At a higher level, ANCA IgG

can also cross-react with other proteins, as demonstrated clearly by the ability of anti-PR3 antibodies to recognize both plasminogen and tissue plasminogen activators, leading to retardation of fibrinolysis and increased likelihood of the development of fibrinoid necrosis within glomeruli [12]. Of the many soluble mediators implicated in ANCA vasculitis, components of the alternative complement pathway are emerging as forerunners since the elegant demonstration of protection from disease in C5 and factor-B knock-out mice [13]. Increasingly it is recognized that ANCA vasculitis in the kidney is not quite so pauci-immune as was once thought [14], while the anaphylatoxin, Belnacasan mw C5a, not only primes neutrophils for an ANCA-induced respiratory burst, but C5a receptor-deficient animals are protected for development of glomerulonephritis [15]. A central

cell in selleck screening library the development of vasculitis remains the neutrophil, as it both contains the target antigens for ANCA (PR3, MPO and LAMP-2) as well as contributing to vascular damage. PR3 and MPO are contained predominantly, but not exclusively, within azurophilic granules. Antigens become expressed at the neutrophil cell membrane following neutrophil activation and, in addition, are captured within the neutrophil extracellular traps (NETS) that contain serine proteases, MPO and chromatin [16]. PR3 and elastase containing NETs

have been detected in affected human glomeruli [17], where inefficient dismantling of these NETs may result in renal damage [18]. Engagement isothipendyl of surface target antigens by ANCA IgG leads to functional responses by the neutrophil after engagement of intracellular signal transduction pathways. The pathways involved are being unravelled and have been shown recently to include diacylglycerol kinase, important in adhesion and degranulation [19] and phosphoinositol-3-kinase-γ, important in the superoxide response and degranulation where inhibition of signalling mitigated glomerulonephritis [20]. Ultimately, interplay between ANCA IgG, chemokines and neutrophils leads to preferential recruitment of neutrophils to microvascular sites [21–23]. While monocyte/macrophages are also believed to play important roles in the development of ANCA vasculitis their precise importance has been difficult to establish, but studies continue to suggest that down-regulating their activities can be beneficial.