the pauci-immune ANCA-associated forms the route is the ALTERNATIVE pathway: factors released by the ANCA-activated neutrophil trigger it, and factor B and C5 knockout mice develop no disease while C4 knockouts (classical and lectin pathways) develop disease comparable to wild type - so the requirement is specifically alternative-pathway. In the immune-complex forms (IgA vasculitis, cryoglobulinaemic vasculitis, cutaneous leukocytoclastic angiitis, rheumatoid vasculitis) deposited complexes engage the CLASSICAL pathway instead, which is why hypocomplementaemia with low C4 is a marker there and not in the pauci-immune forms. What is shared - and what this node is named for - is the convergent output: C5a acting on neutrophil C5aR1. The node therefore binds the parent process GO:0006956 complement activation alongside the alternative pathway, and a conformer in the immune-complex arm should substitute the classical pathway and cite its own complement evidence rather than inheriting the anti-MPO mouse citations below.
Note on the key conformance target: the deep-research report for this module recommended designating THIS node the required hub, on the grounds that it carries the strongest causal evidence (an interventional RCT plus knockouts). The central effector was chosen instead, deliberately, because the key conformance target should be the step that is most disorder-agnostic rather than the step that is best evidenced - and this node is the one place the module admits its members diverge, since the entry route into complement differs by arm and the RCT evidence covers only the ANCA arm. The evidential strength is real, and is why the drug-target pattern hangs here.
Downstream
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Intramural Leukocyte Degranulation and Oxidative Burst
The recruited, C5a-primed neutrophils that have entered the wall are the cells that then degranulate within it.
Intramural Leukocyte Degranulation and Oxidative Burst
central effector
The key conformance target and the rate-limiting, disorder-agnostic step. Leukocytes that have adhered to and penetrated the vessel wall discharge their cytotoxic contents inside it: a respiratory burst generating reactive oxygen species, degranulation releasing serine proteases (proteinase 3, elastase, cathepsin G) and myeloperoxidase, and extrusion of neutrophil extracellular traps that both damage the wall and re-present MPO and PR3 to the immune system, closing a feed-forward loop back to the trigger. The effector leukocyte is the neutrophil in every member; EGPA adds the eosinophil, whose granule proteins contribute to the same intramural cytotoxicity. What defines this node is location, not cell identity - the same degranulation occurring in the lumen or the interstitium does not produce vasculitis. Mechanistically every member of the group passes through this step - it is what the Necrotizing Vasculitides Grouping asserts in its second membership criterion.
That mechanistic claim is not yet matched by the wiring, and the gap is in the disorder entries rather than in the module. Only four of the eight members currently declare conformance here, because most of the others carry a single bundled node fusing this step with its neighbour: IgA vasculitis's "Leukocytoclastic Vasculitis in Skin and Systemic Organs" and Cryoglobulinemic Vasculitis's "Immune-complex small-vessel vascular injury" each describe neutrophil degranulation AND the resulting fibrinoid necrosis in one node, so they are wired to the effector, the more specific of the two claims they make. Splitting those bundled nodes - and giving Primary Polyarteritis Nodosa an intramural-injury node at all - is the follow-up that would let this node carry all eight; it is deliberately left out of the module's own PR rather than done as a drive-by restructuring of eight other curations.
Downstream
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Complement C5a Amplification and Neutrophil Recruitment
The feed-forward arm. NETs extruded during intramural degranulation are themselves a scaffold for alternative-pathway complement activation, so this node re-enters the amplifier rather than only feeding forward. The chain is therefore a loop at this point, not a straight line.
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Fibrinoid Necrosis of the Vessel Wall
The oxidants and proteases released inside the wall are the proximate cause of mural cell death and matrix destruction.
Fibrinoid Necrosis of the Vessel Wall
effector
The defining histopathologic lesion. Endothelial and vascular smooth muscle cells die, the internal elastic lamina and mural extracellular matrix are degraded, and the loss of endothelial barrier integrity lets plasma proteins - fibrinogen above all - insudate into the necrotic wall, where they polymerize to give the smudgy, brightly eosinophilic "fibrinoid" appearance. The infiltrating neutrophils themselves die in place and fragment, scattering nuclear debris ("nuclear dust", leukocytoclasia) through the wall. This is the lesion HP:6000253 Necrotizing vasculitis names and the finding that makes a biopsy report read "necrotizing vasculitis" without naming a disease; it is also the reason the Necrotizing Vasculitides Grouping is anchored on histopathology rather than aetiology. Conformers differ in calibre and site, not in the character of the lesion.
Used by disorders
IgA Vasculitis
as Leukocytoclastic Vasculitis in Skin and Systemic Organs
Downstream
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Luminal Compromise and Downstream Tissue Infarction
Luminal Compromise and Downstream Tissue Infarction
consequence
A wall that has become fibrinoid-necrotic can no longer do either of its jobs. It is thrombogenic, so the lumen occludes; it is mechanically weak, so it dilates into a microaneurysm or ruptures and bleeds; and inflammatory healing narrows it by fibrosis. The result is ischaemic and haemorrhagic injury to whatever the vessel supplied, and this is where the members diverge most visibly even though the lesion is the same: necrotizing crescentic glomerulonephritis and alveolar capillaritis with pulmonary haemorrhage in the ANCA-associated small-vessel forms, palpable purpura where dermal postcapillary venules are involved, mononeuritis multiplex from vasa nervorum occlusion, and mesenteric or renal microaneurysm with organ infarction in medium-vessel polyarteritis nodosa. Untreated, this node is what makes necrotizing vasculitis organ- and life-threatening, and it is the reason the shared therapeutic consequence across the group is prompt induction immunosuppression.
C5a Receptor Antagonist Therapy
Platform:
Small molecule
Avacopan is an oral small-molecule antagonist of C5aR1, the receptor through which C5a recruits and primes neutrophils in the amplification loop. It is the node-specific agent for this module: rather than suppressing immunity broadly, it interrupts the single amplifier step that the complement-knockout and C5aR-deficient-marrow experiments identified as required. In the ADVOCATE trial in GPA and MPA it was non-inferior to a prednisone taper for remission at week 26 and superior for sustained remission at week 52, on a background of rituximab or cyclophosphamide - so it substitutes for glucocorticoid exposure rather than for induction immunosuppression. This is the drug-target design pattern conforming disorders should copy.
Evidence: 2
Anti-CD20 B Cell Depletion
Platform:
Monoclonal antibody
Rituximab depletes CD20-positive B cells and so removes the supply of the autoantibody that constitutes the trigger stimulus in the ANCA-associated members. It acts one step upstream of the module's key conformance target - it does not touch the intramural degranulation directly, but starves the trigger node of ANCA. In the RAVE trial it was non-inferior to cyclophosphamide for induction of remission and more effective in relapsing disease. Conforming disorders in the immune-complex arm should not copy this treatment uncritically: where the antigenic drive is exogenous (hepatitis C in cryoglobulinaemic vasculitis) the first-line logic is to remove the antigen, not the B cell.
Evidence: 1