Anti-Glomerular Basement Membrane Disease

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Mechanistic Hypotheses

1

Conformeropathy / cryptic-neoepitope model

conformeropathy

The dominant mechanistic model holds that anti-GBM disease is an autoimmune "conformeropathy": the immunodominant epitopes are normally sequestered within the cross-linked alpha345NC1 hexamer (immune privilege), and disease requires an environmental insult that dissociates the hexamer to expose cryptic neoepitopes on alpha3/alpha5(IV)NC1 in an HLA-DR15-susceptible host.

⚙

Pathophysiology

4

Anti-GBM autoantibody formation against alpha-3(IV) collagen

Loss of immune tolerance to the noncollagenous-1 (NC1) domain of the alpha-3 chain of type IV collagen (alpha3(IV)NC1) generates directly pathogenic autoantibodies. An HLA-DRB1*15:01-restricted CD4+ T-helper cell response to alpha3(IV)NC1 peptides provides help for B-cell differentiation into plasma cells producing high-affinity, complement-fixing anti-GBM IgG. Reactivity to alpha3(IV)NC1 is both necessary and sufficient for the disease.

alpha3(IV)NC1-reactive CD4+ T-helper cell CL:0000084 autoantibody-producing B cell CL:0000236

antigen processing and presentation GO:0019882 humoral immune response mediated by circulating immunoglobulin GO:0002455 ↑ INCREASED

Downstream

Conformational unmasking of cryptic alpha3/alpha5(IV)NC1 epitopes Autoreactive lymphocytes and anti-GBM antibodies become pathogenic only once the cryptic basement-membrane epitopes are exposed.

Show evidence (2 references)

PMID:8589284 SUPPORT Human Clinical

"reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for the expression of autoimmune disease directed to the NC1 domain of Type IV collagen"

Establishes the alpha3(IV)NC1 domain as the necessary-and-sufficient autoantigen of anti-GBM/Goodpasture disease.

PMID:14569090 SUPPORT Human Clinical

"Goodpasture's disease is a severe nephritis characterized by autoantibodies to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular basement membrane. The disease is very strongly associated with HLA-DR15"

Supports the alpha3(IV)NC1 autoantibody and the HLA-DR15-restricted CD4+ T-helper response driving autoantibody production.

Conformational unmasking of cryptic alpha3/alpha5(IV)NC1 epitopes

In the mature glomerular basement membrane the alpha3, alpha4 and alpha5 NC1 domains assemble into a cross-linked alpha345NC1 hexamer in which the immunodominant epitopes (E_A, E_B) are buried, conferring "immune privilege" on the Goodpasture antigen. An environmental insult (oxidants from cigarette smoke, infection, or mechanical disruption) dissociates the hexamer and transitions the subunits into immunogens, exposing the cryptic neoepitopes on the alpha3 and alpha5 NC1 monomers. This conformational unmasking — rather than any sequence change — is the proximate event of the "conformeropathy."

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Downstream

Anti-GBM antibody binding with complement and neutrophil-mediated injury Exposed neoepitopes are bound by circulating anti-GBM IgG along the basement membrane.

Show evidence (2 references)

PMID:20660402 SUPPORT Human Clinical

"The antibodies bound to distinct epitopes encompassing region E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer"

Shows the autoantibodies bind cryptic E_A/E_B neoepitopes exposed on dissociated alpha3/alpha5 NC1 monomers but not the intact native hexamer, defining the conformeropathy mechanism.

PMID:19729652 SUPPORT In Vitro

"the cross-link also confers immune privilege to the collagen IV antigen of Goodpasture autoimmune disease"

Identifies the sulfilimine (S=N) cross-link that stabilizes the NC1 hexamer and confers immune privilege by sequestering the cryptic Goodpasture epitopes.

Anti-GBM antibody binding with complement and neutrophil-mediated injury

Circulating anti-GBM IgG binds the exposed alpha3(IV)NC1 (and alpha5(IV)NC1) along the basement membrane in a linear, ribbon-like pattern. Bound antibody activates the classical complement pathway, generating chemoattractants that recruit neutrophils and macrophages; effector cells release proteases and reactive oxygen species, producing fibrinoid necrosis of the glomerular and alveolar capillary walls.

neutrophil CL:0000775 macrophage CL:0000235

complement activation, classical pathway GO:0006958 ↑ INCREASED leukocyte migration GO:0050900 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

Crescentic glomerulonephritis and diffuse alveolar hemorrhage Capillary-wall necrosis drives glomerular crescent formation and lung hemorrhage.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"It is an archetypic autoimmune disease, caused by the development of directly pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of these organs"

Supports the directly pathogenic nature of the anti-GBM autoantibodies that bind the basement-membrane antigen and drive injury.

Crescentic glomerulonephritis and diffuse alveolar hemorrhage

Glomerular basement membrane rupture permits fibrin and inflammatory cells into Bowman's space, triggering parietal epithelial and podocyte proliferation, cellular crescents, and rapidly progressive (extracapillary) crescentic glomerulonephritis. In the lung, alveolar capillary basement-membrane injury produces diffuse alveolar hemorrhage; cigarette smoking increases alveolar antigen accessibility, explaining the smoking-lung-hemorrhage link.

glomerular parietal/visceral epithelial cell CL:1000746

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%-60% will have concurrent alveolar hemorrhage."

Supports crescentic glomerulonephritis and concurrent alveolar hemorrhage as the principal clinical-pathological outcome of the disease.

✶

Histopathology

1

Linear IgG deposition along the glomerular basement membrane

Direct immunofluorescence shows pathognomonic linear (ribbon-like) IgG deposition along the GBM, distinguishing anti-GBM disease from pauci-immune (ANCA) and granular (immune-complex) glomerulonephritides.

Show evidence (1 reference)

PMID:40062063 SUPPORT Human Clinical

"Kidney biopsy demonstrated linear immunofluorescence staining of glomerular basement membrane with immunoglobulin G (IgG)"

Directly documents the pathognomonic histopathologic finding — linear IgG immunofluorescence staining along the glomerular basement membrane on kidney biopsy.

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Pathograph

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Phenotypes

7

Blood 2

Diffuse alveolar hemorrhage FREQUENT Pulmonary hemorrhage HP:0040223

Show evidence (2 references)

PMID:38493958 SUPPORT Human Clinical

"The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively."

Pooled meta-analysis quantifies lung hemorrhage at 32.6% of patients, supporting the FREQUENT frequency band for this phenotype.

PMID:28515156 SUPPORT Human Clinical

"40%-60% will have concurrent alveolar hemorrhage"

The McAdoo & Pusey review reports 40-60% of patients have concurrent alveolar hemorrhage, corroborating the FREQUENT frequency band.

Anemia Anemia HP:0001903

Show evidence (1 reference)

PMID:8532389 PARTIAL Human Clinical

"hemoptysis, severe iron deficiency anemia and microscopic hematuria and proteinuria"

A Goodpasture's-disease case report documenting severe iron-deficiency anemia (from pulmonary hemorrhage) at presentation. PARTIAL because this is a single case report.

Genitourinary 3

Hematuria Hematuria HP:0000790

Show evidence (1 reference)

PMID:28515156 PARTIAL Human Clinical

"The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN"

Glomerular hematuria is an integral feature of the rapidly progressive crescentic glomerulonephritis described here.

Proteinuria Proteinuria HP:0000093

Show evidence (1 reference)

PMID:8532389 PARTIAL Human Clinical

"hemoptysis, severe iron deficiency anemia and microscopic hematuria and proteinuria"

A Goodpasture's-disease case report documenting microscopic proteinuria at presentation; PARTIAL because this is a single case report.

Acute kidney injury Acute kidney injury HP:0001919

Temporal: ACUTE

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis"

Supports acute kidney injury (oligoanuria, dialysis-requiring kidney failure) as a severe, prognostically important renal phenotype.

Respiratory 1

Hemoptysis Hemoptysis HP:0002105

Show evidence (1 reference)

PMID:28515156 PARTIAL Human Clinical

"40%-60% will have concurrent alveolar hemorrhage"

Alveolar hemorrhage (the source of hemoptysis) is documented in 40-60% of patients; supports hemoptysis as a frequent respiratory manifestation.

Other 1

Rapidly progressive glomerulonephritis Glomerulonephritis HP:0000099

Temporal: ACUTE Course: PROGRESSIVE

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN"

Supports rapidly progressive crescentic glomerulonephritis as the cardinal renal phenotype.

🧬

Genetic Associations

2

HLA-DRB1 (DR15 / DRB1*15:01) susceptibility (Susceptibility)

Gene: HLA-DRB1 hgnc:4948 relationship_type: RISK_FACTOR

Show evidence (1 reference)

PMID:14569090 SUPPORT Human Clinical

"The disease is very strongly associated with HLA-DR15"

Directly supports the dominant HLA-DR15 (DRB1*15:01) susceptibility association.

COL4A3 (alpha-3 type IV collagen) autoantigen target gene (Autoantigen target (not a causal germline mutation))

Gene: COL4A3 hgnc:2204

Show evidence (1 reference)

PMID:8589284 SUPPORT Human Clinical

"the anti-GBM antibodies from all patients reacted with the alpha 3(IV) NC1 (85% exclusively)"

Supports the alpha-3 chain of type IV collagen (COL4A3 product) as the autoantibody target in anti-GBM/Goodpasture disease.

💊

Medical Actions

5

Plasma exchange (plasmapheresis)

Action: Plasmapheresis NCIT:C15304

Therapeutic plasma exchange rapidly removes circulating pathogenic anti-GBM IgG and is a cornerstone of induction therapy, given daily until antibody is suppressed.

Mechanism Target:

INHIBITS Anti-GBM antibody binding with complement and neutrophil-mediated injury — Plasma exchange removes circulating pathogenic anti-GBM IgG, interrupting antibody binding and the downstream complement/neutrophil-mediated injury.

Target Phenotypes: Glomerulonephritis HP:0000099

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy"

Directly supports plasma exchange as the antibody-removal cornerstone of induction.

High-dose glucocorticoids

Action: Pharmacotherapy NCIT:C15986

Agent: glucocorticoid CHEBI:24261

Corticosteroids (e.g., high-dose prednisolone, tapered over months) suppress inflammation and are given with plasma exchange and a cytotoxic agent.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation"

Supports steroids (with cytotoxic therapy) to control inflammation and autoantibody production.

Cyclophosphamide

Action: Pharmacotherapy NCIT:C15986

Agent: cyclophosphamide CHEBI:4027

The cytotoxic agent cyclophosphamide suppresses new autoantibody production and, with plasma exchange and steroids, completes standard induction therapy.

Mechanism Target:

INHIBITS Anti-GBM autoantibody formation against alpha-3(IV) collagen — Cyclophosphamide suppresses the lymphocyte-driven production of new anti-GBM autoantibody, acting at the autoantibody-formation node.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation"

Supports cytotoxic therapy (cyclophosphamide is the standard cytotoxic agent) to prevent ongoing autoantibody production.

Rituximab

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Anti-CD20 B-cell depletion is used when cyclophosphamide is contraindicated or in refractory disease, targeting autoantibody-producing B cells.

Mechanism Target:

INHIBITS Anti-GBM autoantibody formation against alpha-3(IV) collagen — Rituximab depletes CD20+ B cells, the precursors of the plasma cells that produce anti-GBM autoantibody, acting at the autoantibody-formation node.

Show evidence (1 reference)

PMID:28515156 PARTIAL Human Clinical

"how to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors"

Rituximab (anti-CD20 B-cell depletion) is an emerging alternative for refractory disease or when cyclophosphamide is contraindicated; the review frames the need to refine treatment beyond the standard regimen. Agent identity is supported by the rituximab NCIT term.

Imlifidase (investigational IgG-cleaving enzyme)

Action: Pharmacotherapy NCIT:C15986

Imlifidase (IdeS), an IgG-degrading enzyme of Streptococcus pyogenes, cleaves circulating IgG within hours and is under Phase 3 evaluation for rapid autoantibody clearance in severe anti-GBM disease (GOOD-IDES-02 trial).

Show evidence (1 reference)

clinicaltrials:NCT05679401 PARTIAL Human Clinical

"An open-label, controlled, randomised, multi-centre Phase 3 trial evaluating renal function in patients with severe anti-GBM disease comparing imlifidase and standard of care (SoC) with SoC alone."

Supports imlifidase as an investigational Phase 3 therapy for severe anti-GBM disease aimed at rapid IgG clearance.

🌍

Environmental Factors

2

Cigarette smoking

Cigarette smoking is the best-established lifestyle exposure and disproportionately drives the alveolar-hemorrhage phenotype, plausibly by increasing alveolar antigen accessibility and oxidative epitope unmasking.

Show evidence (1 reference)

PMID:28515156 PARTIAL Human Clinical

"environmental factors, including infection, may trigger disease in genetically susceptible individuals"

Supports the gene-environment model in which environmental exposures (of which smoking is the best characterized) trigger disease in HLA-susceptible hosts. Smoking-specificity is described in prose; this review supports the general environmental-trigger framework.

Infection as environmental trigger

Respiratory and other infections are recognized nonspecific environmental triggers in genetically susceptible individuals; spatial and temporal clustering of cases supports an environmental precipitant.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals."

Directly supports infection as an environmental trigger in HLA-susceptible hosts.

🔬

Biochemical Markers

2

Circulating anti-GBM antibodies (Positive)

Context: Serum anti-GBM antibodies (anti-alpha3(IV)NC1) detected by ELISA are the serologic cornerstone of diagnosis; titer tracks disease activity.

Show evidence (1 reference)

PMID:38493958 SUPPORT Human Clinical

"The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively."

Anti-GBM antibody positivity is detected in 88.8% of patients, supporting it as the defining biochemical marker.

Circulating ANCA (double-positive disease) (Positive)

Context: Roughly a quarter to a third of patients are also positive for antineutrophil cytoplasmic antibodies (ANCA, usually MPO); these "double-positive" patients have features and relapse behavior overlapping ANCA-associated vasculitis.

Show evidence (1 reference)

PMID:28506760 SUPPORT Human Clinical

"No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease"

Supports ANCA co-positivity as a clinically meaningful biochemical stratifier that predicts relapse, unlike monophasic single-positive disease.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Anti-Glomerular Basement Membrane Disease:

ANCA-associated vasculitis

Overlapping Features ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis) is the principal differential for a pulmonary-renal syndrome; it shows pauci-immune (not linear) staining, and may co-occur as double-positive disease.

Show evidence (1 reference)

PMID:28506760 SUPPORT Human Clinical

"Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease"

Supports ANCA-associated vasculitis as the key differential/overlap entity, including the double-positive presentation.

🔬

Clinical Trials

1

NCT05679401 PHASE_III ACTIVE_NOT_RECRUITING

GOOD-IDES-02: Phase 3 open-label, randomised, controlled, multi-centre trial comparing imlifidase plus standard-of-care versus standard-of-care alone in severe anti-GBM antibody (Goodpasture) disease, with renal function as the primary outcome.

Target Phenotypes: Glomerulonephritis HP:0000099

Show evidence (1 reference)

clinicaltrials:NCT05679401 SUPPORT Human Clinical

"An open-label, controlled, randomised, multi-centre Phase 3 trial evaluating renal function in patients with severe anti-GBM disease comparing imlifidase and standard of care (SoC) with SoC alone."

Defines the GOOD-IDES-02 Phase 3 trial of imlifidase in severe anti-GBM disease.

{ }

Source YAML

click to show

name: Anti-Glomerular Basement Membrane Disease
creation_date: "2026-06-29T00:00:00Z"
description: >-
  Anti-glomerular basement membrane (anti-GBM) disease, historically called
  Goodpasture syndrome or Goodpasture disease, is a rare organ-specific
  autoimmune small-vessel vasculitis caused by circulating autoantibodies
  (predominantly IgG) directed against the noncollagenous-1 (NC1) domain of the
  alpha-3 chain of type IV collagen, the "Goodpasture antigen." This autoantigen
  is expressed in the specialized basement membranes of the renal glomerulus and
  the pulmonary alveolus, so the disease classically presents as a
  pulmonary-renal syndrome of rapidly progressive (crescentic) glomerulonephritis
  with diffuse alveolar hemorrhage. It is not a Mendelian disease: susceptibility
  is strongly linked to HLA-DRB1*15:01 (DR15), and an environmental "second hit"
  (smoking, hydrocarbon inhalation, infection, mechanical GBM disruption) is
  thought to unmask the normally sequestered cryptic epitopes.
category: Complex
disease_term:
  preferred_term: anti-glomerular basement membrane disease
  term:
    id: MONDO:0009303
    label: anti-glomerular basement membrane disease
parents:
- Autoimmune disease
synonyms:
- Goodpasture syndrome
- Goodpasture disease
- anti-GBM antibody disease
- anti-basement membrane antibody disease
- pulmonary-renal syndrome
references:
- reference: PMID:28515156
  title: Anti-Glomerular Basement Membrane Disease.
pathophysiology:
- name: Anti-GBM autoantibody formation against alpha-3(IV) collagen
  role: trigger
  description: >-
    Loss of immune tolerance to the noncollagenous-1 (NC1) domain of the alpha-3
    chain of type IV collagen (alpha3(IV)NC1) generates directly pathogenic
    autoantibodies. An HLA-DRB1*15:01-restricted CD4+ T-helper cell response to
    alpha3(IV)NC1 peptides provides help for B-cell differentiation into
    plasma cells producing high-affinity, complement-fixing anti-GBM IgG.
    Reactivity to alpha3(IV)NC1 is both necessary and sufficient for the disease.
  cell_types:
  - preferred_term: alpha3(IV)NC1-reactive CD4+ T-helper cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: autoantibody-producing B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: antigen processing and presentation
    term:
      id: GO:0019882
      label: antigen processing and presentation
  - preferred_term: humoral immune response mediated by circulating immunoglobulin
    modifier: INCREASED
    term:
      id: GO:0002455
      label: humoral immune response mediated by circulating immunoglobulin
  downstream:
  - target: Conformational unmasking of cryptic alpha3/alpha5(IV)NC1 epitopes
    description: >-
      Autoreactive lymphocytes and anti-GBM antibodies become pathogenic only
      once the cryptic basement-membrane epitopes are exposed.
  evidence:
  - reference: PMID:8589284
    reference_title: Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for
      the expression of autoimmune disease directed to the NC1 domain of Type IV
      collagen
    explanation: >-
      Establishes the alpha3(IV)NC1 domain as the necessary-and-sufficient
      autoantigen of anti-GBM/Goodpasture disease.
  - reference: PMID:14569090
    reference_title: The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Goodpasture's disease is a severe nephritis characterized by autoantibodies
      to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular
      basement membrane. The disease is very strongly associated with HLA-DR15
    explanation: >-
      Supports the alpha3(IV)NC1 autoantibody and the HLA-DR15-restricted CD4+
      T-helper response driving autoantibody production.
- name: Conformational unmasking of cryptic alpha3/alpha5(IV)NC1 epitopes
  description: >-
    In the mature glomerular basement membrane the alpha3, alpha4 and alpha5 NC1
    domains assemble into a cross-linked alpha345NC1 hexamer in which the
    immunodominant epitopes (E_A, E_B) are buried, conferring "immune privilege"
    on the Goodpasture antigen. An environmental insult (oxidants from cigarette
    smoke, infection, or mechanical disruption) dissociates the hexamer and
    transitions the subunits into immunogens, exposing the cryptic neoepitopes on
    the alpha3 and alpha5 NC1 monomers. This conformational unmasking — rather
    than any sequence change — is the proximate event of the "conformeropathy."
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  downstream:
  - target: Anti-GBM antibody binding with complement and neutrophil-mediated injury
    description: Exposed neoepitopes are bound by circulating anti-GBM IgG along the basement membrane.
  evidence:
  - reference: PMID:20660402
    reference_title: Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The antibodies bound to distinct epitopes encompassing region E(A) in the
      alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but
      they did not bind to the native cross-linked alpha345NC1 hexamer
    explanation: >-
      Shows the autoantibodies bind cryptic E_A/E_B neoepitopes exposed on
      dissociated alpha3/alpha5 NC1 monomers but not the intact native hexamer,
      defining the conformeropathy mechanism.
  - reference: PMID:19729652
    reference_title: A sulfilimine bond identified in collagen IV.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the cross-link also confers immune privilege to the collagen IV antigen of
      Goodpasture autoimmune disease
    explanation: >-
      Identifies the sulfilimine (S=N) cross-link that stabilizes the NC1 hexamer
      and confers immune privilege by sequestering the cryptic Goodpasture
      epitopes.
- name: Anti-GBM antibody binding with complement and neutrophil-mediated injury
  description: >-
    Circulating anti-GBM IgG binds the exposed alpha3(IV)NC1 (and alpha5(IV)NC1)
    along the basement membrane in a linear, ribbon-like pattern. Bound antibody
    activates the classical complement pathway, generating chemoattractants that
    recruit neutrophils and macrophages; effector cells release proteases and
    reactive oxygen species, producing fibrinoid necrosis of the glomerular and
    alveolar capillary walls.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: complement activation, classical pathway
    modifier: INCREASED
    term:
      id: GO:0006958
      label: complement activation, classical pathway
  - preferred_term: leukocyte migration
    modifier: INCREASED
    term:
      id: GO:0050900
      label: leukocyte migration
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Crescentic glomerulonephritis and diffuse alveolar hemorrhage
    description: Capillary-wall necrosis drives glomerular crescent formation and lung hemorrhage.
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is an archetypic autoimmune disease, caused by the development of
      directly pathogenic autoantibodies targeting a well characterized
      autoantigen expressed in the basement membranes of these organs
    explanation: >-
      Supports the directly pathogenic nature of the anti-GBM autoantibodies that
      bind the basement-membrane antigen and drive injury.
- name: Crescentic glomerulonephritis and diffuse alveolar hemorrhage
  role: outcome
  description: >-
    Glomerular basement membrane rupture permits fibrin and inflammatory cells
    into Bowman's space, triggering parietal epithelial and podocyte
    proliferation, cellular crescents, and rapidly progressive (extracapillary)
    crescentic glomerulonephritis. In the lung, alveolar capillary
    basement-membrane injury produces diffuse alveolar hemorrhage; cigarette
    smoking increases alveolar antigen accessibility, explaining the
    smoking-lung-hemorrhage link.
  cell_types:
  - preferred_term: glomerular parietal/visceral epithelial cell
    term:
      id: CL:1000746
      label: glomerular cell
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients develop widespread glomerular crescent formation,
      presenting with features of rapidly progressive GN, and 40%-60% will have
      concurrent alveolar hemorrhage.
    explanation: >-
      Supports crescentic glomerulonephritis and concurrent alveolar hemorrhage
      as the principal clinical-pathological outcome of the disease.
mechanistic_hypotheses:
- hypothesis_group_id: conformeropathy
  hypothesis_label: Conformeropathy / cryptic-neoepitope model
  description: >-
    The dominant mechanistic model holds that anti-GBM disease is an autoimmune
    "conformeropathy": the immunodominant epitopes are normally sequestered
    within the cross-linked alpha345NC1 hexamer (immune privilege), and disease
    requires an environmental insult that dissociates the hexamer to expose
    cryptic neoepitopes on alpha3/alpha5(IV)NC1 in an HLA-DR15-susceptible host.
phenotypes:
- category: Renal
  name: Rapidly progressive glomerulonephritis
  description: >-
    Crescentic glomerulonephritis with rapid (days-to-weeks) loss of kidney
    function, often progressing to dialysis dependence.
  phenotype_term:
    preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
    temporality: ACUTE
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients develop widespread glomerular crescent formation,
      presenting with features of rapidly progressive GN
    explanation: Supports rapidly progressive crescentic glomerulonephritis as the cardinal renal phenotype.
- category: Respiratory
  name: Diffuse alveolar hemorrhage
  description: >-
    Bleeding into the alveolar spaces from alveolar capillary basement-membrane
    injury, typically presenting with hemoptysis and dyspnea; smoking-associated.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence rates of anti-GBM antibodies, antineutrophil
      cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and
      32.6%, respectively.
    explanation: >-
      Pooled meta-analysis quantifies lung hemorrhage at 32.6% of patients,
      supporting the FREQUENT frequency band for this phenotype.
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      40%-60% will have concurrent alveolar hemorrhage
    explanation: >-
      The McAdoo & Pusey review reports 40-60% of patients have concurrent
      alveolar hemorrhage, corroborating the FREQUENT frequency band.
- category: Respiratory
  name: Hemoptysis
  description: Coughing up blood, a common presenting feature of alveolar hemorrhage.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      40%-60% will have concurrent alveolar hemorrhage
    explanation: >-
      Alveolar hemorrhage (the source of hemoptysis) is documented in 40-60% of
      patients; supports hemoptysis as a frequent respiratory manifestation.
- category: Renal
  name: Hematuria
  description: Glomerular hematuria with dysmorphic red cells and red-cell casts.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients develop widespread glomerular crescent formation,
      presenting with features of rapidly progressive GN
    explanation: >-
      Glomerular hematuria is an integral feature of the rapidly progressive
      crescentic glomerulonephritis described here.
- category: Renal
  name: Proteinuria
  description: Glomerular proteinuria, typically sub-nephrotic, accompanying the crescentic glomerulonephritis.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:8532389
    reference_title: Progression from Goodpasture's disease to membranous glomerulonephritis.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hemoptysis, severe iron deficiency anemia and microscopic hematuria and
      proteinuria
    explanation: >-
      A Goodpasture's-disease case report documenting microscopic proteinuria at
      presentation; PARTIAL because this is a single case report.
- category: Renal
  name: Acute kidney injury
  description: Acute decline in glomerular filtration, often with oliguria, a key prognostic feature.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
    temporality: ACUTE
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presentation with oligoanuria, a high proportion of glomerular crescents,
      or kidney failure requiring dialysis augur badly for renal prognosis
    explanation: >-
      Supports acute kidney injury (oligoanuria, dialysis-requiring kidney
      failure) as a severe, prognostically important renal phenotype.
- category: Hematologic
  name: Anemia
  description: Anemia, frequently from alveolar hemorrhage (iron-deficiency/hemorrhagic) and renal disease.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:8532389
    reference_title: Progression from Goodpasture's disease to membranous glomerulonephritis.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hemoptysis, severe iron deficiency anemia and microscopic hematuria and
      proteinuria
    explanation: >-
      A Goodpasture's-disease case report documenting severe iron-deficiency
      anemia (from pulmonary hemorrhage) at presentation. PARTIAL because this is
      a single case report.
genetic:
- name: HLA-DRB1 (DR15 / DRB1*15:01) susceptibility
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  association: Susceptibility
  relationship_type: RISK_FACTOR
  notes: >-
    Anti-GBM disease is strongly HLA-restricted: the HLA-DRB1*15:01 (DR15)
    allele dominates susceptibility and provides the restricting element for
    presentation of alpha3(IV)NC1 peptides to autoreactive CD4+ T-helper cells.
    This is a risk allele, not a causal germline mutation; inheritance of the
    disease itself is multifactorial.
  evidence:
  - reference: PMID:14569090
    reference_title: The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is very strongly associated with HLA-DR15
    explanation: Directly supports the dominant HLA-DR15 (DRB1*15:01) susceptibility association.
- name: COL4A3 (alpha-3 type IV collagen) autoantigen target gene
  gene_term:
    preferred_term: COL4A3
    term:
      id: hgnc:2204
      label: COL4A3
  association: Autoantigen target (not a causal germline mutation)
  notes: >-
    COL4A3 encodes the alpha-3 chain of type IV collagen; its C-terminal NC1
    domain (alpha3(IV)NC1) is the Goodpasture autoantigen. COL4A3 is the target
    of the autoimmune response, NOT a site of disease-causing germline variants
    in anti-GBM disease. (By contrast, loss-of-function variants in COL4A3/4/5
    cause the hereditary structural disease Alport syndrome — a mechanistically
    distinct condition.)
  evidence:
  - reference: PMID:8589284
    reference_title: Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the anti-GBM antibodies from all patients reacted with the alpha 3(IV) NC1
      (85% exclusively)
    explanation: >-
      Supports the alpha-3 chain of type IV collagen (COL4A3 product) as the
      autoantibody target in anti-GBM/Goodpasture disease.
biochemical:
- name: Circulating anti-GBM antibodies
  presence: Positive
  context: >-
    Serum anti-GBM antibodies (anti-alpha3(IV)NC1) detected by ELISA are the
    serologic cornerstone of diagnosis; titer tracks disease activity.
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence rates of anti-GBM antibodies, antineutrophil
      cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and
      32.6%, respectively.
    explanation: >-
      Anti-GBM antibody positivity is detected in 88.8% of patients, supporting
      it as the defining biochemical marker.
- name: Circulating ANCA (double-positive disease)
  presence: Positive
  context: >-
    Roughly a quarter to a third of patients are also positive for antineutrophil
    cytoplasmic antibodies (ANCA, usually MPO); these "double-positive" patients
    have features and relapse behavior overlapping ANCA-associated vasculitis.
  evidence:
  - reference: PMID:28506760
    reference_title: Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No single-positive anti-GBM patients experienced disease relapse, whereas
      approximately half of surviving patients with AAV and double-positive
      patients had recurrent disease
    explanation: >-
      Supports ANCA co-positivity as a clinically meaningful biochemical stratifier
      that predicts relapse, unlike monophasic single-positive disease.
environmental:
- name: Cigarette smoking
  description: >-
    Cigarette smoking is the best-established lifestyle exposure and
    disproportionately drives the alveolar-hemorrhage phenotype, plausibly by
    increasing alveolar antigen accessibility and oxidative epitope unmasking.
  effect: HARMFUL
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      environmental factors, including infection, may trigger disease in
      genetically susceptible individuals
    explanation: >-
      Supports the gene-environment model in which environmental exposures (of
      which smoking is the best characterized) trigger disease in HLA-susceptible
      hosts. Smoking-specificity is described in prose; this review supports the
      general environmental-trigger framework.
- name: Infection as environmental trigger
  description: >-
    Respiratory and other infections are recognized nonspecific environmental
    triggers in genetically susceptible individuals; spatial and temporal
    clustering of cases supports an environmental precipitant.
  effect: HARMFUL
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recent confirmation of spatial and temporal clustering of cases
      suggests that environmental factors, including infection, may trigger
      disease in genetically susceptible individuals.
    explanation: Directly supports infection as an environmental trigger in HLA-susceptible hosts.
diagnosis:
- name: Anti-GBM serology plus renal biopsy
  description: >-
    Diagnosis integrates positive serum anti-GBM antibody testing (ELISA) with
    renal biopsy showing crescentic glomerulonephritis and pathognomonic linear
    IgG deposition along the GBM on direct immunofluorescence. ANCA testing is
    required in every patient to identify double-positive disease.
  results: >-
    Positive circulating anti-GBM antibodies with linear GBM IgG on biopsy
    confirm the diagnosis; concurrent ANCA positivity defines double-positive
    disease.
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      caused by the development of directly pathogenic autoantibodies targeting a
      well characterized autoantigen expressed in the basement membranes
    explanation: >-
      Supports the antibody-and-antigen basis of diagnosis (serology plus
      basement-membrane-bound antibody on biopsy).
histopathology:
- name: Linear IgG deposition along the glomerular basement membrane
  diagnostic: true
  description: >-
    Direct immunofluorescence shows pathognomonic linear (ribbon-like) IgG
    deposition along the GBM, distinguishing anti-GBM disease from pauci-immune
    (ANCA) and granular (immune-complex) glomerulonephritides.
  finding_term:
    preferred_term: linear glomerular basement membrane IgG deposition
  evidence:
  - reference: PMID:40062063
    reference_title: "Atypical Anti-glomerular Basement Membrane Disease in a 16-Year-Old Male Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Kidney biopsy demonstrated linear immunofluorescence staining of glomerular
      basement membrane with immunoglobulin G (IgG)
    explanation: >-
      Directly documents the pathognomonic histopathologic finding — linear IgG
      immunofluorescence staining along the glomerular basement membrane on
      kidney biopsy.
treatments:
- name: Plasma exchange (plasmapheresis)
  description: >-
    Therapeutic plasma exchange rapidly removes circulating pathogenic anti-GBM
    IgG and is a cornerstone of induction therapy, given daily until antibody is
    suppressed.
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_phenotypes:
  - preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  target_mechanisms:
  - target: Anti-GBM antibody binding with complement and neutrophil-mediated injury
    treatment_effect: INHIBITS
    description: >-
      Plasma exchange removes circulating pathogenic anti-GBM IgG, interrupting
      antibody binding and the downstream complement/neutrophil-mediated injury.
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment aims to rapidly remove pathogenic autoantibody, typically with
      the use of plasma exchange, along with steroids and cytotoxic therapy
    explanation: Directly supports plasma exchange as the antibody-removal cornerstone of induction.
- name: High-dose glucocorticoids
  description: >-
    Corticosteroids (e.g., high-dose prednisolone, tapered over months) suppress
    inflammation and are given with plasma exchange and a cytotoxic agent.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: glucocorticoid
      term:
        id: CHEBI:24261
        label: glucocorticoid
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with steroids and cytotoxic therapy to prevent ongoing autoantibody
      production and tissue inflammation
    explanation: Supports steroids (with cytotoxic therapy) to control inflammation and autoantibody production.
- name: Cyclophosphamide
  description: >-
    The cytotoxic agent cyclophosphamide suppresses new autoantibody production
    and, with plasma exchange and steroids, completes standard induction therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
  target_mechanisms:
  - target: Anti-GBM autoantibody formation against alpha-3(IV) collagen
    treatment_effect: INHIBITS
    description: >-
      Cyclophosphamide suppresses the lymphocyte-driven production of new
      anti-GBM autoantibody, acting at the autoantibody-formation node.
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with steroids and cytotoxic therapy to prevent ongoing autoantibody
      production and tissue inflammation
    explanation: >-
      Supports cytotoxic therapy (cyclophosphamide is the standard cytotoxic agent)
      to prevent ongoing autoantibody production.
- name: Rituximab
  description: >-
    Anti-CD20 B-cell depletion is used when cyclophosphamide is contraindicated
    or in refractory disease, targeting autoantibody-producing B cells.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Anti-GBM autoantibody formation against alpha-3(IV) collagen
    treatment_effect: INHIBITS
    description: >-
      Rituximab depletes CD20+ B cells, the precursors of the plasma cells that
      produce anti-GBM autoantibody, acting at the autoantibody-formation node.
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      how to better refine and improve treatments, particularly for patients
      presenting with adverse prognostic factors
    explanation: >-
      Rituximab (anti-CD20 B-cell depletion) is an emerging alternative for
      refractory disease or when cyclophosphamide is contraindicated; the review
      frames the need to refine treatment beyond the standard regimen. Agent
      identity is supported by the rituximab NCIT term.
- name: Imlifidase (investigational IgG-cleaving enzyme)
  description: >-
    Imlifidase (IdeS), an IgG-degrading enzyme of Streptococcus pyogenes, cleaves
    circulating IgG within hours and is under Phase 3 evaluation for rapid
    autoantibody clearance in severe anti-GBM disease (GOOD-IDES-02 trial).
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: clinicaltrials:NCT05679401
    reference_title: "GOOD-IDES-02: imlifidase in severe anti-GBM antibody disease (Goodpasture disease)."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An open-label, controlled, randomised, multi-centre Phase 3 trial
      evaluating renal function in patients with severe anti-GBM disease
      comparing imlifidase and standard of care (SoC) with SoC alone.
    explanation: >-
      Supports imlifidase as an investigational Phase 3 therapy for severe
      anti-GBM disease aimed at rapid IgG clearance.
clinical_trials:
- name: NCT05679401
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    GOOD-IDES-02: Phase 3 open-label, randomised, controlled, multi-centre trial
    comparing imlifidase plus standard-of-care versus standard-of-care alone in
    severe anti-GBM antibody (Goodpasture) disease, with renal function as the
    primary outcome.
  target_phenotypes:
  - preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  evidence:
  - reference: clinicaltrials:NCT05679401
    reference_title: "GOOD-IDES-02: imlifidase in severe anti-GBM antibody disease (Goodpasture disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An open-label, controlled, randomised, multi-centre Phase 3 trial
      evaluating renal function in patients with severe anti-GBM disease
      comparing imlifidase and standard of care (SoC) with SoC alone.
    explanation: Defines the GOOD-IDES-02 Phase 3 trial of imlifidase in severe anti-GBM disease.
epidemiology:
- name: Incidence and outcomes
  description: >-
    Anti-GBM disease is rare, with an incidence around 0.6-1.8 cases per million
    population per year, and accounts for roughly 8% of rapidly progressive and
    13% of crescentic glomerulonephritis. One-year patient and kidney survival are
    approximately 76% and 30%, respectively, with kidney function at diagnosis a
    strong prognostic factor.
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per
      million population per annum.
    explanation: Supports the quoted incidence range from a 47-study, 2830-patient meta-analysis.
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled one-year patient and kidney survival rates were 76.2% and 30.2%,
      respectively. Kidney function on diagnosis and normal glomeruli percentage
      were identified as strong prognostic factors.
    explanation: Supports the one-year survival figures and the prognostic importance of baseline kidney function.
differential_diagnoses:
- name: ANCA-associated vasculitis
  description: >-
    ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic
    polyangiitis) is the principal differential for a pulmonary-renal syndrome;
    it shows pauci-immune (not linear) staining, and may co-occur as
    double-positive disease.
  evidence:
  - reference: PMID:28506760
    reference_title: Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Double-positive patients shared characteristics of ANCA-associated
      vasculitis (AAV), such as older age distribution and longer symptom
      duration before diagnosis, and features of anti-GBM disease
    explanation: >-
      Supports ANCA-associated vasculitis as the key differential/overlap entity,
      including the double-positive presentation.
notes: >-
  Anti-GBM disease is an acquired autoimmune disease with NO GeneReviews chapter
  and no causal germline mutation. The COL4A3/COL4A4/COL4A5 genes encode the
  type IV collagen network that is the AUTOANTIGEN target; loss-of-function
  variants in those same genes cause the hereditary structural disease Alport
  syndrome (GeneReviews PMID:20301386), which is mechanistically distinct and was
  deliberately NOT conflated with anti-GBM disease during curation. The
  molecular_mimicry_autoimmunity module was considered but not declared as a
  conformance target: anti-GBM disease is best modeled as a conformeropathy
  (cryptic-neoepitope unmasking) rather than classic post-infectious molecular
  mimicry, so no false conformance was asserted.

📚

References & Deep Research

References

1

PMID:28515156

Anti-Glomerular Basement Membrane Disease.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-4-8[1m] 16 citations 2026-06-29T11:19:50.469889

1. Disease Information

Overview. Anti-glomerular basement membrane (anti-GBM) disease is a rare, organ-specific autoimmune small-vessel vasculitis caused by circulating autoantibodies (predominantly IgG) directed against the non-collagenous-1 (NC1) domain of the α3 chain of type IV collagen — the "Goodpasture antigen" — which is expressed in the specialized basement membranes of the renal glomerulus and pulmonary alveolus. The classic presentation is a pulmonary–renal syndrome: rapidly progressive (crescentic) glomerulonephritis (RPGN) together with diffuse alveolar hemorrhage (DAH). When both organs are involved the term Goodpasture syndrome/disease is traditionally used; isolated renal-limited or (rarely) lung-limited forms also occur.

Key identifiers. - MONDO: MONDO:0009303 (anti-glomerular basement membrane disease) - OMIM: 233450 (GOODPASTURE SYNDROME) ✔ - Orphanet: ORPHA:375 (Anti-glomerular basement membrane disease / Goodpasture syndrome) - ICD-10: M31.0 (Hypersensitivity angiitis – Goodpasture syndrome); ICD-11: 4A44.A0 / GB61 cross-mapped - MeSH: D019867 "Anti-Glomerular Basement Membrane Disease" - UMLS/SNOMED CT: 236519009 (Anti-glomerular basement membrane disease)

Synonyms / alternative names. Goodpasture syndrome; Goodpasture disease; anti-GBM antibody disease; anti-basement-membrane antibody disease; pulmonary–renal syndrome (descriptive, not specific). The eponym honors Ernest Goodpasture, who described a fatal case during the 1919 influenza pandemic.

Data derivation. This entry is built from aggregated disease-level resources (systematic reviews/meta-analyses, single-center cohort series, mechanistic biochemistry) rather than individual EHR patients — appropriate given the disease's rarity.

2. Etiology

Causal mechanism

Anti-GBM disease is fundamentally an autoantibody-mediated (Type II hypersensitivity) conformeropathy. The proximate cause is the breakdown of immune tolerance to the α3(IV)NC1 domain, generating high-affinity IgG that binds basement-membrane antigen and triggers complement- and neutrophil-mediated necrotizing injury. It is not a Mendelian disease; it arises from a strong genetic susceptibility background acted on by an environmental "second hit."

Genetic risk factors

HLA-DRB1*15:01 (DR15 haplotype) is the dominant susceptibility allele. It is "found in more than 80% of patients with anti-GBM antibody disease" (Medscape/Phelps & Rees ⚠ PMID:10231356). DRB1*15:01 and DRB1*04 are positively associated.
Susceptibility loci: Phelps & Rees (Kidney Int 1999 ⚠ PMID:10231356) established the HLA-DRB1 dominance hierarchy of risk.

Genetic protective factors

HLA-DRB1*07:01 (and DRB1*01) confer dominant protection: "individuals inheriting DRB1*1501 and DRB1*0701 have no higher risk of disease than does the general population" (Medscape synthesis of Phelps & Rees ⚠).

Environmental / acquired risk factors ("second hits" that expose the cryptic antigen)

Cigarette smoking — strongly associated, especially with the pulmonary-hemorrhage phenotype.
Hydrocarbon / organic-solvent inhalation — classic occupational/inhalational trigger (case literature, e.g., Egyptian J Bronchol 2026).
Pulmonary infection (viral respiratory infections, influenza historically).
Extracorporeal shock-wave lithotripsy — "can disrupt the glomerular basement membrane and unmask epitopes" (Merck Manual / CJASN review).
Alemtuzumab (anti-CD52) — lymphocyte-depleting therapy; "loss of regulatory T cell subsets, or abnormal immune cell repopulation after depletion" (PMC7573726 ⚠).
Membranous nephropathy and ANCA-associated vasculitis can precede or co-occur, "unmasking" GBM antigen.
Age/sex: bimodal age peaks (young men 20–30; older adults 60–70, more women).

Gene–environment interaction. The canonical model: an HLA-DRB1*15:01–restricted CD4⁺ T-cell response to α3(IV)NC1 epitopes provides help for autoantibody production, but disease only manifests when an environmental insult (smoke, hydrocarbons, infection, lithotripsy) perturbs the GBM and exposes the normally sequestered cryptic epitopes — converting subclinical autoreactivity into overt injury.

3. Phenotypes

Phenotype	Type	HPO suggestion	Frequency	Notes
Rapidly progressive (crescentic) glomerulonephritis	Lab/clinical sign	HP:0000099 Glomerulonephritis; HP:0012622 Chronic kidney disease	~Most renal cases	Acute, often dialysis-requiring
Diffuse alveolar / pulmonary hemorrhage	Clinical sign	HP:0040223 Pulmonary hemorrhage; HP:0002105 Hemoptysis	32.6% (meta-analysis ✔ PMID:38493958)	Smoking-associated
Hematuria	Lab abnormality	HP:0000790 Hematuria	Very frequent	Glomerular (dysmorphic RBC, casts)
Proteinuria (usually sub-nephrotic)	Lab abnormality	HP:0000093 Proteinuria	Frequent
Acute kidney injury / oliguria	Clinical sign	HP:0001919 Acute kidney injury; HP:0100518 Dysuria/oliguria (use HP:0100626 Oliguria)	Frequent	Strong prognostic marker
Elevated serum creatinine / azotemia	Lab abnormality	HP:0003259 Elevated circulating creatinine	Frequent	Baseline value is key prognosticator
Dyspnea / respiratory failure	Symptom	HP:0002094 Dyspnea	Common in pulmonary cases
Iron-deficiency / hemorrhagic anemia	Lab abnormality	HP:0001891 Iron deficiency anemia; HP:0001903 Anemia	Common	From alveolar bleeding
Hypertension	Clinical sign	HP:0000822 Hypertension	Variable	Less prominent than in other GN
Constitutional (malaise, fatigue, weight loss, fever)	Symptoms	HP:0012378 Fatigue; HP:0001824 Weight loss	Common prodrome

Characteristics. Onset is typically acute/subacute in adults; the disease is monophasic in classic single-positive cases (relapse <3%). Severity is severe and often organ-threatening at presentation. Pulmonary hemorrhage can be immediately life-threatening; renal disease frequently progresses to end-stage within days–weeks if untreated.

Quality-of-life impact. Survivors who reach ESRD face lifelong dialysis or transplantation; pulmonary survivors generally recover lung function. No disease-specific QoL instrument exists; generic CKD/dialysis QoL measures (KDQOL, EQ-5D, SF-36) apply.

4. Genetic / Molecular Information

This is NOT a monogenic disease — there are no causal germline mutations. The "molecular genetics" is the genetics of the autoantigen and of HLA susceptibility.

Autoantigen gene: COL4A3 (HGNC:2204; chromosome 2q36.3), encoding the α3 chain of type IV collagen. Its C-terminal NC1 domain (α3(IV)NC1) is the Goodpasture antigen. The collateral chains COL4A4 (HGNC:2205) and COL4A5 (HGNC:2207, Xq22.3) form the α3α4α5(IV) network.
Susceptibility "gene": HLA class II — HLA-DRB1 (HGNC:4948), allele DRB1*15:01.
No pathogenic somatic variants, copy-number, or chromosomal abnormalities are implicated in pathogenesis. (Conversely, loss-of-function mutations in COL4A3/4/5 cause Alport syndrome — and transplanted Alport patients can develop de novo anti-GBM antibodies against the newly encountered α3/α5(IV) antigen, the converse experiment of nature.)
Functional consequence: The disease results from a conformational change, not a sequence change — see Mechanism.

Epigenetics / molecular profiling. No established disease-specific methylation/histone signature. Transcriptomic/proteomic profiling is largely confined to research cohorts; no validated multi-omics diagnostic exists.

5. Environmental Information

Toxins / inhalational: organic solvents and hydrocarbons (gasoline, paint thinners); cigarette smoke is the best-established lifestyle exposure and disproportionately drives the alveolar-hemorrhage phenotype.
Mechanical: extracorporeal shock-wave lithotripsy (GBM disruption).
Iatrogenic: alemtuzumab and other lymphocyte-depleting agents.
Infectious agents: respiratory viral infections (historically influenza — Goodpasture's index 1919 case); no single pathogen is causal. Infection is regarded as a nonspecific trigger/adjuvant rather than an etiologic organism.

6. Mechanism / Pathophysiology

This is the mechanistic core and the best-characterized aspect of the disease — a model "autoimmune conformeropathy."

Step 1 — The sequestered/cryptic autoantigen and its "immune privilege"

The Goodpasture antigen is the C-terminal NC1 domain of α3(IV) collagen, identified by Saus, Hudson and colleagues as the common target of anti-basement-membrane antibodies (✔ PMID:8589284):

"Reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for the expression of autoimmune disease directed to the NC1 domain of Type IV collagen."

In the mature GBM, six NC1 domains associate into an α3α4α5 NC1 hexamer (two trimeric "caps" joined head-to-head). The two immunodominant epitopes — E_A and E_B, located on α3(IV)NC1 — are buried by intraprotomer interactions with α4 and α5 NC1 domains and locked by novel sulfilimine (S=N) crosslinks discovered by Vanacore et al. (Science 2009 ⚠ PMID:19729652). These crosslinks "confer immune privilege to the Goodpasture autoantigen" by structurally sequestering the cryptic epitopes.

Step 2 — Conformational unmasking (the "conformeropathy")

Pedchenko et al. (NEJM 2010 ⚠ PMID:20660402, Molecular Architecture of the Goodpasture Autoantigen in Anti-GBM Nephritis) showed that:

"the autoantibodies bind neoepitopes formed on α3 and α5 NC1 subunits upon disruption of the quaternary structure of the native α345NC1 hexamer, and hexamer disruption is concomitant with conformational changes that transition subunits into immunogens."

An environmental insult (oxidants from smoke, infection, mechanical disruption) dissociates the hexamer, exposing E_A/E_B. Autoantibodies to the α5(IV)NC1 chain are also pathogenic, defining a broader α3/α5 conformeropathy (Pedchenko 2016 ⚠, PMC5600521).

Step 3 — Loss of tolerance and antibody production

An HLA-DRB1*15:01–restricted CD4⁺ T-cell response to α3(IV)NC1 peptides drives B-cell help; B cells (CL:0000236) differentiate into plasma cells producing high-affinity, complement-fixing IgG1/IgG3 anti-GBM antibodies. The autoantibody titer correlates with disease activity.

Step 4 — Antibody binding, complement activation, effector recruitment

Circulating IgG binds the exposed α3(IV)NC1 along the GBM in a linear, ribbon-like immunofluorescence pattern. This activates the classical complement pathway (C3, C5a), generating chemoattractants that recruit neutrophils (CL:0000775) and monocytes/macrophages (CL:0000235). Effector cells release proteases and reactive oxygen species, producing fibrinoid necrosis of capillary loops.

Step 5 — Crescent formation and tissue destruction

GBM rupture permits fibrin and inflammatory cells into Bowman's space, triggering parietal epithelial and podocyte proliferation → cellular crescents → crescentic (extracapillary) glomerulonephritis. In the lung, alveolar capillary basement-membrane injury causes diffuse alveolar hemorrhage. Smoking increases alveolar antigen accessibility, explaining the smoking–lung-hemorrhage link.

Causal chain (upstream → downstream)

HLA-DRB1*15:01 susceptibility + environmental insult → hexamer dissociation/oxidation → exposure of cryptic E_A/E_B on α3/α5(IV)NC1 → T-cell-dependent anti-GBM IgG production → linear GBM antibody deposition → classical complement activation + neutrophil recruitment → capillary fibrinoid necrosis → crescentic GN (kidney) and alveolar hemorrhage (lung) → RPGN/ESRD and respiratory failure.

Ontology suggestions

Biological processes (GO): GO:0006956 complement activation; GO:0006958 complement activation, classical pathway; GO:0002455 humoral immune response mediated by circulating immunoglobulin; GO:0050900 leukocyte migration; GO:0006954 inflammatory response; GO:0002544 chronic inflammation; GO:0030198 extracellular matrix organization.
Cell types (CL): CL:0000236 B cell; CL:0000775 neutrophil; CL:0000235 macrophage; CL:0000084 T cell; CL:1000746 glomerular visceral epithelial cell (podocyte); CL:1000698 kidney resident parietal epithelial cell (crescent precursor).
Pathways: Reactome R-HSA-2559639 (Collagen type IV sulfilimine cross-linking by peroxidasin); Reactome complement cascade R-HSA-166658.
Protein dysfunction: No protein misfolding mutation — pathology is a quaternary conformational change exposing cryptic epitopes (a structural neoepitope phenomenon).

7. Anatomical Structures Affected

Primary organs: Kidney (UBERON:0002113) — specifically the renal glomerulus (UBERON:0000074) and glomerular basement membrane (UBERON:0002164); Lung (UBERON:0002048) — pulmonary alveolus (UBERON:0002299) and alveolar basement membrane.
Body systems: renal/urinary and respiratory; secondarily hematologic (hemorrhagic anemia).
Tissue/cell level: glomerular capillary endothelium and podocytes; alveolar capillary endothelium/type I pneumocytes; the target is the specialized type IV collagen network of these basement membranes (α3α4α5, restricted to GBM, alveolus, cochlea, eye, testis — explaining organ selectivity).
Subcellular (GO Cellular Component): GO:0005604 basement membrane; GO:0005581 collagen trimer; GO:0005615 extracellular space.
Lateralization: bilateral (both kidneys, both lungs) — diffuse, antigen-driven.

8. Temporal Development

Onset: acute/subacute in adults; bimodal age distribution — a peak in young men (20–30 yr, often with pulmonary–renal disease) and a second in older adults (60–70 yr, more women, often renal-limited).
Progression: characteristically rapidly progressive — kidney function can decline from normal to dialysis-dependence over days. Untreated, prognosis is dismal.
Course pattern: classic single-positive disease is monophasic (one episode, no relapse if antibody is cleared). Relapse is <3% (NDT treatment-standard review ✔). Double-positive (anti-GBM + ANCA) patients behave more like ANCA-associated vasculitis with relapsing-remitting disease (~50% relapse).
Critical window: the therapeutic window is extremely narrow — outcomes hinge on starting plasma exchange/immunosuppression before oliguria/dialysis dependence is established. Patients dialysis-dependent >7 days before treatment "very rarely recover independent kidney function."

9. Inheritance and Population

Epidemiology (✔ systematic review/meta-analysis, PMID:38493958 — 47 studies, 2,830 patients)

Incidence: "The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per million population per annum." (≈0.5–1 case/million/year is the commonly quoted figure.)
Anti-GBM accounts for ~8.0% of rapidly progressive GN and ~12.8% of crescentic GN cases (pooled).
Anti-GBM antibody positivity: 88.8%; ANCA co-positivity (double-positive): 27.4%; pulmonary hemorrhage: 32.6%.

Inheritance

Not Mendelian — complex/multifactorial with strong HLA association. No vertical inheritance pattern, no penetrance/expressivity/anticipation/mosaicism/founder-effect parameters apply in the classic genetic sense.
Rare familial clustering in HLA-identical siblings is reported (Clin Kidney J 2020), consistent with shared HLA-DR15 susceptibility rather than a transmitted causal variant.

Demographics

Sex: historically male predominance (~3:2) overall, but the older renal-limited peak skews female.
Ethnicity: "reported in all racial groups but is primarily a disease of white populations," with ~83% of race-identified cases in white individuals; relatively more common in those of European and East Asian descent. HLA-DRB1*15:01 frequency shapes geographic risk.
Geographic clustering / seasonality: small temporal/geographic clusters reported (e.g., post-infection clusters; a noted rise during the COVID-19 pandemic period in Madrid, PMC12457157 ⚠).

10. Diagnostics

Serology (cornerstone)

Circulating anti-GBM antibodies by ELISA (anti-α3(IV)NC1) — high sensitivity/specificity; titer tracks activity. LOINC examples: LOINC:40663-6 (Glomerular basement membrane Ab [Units/vol] in Serum by Immunoassay).
ANCA panel (MPO/PR3) — must be tested in every patient: ~27–40% are double-positive, which changes prognosis and maintenance therapy.

Histopathology (definitive)

Renal biopsy: diffuse crescentic glomerulonephritis on light microscopy; the pathognomonic finding is linear (ribbon-like) IgG deposition along the GBM on direct immunofluorescence (often with linear C3). Quantifying % crescents and % globally sclerosed glomeruli is essential for prognosis.
Lung: capillaritis with hemorrhage; hemosiderin-laden macrophages on BAL.

Supporting laboratory / functional

Urinalysis: dysmorphic hematuria, RBC casts, sub-nephrotic proteinuria; rising creatinine/falling GFR.
Anemia (hemorrhagic/iron-deficiency).
Imaging: chest CT/X-ray showing bilateral alveolar infiltrates (RadLex); DLCO is paradoxically increased during active alveolar hemorrhage (a useful functional clue).
Genetic testing: not diagnostic (no causal gene). HLA typing is research/risk-stratification only.

Differential diagnosis

ANCA-associated vasculitis (GPA/MPA), lupus nephritis, other causes of pulmonary–renal syndrome, IgA/IgA-vasculitis nephritis, thrombotic microangiopathy, and (importantly) double-positive anti-GBM/ANCA disease. Distinguishing feature: linear (anti-GBM) vs pauci-immune (ANCA) vs granular (immune-complex) IF staining.

11. Outcome / Prognosis

Survival (✔ meta-analysis PMID:38493958)

1-year patient survival: 76.2%; 1-year kidney survival: 30.2%.

Landmark prognostic cohort (Levy et al., Ann Intern Med 2001 ⚠ PMID:11712875; n=71, plasma exchange + prednisolone + cyclophosphamide)

Patients presenting with creatinine <500 µmol/L (<5.7 mg/dL): ~100% patient and 95% renal survival at 1 year (84%/74% longer-term).
Patients presenting dialysis-dependent / creatinine very high / ~100% crescents: dismal renal recovery.

Strongest prognostic factors

Baseline serum creatinine / dialysis dependence at presentation (the single most powerful predictor).
Oliguria.
Percentage of glomeruli with crescents and normal-glomeruli percentage (✔ meta-analysis: "Kidney function on diagnosis and normal glomeruli percentage were identified as strong prognostic factors").
Time from symptom onset to treatment.

For dialysis-dependent patients, only ~8% recovered independent kidney function at 1 year (recent series ~17–20%); recovery is essentially confined to those with <100% crescents, <50% glomerulosclerosis, non-oliguric, and dialysis started <72 h (NDT review ✔).

Disease course / complications

Pulmonary hemorrhage: high remission with treatment (90–100%) but acutely life-threatening.
Complications: ESRD requiring dialysis/transplant; treatment-related infection (immunosuppression), hemorrhage.
Relapse: <3% in classic single-positive disease; high in double-positive disease.

12. Treatment

The triad of plasma exchange + corticosteroids + cyclophosphamide remains standard of care; it transformed a near-uniformly fatal disease into a treatable one. Specifics below are from the 2026 NDT treatment-standard review (✔).

Standard induction

Plasma exchange (PLEX) — MAXO:0000548 (therapeutic plasmapheresis) / NCIT:C15304 (Plasmapheresis): "Daily 40–60 mL/kg exchange for 5% human albumin solution" until antibody fully suppressed, "typically 14 days." Removes circulating pathogenic IgG. (Use fresh frozen plasma replacement if pulmonary hemorrhage/recent biopsy.)
Glucocorticoids — MAXO:0000058 / NCIT:C15986 (Pharmacotherapy), agent corticosteroid: "Prednisolone 1 mg/kg/day (maximum 60 mg) orally," tapered to 20 mg by 6 weeks then off by 6 months. Suppresses inflammation.
Cyclophosphamide — MAXO:0000647 (chemotherapy/cytotoxic), agent cyclophosphamide CHEBI:4027: "2–3 mg/kg/day (ideal body weight; maximum 200 mg) orally for 2–3 months," dose-reduced in age >55 or dialysis dependence. Suppresses new autoantibody production.

Emerging / alternative agents

Rituximab (anti-CD20, B-cell depletion; NCIT:C1702): "2× 1 g at day 0 and 14 OR 375 mg/m² weekly ×4"; used when cyclophosphamide is contraindicated or in refractory disease. A 2025 review of 67 patients reported 91% patient survival, 67% kidney survival (✔). Evidence base remains limited.
Imlifidase (IdeS, IgG-degrading enzyme of S. pyogenes; NCIT term for imlifidase): "Cleaves all circulating (and potentially tissue bound) IgG at the hinge region" with onset in 2–6 h. Phase 2: 67% dialysis-independent at 6 months vs 18% historic controls; pivotal Phase 3 GOOD-IDES-02 (NCT05679401) completed recruitment, results anticipated late 2025. Dose 0.25–0.5 mg/kg single dose. Potential paradigm shift for rapid antibody clearance.

Treatment-decision rules

Treat pulmonary hemorrhage aggressively regardless of renal status: "Treatment is always recommended when alveolar haemorrhage is present, regardless of the presence or severity of kidney disease."
Dialysis-dependent with 100% crescents and no lung hemorrhage: intensive immunosuppression often withheld (futile renal recovery, high infection risk) — individualized.

Supportive / prophylactic care

Pneumocystis jirovecii prophylaxis, antifungal and peptic-ulcer prophylaxis, osteoporosis prevention during high-dose steroids/cyclophosphamide. MAXO:0000950 (supportive care).

Maintenance & transplantation

Classic single-positive disease: maintenance immunosuppression not routinely required (monophasic).
Double-positive disease: treat maintenance as for ANCA-associated vasculitis.
Kidney transplantation (MAXO:0010039 organ transplantation): delay until ≥6 months of sustained anti-GBM seronegativity; transplanting with circulating antibody risks recurrence "up to 50%," but with seronegativity recurrence is rare.

Pharmacogenomics

No validated PGx markers specific to anti-GBM; standard cyclophosphamide considerations (gonadal toxicity, fertility preservation counseling) apply.

13. Prevention

Primary prevention: no vaccine/screening (rare, sporadic). Risk-factor modification is the main lever — smoking cessation and avoiding hydrocarbon/solvent exposure, especially in HLA-DR15 carriers (e.g., after lithotripsy or in Alport transplant recipients).
Secondary prevention: early recognition of pulmonary–renal syndrome and urgent anti-GBM/ANCA serology + biopsy — the closest analog to "early detection," because outcome is time-critical.
Tertiary prevention: monitor antibody titers to confirm clearance before transplantation; treat double-positive patients with maintenance therapy to prevent relapse; infection prophylaxis during immunosuppression.
Genetic counseling: limited utility — HLA association is a risk factor, not a deterministic inherited mutation; familial recurrence is rare.

14. Other Species / Natural Disease

Taxonomy: primarily a human disease (NCBITaxon:9606).
Natural animal disease: spontaneous anti-GBM/Goodpasture-like disease is uncommon in domestic animals; isolated case reports exist in dogs and horses. The α3α4α5(IV) collagen network is evolutionarily conserved across mammals, so the antigen exists in all species.
Comparative biology: the conserved type IV collagen network and sulfilimine crosslinks (found broadly across Metazoa) underlie why rodent immunization models faithfully reproduce human disease. Orthologs: mouse Col4a3, Col4a4, Col4a5.
Zoonosis: none — autoimmune, not transmissible.

15. Model Organisms

Experimental autoimmune glomerulonephritis (EAG): the principal model — rats (WKY strain) and mice immunized with α3(IV)NC1 or GBM preparations develop crescentic GN and linear IgG deposition, recapitulating human kidney pathology. Used to define T-cell epitopes and HLA-restricted responses.
Nephrotoxic nephritis (NTN / "anti-GBM nephritis"): heterologous anti-GBM antiserum injected into rodents — a workhorse model of crescentic GN effector mechanisms (complement, neutrophils, macrophages). Caveat: models antibody effector injury, not the spontaneous loss of tolerance.
HLA-transgenic mice (DR15 / DR4 / DR1): demonstrate HLA-restricted susceptibility/protection, directly modeling the human HLA association.
Col4a3-knockout mouse (Alport model): lacks the antigen; used to study de novo anti-GBM/alloimmunity after antigen re-exposure (analogous to post-transplant Alport anti-GBM).
Model characteristics: EAG reproduces linear IF, crescents, and pulmonary involvement (variably); limitations — rodent disease is often less fulminant in the lung, and tolerance-breaking is artificially induced rather than spontaneous.
Resources: MGI for Col4a3/4/5; rat models via RGD; immunization protocols in primary EAG literature.

Key References (verify PMIDs before KB ingestion)

✔ Hellmark/Saus/Hudson et al. Identification of the α3 chain of type IV collagen as the common autoantigen in anti-basement-membrane disease and Goodpasture syndrome. PMID:8589284. — "Reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary…"
⚠ Pedchenko V, et al. Molecular Architecture of the Goodpasture Autoantigen in Anti-GBM Nephritis. N Engl J Med 2010;363:343–354. PMID:20660402. — conformeropathy / neoepitope mechanism.
⚠ Vanacore R, et al. A sulfilimine bond identified in collagen IV. Science 2009;325:1230–1234. PMID:19729652. — immune-privilege crosslink (PMC2876822).
✔ Systematic review & meta-analysis (47 studies, 2,830 patients). PMID:38493958. — incidence 0.60–1.79/million/yr; 1-yr patient survival 76.2%, kidney survival 30.2%; pulmonary hemorrhage 32.6%; ANCA 27.4%.
⚠ Levy JB, et al. Long-term outcome of anti-GBM antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033. PMID:11712875. — creatinine-stratified prognosis.
✔ Levy JB, et al. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int 2004. PMID:15458448.
✔ McAdoo SP, et al. Patients double-seropositive for ANCA and anti-GBM antibodies… Kidney Int 2017. PMID:28506760.
⚠ McAdoo SP, Pusey CD. Anti-Glomerular Basement Membrane Disease. Clin J Am Soc Nephrol 2017;12:1162. PMID:28515156 (review).
⚠ Phelps RG, Rees AJ. The HLA complex in Goodpasture's disease. Kidney Int 1999. PMID:10231356 — DRB1*15:01 risk, DRB1*07:01 protection.
⚠ Anti-GBM disease — treatment standard. Nephrol Dial Transplant 2026;41:42. — regimen, rituximab, imlifidase/GOOD-IDES-02 (NCT05679401).

Sources (URLs): - PubMed 8589284 — α3(IV) autoantigen - NEJM — Molecular Architecture of the Goodpasture Autoantigen (Pedchenko 2010) - Antibodies to α5(IV) are pathogenic — PMC5600521 - PubMed 38493958 — Epidemiology/outcomes systematic review & meta-analysis - Levy 2001 — Ann Intern Med long-term outcome - PubMed 15458448 — ANCA + anti-GBM double-positive (Levy 2004) - PubMed 28506760 — double-seropositive renal survival/relapse (McAdoo 2017) - CJASN 2017 — McAdoo & Pusey review - NDT 2026 — Anti-GBM disease treatment standard - HLA-DRB1 susceptibility — ScienceDirect/Kidney Int - Medscape — Anti-GBM Antibody Disease (HLA, demographics) - Merck Manual — Anti-GBM Disease (triggers) - Vanacore 2009 Science — sulfilimine bond (PMC2876822) - Goodpasture conformeropathy review — PMC6482832 - Alemtuzumab-related anti-GBM — PMC7573726 - OMIM 233450 — Goodpasture syndrome

Summary for KB population

The existing kb/disorders/Anti-GBM_Disease.yaml already captures the correct backbone (MONDO:0009303, α3(IV)NC1 autoantigen, HLA-DRB1*15:01, the 3-node B-cell→complement/neutrophil→crescentic-GN/alveolar-hemorrhage pathophysiology chain, and plasma exchange treatment). This report supplies the evidence to flesh it out: add the conformeropathy/neoepitope mechanism node (PMID:20660402, 8589284) with the sulfilimine immune-privilege detail (PMID:19729652); add double-positive ANCA as a distinct trajectory; add quantitative phenotype frequencies (pulmonary hemorrhage 32.6%) and outcomes (1-yr survival 76.2%/30.2%) from PMID:38493958; add cyclophosphamide, corticosteroids, rituximab, and imlifidase treatments with MAXO/NCIT/CHEBI terms and the GOOD-IDES-02 trial (NCT05679401); and add smoking/hydrocarbon/lithotripsy/alemtuzumab environmental triggers. Re-fetch and substring-verify every ⚠ PMID with just fetch-reference before adding any evidence snippet.

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Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Differential Diagnoses

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Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

Causal mechanism

Genetic risk factors

Genetic protective factors

Environmental / acquired risk factors ("second hits" that expose the cryptic antigen)

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Step 1 — The sequestered/cryptic autoantigen and its "immune privilege"

Step 2 — Conformational unmasking (the "conformeropathy")

Step 3 — Loss of tolerance and antibody production

Step 4 — Antibody binding, complement activation, effector recruitment

Step 5 — Crescent formation and tissue destruction

Causal chain (upstream → downstream)

Ontology suggestions

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

Epidemiology (✔ systematic review/meta-analysis, PMID:38493958 — 47 studies, 2,830 patients)

Inheritance

Demographics

10. Diagnostics

Serology (cornerstone)

Histopathology (definitive)

Supporting laboratory / functional

Differential diagnosis

11. Outcome / Prognosis

Survival (✔ meta-analysis PMID:38493958)

Landmark prognostic cohort (Levy et al., Ann Intern Med 2001 ⚠ PMID:11712875; n=71, plasma exchange + prednisolone + cyclophosphamide)

Strongest prognostic factors

Disease course / complications

12. Treatment

Standard induction

Emerging / alternative agents

Treatment-decision rules

Supportive / prophylactic care

Maintenance & transplantation

Pharmacogenomics

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key References (verify PMIDs before KB ingestion)

Summary for KB population