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 signalling 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 titre 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
- 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
- bacterial
- 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 necrotising glomerulonephritis and glomerulitis with polyangiitis 5.