Antineutrophil cytoplasmic autoantibodies (ANCAs) are associated with, and are the probable cause of, a distinct form of vasculitis that can affect any organ in the body. Although small vessels are the predominant target, ANCA-associated vasculitis (AAV) can affect many different types of vessels including arteries, arterioles, capillaries, venules and veins. Immunopathologically, AAV has an absence or paucity of immunoglobulin deposition in injured vessels (pauci-immune vasculitis), compared with the more extensive deposition of immunoglobulin in immune-complex-mediated small-vessel vasculitis.1 AAV can be limited to one organ at the time of presentation (for example, lung-limited disease or renal-limited disease) or involve multiple organs. Frequent target tissues are the upper and lower respiratory tract, kidneys, skin and peripheral nerves. Onset and exacerbations induce signs and symptoms of high levels of circulating inflammatory cytokines, such as fever, arthralgia and myalgia. In addition to these nonspecific systemic inflammatory manifestations, inflammation of vessel walls causes more specific signs and symptoms of vasculitis depending on which vessels and which organs are affected, for example purpura caused by dermal venulitis; pulmonary haemorrhage caused by alveolar capillaritis; glomerulonephritis caused by glomerular capillaritis; peripheral neuropathy caused by epineural arteritis; and ocular inflammation caused by vasculitis in small vessels in the eye and orbit. In addition to vasculitis, some variants of ANCA-associated disease have extravascular necrotizing granulomatous inflammation (granulomatosis)—seemingly not arising from vascular inflammation—that most often affects the upper and lower respiratory tracts but can affect any organ.
AAV can also be classified on the basis of autoantigen specificity. In patients with vasculitis, the two best-documented autoantigen targets of ANCA are myeloperoxidase (MPO) and proteinase 3 (PR3). Classification of AAV by antigen specificity clearly shows differences in clinical presentations and outcomes, organ system involvement, patterns of extravascular inflammation, and genetic associations including HLA associations.
An important role for ANCAs in the pathogenesis of vasculitis and glomerulonephritis is supported by clinical evidence and by in vitro and in vivo experimental data. The leading theory proposes that circulating neutrophils and monocytes that have been primed by inflammatory stimuli display ANCA antigens at or near the cell surface, and that interaction of these antigens with ANCAs results in neutrophil activation and initiation of vascular inflammation. An extension of this theory proposes that primed extravascular neutrophils interact with interstitial ANCAs, causing necrotizing inflammation and resultant reactive granulomatous inflammation.
- Nature Reviews Rheumatology | 10, 463–473 | (2014) doi:10.1038/nrrheum.2014.103 | Published online 08 July 2014
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