What is the role of ANCAs in the etiology of granulomatosis with polyangiitis (GPA)?

Updated: Aug 31, 2021
  • Author: Christopher L Tracy, MD; Chief Editor: Herbert S Diamond, MD  more...
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The discovery of ANCAs within neutrophils in the majority of patients with GPA suggested the role of humoral autoimmunity. GPA is usually associated with the presence of diffuse staining cytoplasmic ANCA (C-ANCA) directed against serine proteinase 3 antigen (PR3-ANCA), the so-called Wegener autoantigen.

The other AAVs include microscopic polyangiitis, renal-limited vasculitis, and Churg-Strauss syndrome (allergic granulomatous angiitis), which are more commonly associated with perinuclear-staining ANCA (P-ANCA) directed against myeloperoxidase (MPO-ANCA).

A pathogenic role for PR3-ANCAs in GPA has been proposed, because PR3-ANCA is strongly associated with the disease; over 90% of GPA patients have been reported to have ANCA positivity during active disease. [13] Longitudinal observations have indicated that relapse is sometimes heralded by a rise in PR3-ANCA titers, although other studies could not confirm these results. [14, 15, 16]

Schlieben et al reported that a newborn developed a pulmonary-renal syndrome associated with transplacental passage of MPO-ANCA immunoglobulin G (IgG) from a mother with ANCA disease who developed a clinical and serologic flare of disease during pregnancy. [17]

Another argument for the pathogenic role of PR3-ANCA comes from observations that ANCA persistence after induction of remission in patients with GPA is associated with relapse. [18] Additionally, efficacy of treatment with rituximab, a B-cell depleting monoclonal antibody and, thus, an inhibitor of antibody production, supports a pathogenic role of ANCA in patients with AAV. [19, 20]

Evidence also comes from in vitro studies. The in vitro effects of PR3-ANCA described to date include activation of primed neutrophils, leading to production of reactive oxygen species, and release of lytic enzymes such as elastase and PR3, which act to promote tissue injury. [21, 22] In vitro data also demonstrate the role of complement in AAV and show that ANCAs are involved in neutrophil-endothelial cell activation. Both of these processes likely help to target the endothelium, resulting in necrotizing vasculitis. [23]

In vivo experimental studies have demonstrated a pathogenic role for MPO-ANCA in mice and rat models. MPO-ANCA induces a pauci-immune necrotizing glomerulonephritis and hemorrhagic capillaritis in these animal models. [24] Neutrophils, as well as the complement system, are necessary for lesion development. [23] Despite this in vivo evidence for a pathogenic role of MPO-ANCA in AAV-like syndromes in animal models, no definitive in vivo evidence has yet been found for PR3-ANCA. Further research is necessary to further elaborate its role in GPA.

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