Antineutrophil cytoplasmic antibody

Antineutrophil cytoplasmic antibodies (ANCAs) are a heterogenous class of IgG autoantibodies raised against the cellular contents of neutrophils, monocytes and endothelial cells ¹. Under indirect immunofluorescence (IIF) microscopy, three ANCA staining patterns are observed, based on the varying intracellular distribution of their antigenic targets ²:

• perinuclear (p-ANCA)
  • classical antigen specificity: myeloperoxidase (MPO-ANCA), an enzyme present in neutrophil azurophilic granules and monocyte lysosomes
  • a broad array of non-MPO p-ANCA antigen specificities are described (e.g. elastase, lysozyme), each with subtle variations in IIF staining (which may class them as atypical)
• cytoplasmic (c-ANCA)
  • classical antigen specificity: proteinase-3 (PR3-ANCA), present in neutrophil azurophilic granules
  • other atypical c-ANCA antigens exist, but are poorly described and many remain largely unknown
• atypical (a-ANCA)
  • commonly demonstrates a pattern of combined perinuclear and cytoplasmic staining

ANCAs are implicated in both the initiation and amplification of vasculitic disease, due to their ability to directly activate cytokine-primed neutrophils, leading to increased neutrophil adhesion and diapedesis ^1,3. Neutrophils degranulate and become necrotic, secondary to altered apoptotic signaling as a result of ANCA binding. Inflammatory cells (e.g. neutrophils, monocytes), and more ANCA antibodies are recruited, perpetuating endothelial damage and vasculitis in a vicious cycle ^1,3.

ANCAs not directed against MPO or PR3 are commonly associated with non-vasculitic inflammatory diseases ^1,4. Diseases associated with high ANCA titer include ⁴:

• ANCA-associated vasculitides
  • granulomatosis with polyangiitis (Wegener granulomatosis): c-ANCA
  • microscopic polyangiitis: p-ANCA
  • eosinophilic granulomatosis with polyangiitis: p-ANCA
• inflammatory bowel diseases: p-ANCA > c-ANCA, often non-classical antigen specificities
  • ulcerative colitis (50-70%)
  • Crohn disease (20-40%)
• autoimmune hepatic diseases: p-ANCA > c-ANCA, non-classical antigen specificities
  • autoimmune hepatitis (type 1; 80%)
  • primary sclerosing cholangitis (70%)
  • primary biliary cholangitis (PBC) (30%)
• connective tissue disorders: p-ANCA > c-ANCA
  • systemic lupus erythematosus (20-30%)
  • rheumatoid arthritis (20-30%)
  • Sjogren syndrome
  • dermatomyositis
  • reactive arthritis
  • relapsing polychondritis
  • antiphospholipid syndrome
• drug-induced vasculitis/hepatitis/lupus: p-ANCA and/or c-ANCA
  • propylthiouracil (20%): p-ANCA, especially MPO-ANCA
  • minocycline
  • levamisole
  • sulfasalazine
  • hydralazine
  • large doses of intravenous immunoglobulin
• other vasculitides: p-ANCA > c-ANCA, non-classical antigen specificities
  • mixed cryoglobulinaemia
  • Behçet disease
  • paraneoplastic Henoch-Schönlein purpura
  • Buerger disease
• other glomerulonephritides: p-ANCA, especially MPO-ANCA
  • anti-GBM antibody-associated glomerulonephritis (30%)
  • immune complex-associated glomerulonephritis (15%)
  • post-streptococal glomerulonephritis
• infection:
  • bacterial
    • subacute bacterial endocarditis
    • bacterial respiratory tract infection
    • tuberculosis
    • leprosy
    • enteritis
    • periodontitis
  • fungal
    • fungal respiratory tract infection
    • chromomycosis
  • viral
    • HIV
    • parvovirus B19
  • parasitic
    • malaria
    • onchocerciasis
    • invasive amoebiasis
• cystic fibrosis (80%): c-ANCA > p-ANCA
• hypergammaglobulinaemia

History and etymology

ANCAs were first described in 1982 by Davies et al. in patients with segmental necrotizing glomerulonephritis and glomerulitis with polyangiitis ⁵.