Page 212 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

188 Constantina Yiannakis, Lorna Ward and Matthew David Morgan

Complement-Mediated Mechanisms

The presence of immune complex deposits in skin tissue of patients with vasculitic skin
lesions, and detected by electron microscopy (EM) in renal biopsy tissue in those with
ANCA-associated crescentic glomerulonephritis, suggests a role for complement-mediated
immune mechanisms in development of inflammation and glomerular damage in AAV [147].

Chen and colleagues [148] demonstrated that approximately 33% of renal biopsy samples
from patients with ANCA-associated NCGN demonstrated C3c expression. Membrane attack
complex (MAC), along with C3d and factors B and P were found in glomeruli and
microvasculature of human renal biopsy tissue [149].

Xiao and others [150] employed renal biopsy samples from patients with MPO-ANCA-
associated pauci-immune NCGN to study the various components of complement. All biopsy
samples showed MAC, factor B and C3d. Diseased glomeruli were found to express C3d and
factor B that co-localized with expression of MAC.

This, coupled with the fact that C4d was not detected in either frozen renal sections or
paraffin-fixed sections, strongly suggested that the renal damage associated with AAV was
secondary to the alternative pathway of the complement system [149].

In addition, complement deposition was associated with more severe renal disease [148].
The role of C5a, acting via the neutrophil C5a receptor (C5aR) in priming neutrophils for
ANCA activation via the alternative pathway was demonstrated by in vitro studies suggesting
that an amplification loop, comprised of C5a and neutrophil C5aR, might exist for ANCA-
mediated neutrophil activation [151, 152].
Perhaps the most convincing evidence of the role of the complement comes from animal
models where the development of vasculitis is completely blocked by complement depletion
[153]. Xiao and co-workers [152] studied the role of specific complement activation
pathways in the development of NCGN and vasculitis using wild type and knockout mice for
the common pathway component C5, the classic and lectin binding pathway component C4,
and the alternative pathway component Factor B, noting that C5 -/- and Factor B -/- deficient
mice but not C4 -/- mice were protected from disease development after injection of anti-
MPO IgG.
Their findings suggested that stimulation of neutrophils by ANCA caused release of
factors that activate complement via the alternative pathway, initiating an inflammatory
amplification loop that mediated severe necrotizing inflammation.
Inhibition of complement factor C5 protected against anti-MPO IgG-mediated NCGN
with an 80% reduction in glomerular crescent formation when anti-C5 monoclonal antibodies
were administered one day after disease induction [153].

Conclusion

The AAV comprising GPA, MPA and RLV are life-threatening diseases affecting small
to medium sized vessels with significant overlap in their non-organ specific and organ
specific features.

Current diagnosis of AAV relies on recognition of a clinical picture and supporting
evidence from radiological, immunological and histological investigations. Their highly

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