The interaction between the activated alternative complement pathway, neutrophils and C5a is at the heart of vasculitic damage in AAV.1
The development of AAV is a complex and multifactorial autoimmune process2,3
The initial causes of AAV are currently unclear.2,3 Predisposing factors such as microbial infection, genetic influence, environmental agents and specific drugs are all fundamental to the development of AAV.2,3
Exposure to silica, pesticides, fumes, construction materials, hydrocarbon (cleaning agents, paint, diesel), drugs (propylthiouracil, hydralazine, D-penicillamine, cefotaxime, minocycline, anti-TNF agents, phenytoin) and certain psychoactive agents may all cause AAV.2,3
Loss of immune tolerance to ANCA antigens and development of ANCA by plasma cells1
ANCA are most commonly directed against the neutrophil lysosomal enzymes PR3 and MPO in GPA and MPA, respectively1-5
Neutrophils are primed
Neutrophils are primed by inflammatory cytokines (TNF-α, IL-1 and IL-18) produced in response to an infection or another event, with genetic predisposition also relevant2,6,7
ANCA antigens presented
Primed neutrophils present ANCA antigens (e.g. MPO and PR3) at their cell surface that bind to ANCA, resulting in neutrophil activation1,2,6,7
Inflammation mediators released
Activated neutrophils adhere to and penetrate the blood vessel wall, and release mediators of inflammation and cell injury, e.g. NETS1,2,6
Alternative complement pathway activated
Activated neutrophils also release factors such as properdin that have an autocrine role in activating the alternative complement pathway, leading to the generation of C5a1,6
Binding of C5a to C5aR1
Binding of C5a to C5aR1 amplifies ANCA-induced inflammation and vascular damage6
This process leads to necrotising vasculitis in small blood vessels6
Over a few days, acute inflammation and necrosis are replaced by chronic inflammation and scarring6
Hutton HL, et al. Semin Nephrol 2017;37(5):418–35.
Bekker P, et al. PLoS One 2016;11(10):e0164646.
Little MA, et al. Ann Rheum Dis 2010;69(6):1036−43.
Rutherford P, et al. Patient experience in ANCA-associated vasculitis evolves over time from diagnosis and both benefits and adverse impacts are felt with current therapy. Poster presented at: ACR/ARHP 2018, 19–24 October 2018, Chicago, IL, USA (abstract 2723).
Rutherford P, et al. Arthritis Rheumatol 2018(Suppl 10[Abstract 2723]).
Robson JC, et al. Rheumatol Int 2018;38(4):675–82.
This website is educational, non-promotional and intended for healthcare professionals practicing outside of the United States.
For more information contact firstname.lastname@example.org. HQ-AVA-2000105 / Last updated: November 2020