The interaction between the activated alternative complement pathway, neutrophils and C5a is at the heart of vasculitic damage in AAV.1
AAV pathogenesis
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
ANCA involvement
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
Necrotising vasculitis
This process leads to necrotising vasculitis in small blood vessels6
Chronic inflammation
Over a few days, acute inflammation and necrosis are replaced by chronic inflammation and scarring6
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The three pathways of complement activation (classical, lectin and alternative) result in the formation of C3a, C3b, C5a and C5b-91
The alternative complement pathway is constantly ticking over through the spontaneous breakdown of C3 to C3b.2 It is the dysregulation of this pathway that is relevant in AAV1
C5 convertase formed during the amplification loop cleaves C5 into C5a and C5b1
C5b combines with complement components C6, C7, C8 and C9 to form C5b-9, also known as the terminal complement complex or membrane attack complex1
C5b-9 is needed for host resistance to encapsulated bacterial infections, such as Neisseria meningitides1,3
C5a is the downstream terminal effector molecule in the complement cascade and a potent pro-inflammatory mediator critical in AAV1,4
Binding of C5a to C5aR1 results in two key events that act in a vicious cycle to amplify ANCA-induced inflammation and vascular damage:1,4,5
Rapid induction of the expression of adhesion molecules on the cell surface that causes leukocyte chemotaxis1
Further exposure of ANCA antigens at the neutrophil cell surface facilitates subsequent neutrophil activation5
New data suggest C5aR1 plays a role in promoting autoimmunity to ANCA antigens and increasing ANCA production6
C5a also mediates inflammation by stimulating vascular permeability, neutrophil degranulation, and release of lysosomal proteases and oxidative free radicals1,7
C5L2 activation does not play a role in AAV; in other conditions, it has a currently unclear pattern of pro- and anti-inflammatory actions1,8
C5a is rapidly degraded by removal of the C-terminal arginine, forming C5a des Arg with approximately 10-fold reduced activity on C5aR11,9
C5a des Arg binds with high affinity to the C5L2 receptor, and is subsequently internalised and degraded1,10
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.
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