Page 209 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Classification and Pathogenicity of ANCA-Associated Vasculitis 185

endothelial cells, in shear stress models employing human endothelial cells and healthy donor
neutrophils [106-108].

ANCA Extra-cellular
Space
Adhesion
O2·-
PR3 MPO NADPH
CD18 CD11b Fc?R oxidase O2
CD177
DAG Plasma
Gi DKG PtOH PIPKin membrane

NADPH

NADP+

Src Syk PLC? DAG
cPKC p21ras Cytosol

IP3 Ca2+

PI3K PIP3

Figure 1. Summary of the neutrophil intracellular signaling pathways activated by ANCA cross ligation
of MPO or PR3 and Fc? receptors. This activation results in superoxide production, degranulation and
adhesion to the endothelium. Separate pathways are activated by either interaction with the ANCA
antigens or Fc? receptors. Signaling must be induced via both pathways for full neutrophil activation
which is highlighted by the protection to development of vasculitis demonstrated in mice lacking
phosphatidylinositol-3 kinase ?.

Abbreviations: Cbl, Casitas b-lymphoma protein; cPKC, protein kinase C; DAG, diacylglycerol; DGK,
diacylglycerol kinase; Gi, G protein; IP3, inositol 1, 4, 5-triphosphate; PI3K, phosphatidylinositol
3-kinase; PIP3, phosphatidylinositol 3, 4, 5-triphosphate; PIPKin, phosphatidylinositol-4-
phosphate-5-kinase; PLC?, phospholipase C ?; PtOH, phosphatidic acid; Src, tyrosine kinase; Syk,
spleen tyrosine kinase.

An MPO-/- animal model demonstrated stimulation of neutrophil-endothelial adhesion
dependent on the action of CD18 [83].

In activated neutrophils intracellular F-actin polymerizes making the neutrophil more
rigid and less deformable which may lead to retention of neutrophils in small diameter
capillaries and increase their contact with endothelium and promote damage leading to cell
detachment and lysis [109, 110].

A recent study demonstrated reduced CXCR1 and CXCR2 expression on neutrophils
from AAV patients, even those in remission where expression showed an inverse relationship
with serum IL-8 concentrations. Reduced chemokine receptor expression impaired

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