Page 207 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Classification and Pathogenicity of ANCA-Associated Vasculitis 183

LAMP-2 which is in turn recognized by anti-LAMP-2 antibodies in pauci-immune NCGN
[62, 63], although these results have not been replicated by other researchers [64].

The development of AAV has been linked to several drug exposures, most commonly
propylthiouracil with a prevalence of ANCA expression ranging from 4% to 46% [65, 66]. D-
penicillamine, hydralazine and minocycline have also been associated with AAV occurrence.
Sulfasalazine and other similar drugs may increase autoantibody production as they induce
apoptosis which in turn increases expression of ANCA target antigen on the surface of
apoptotic neutrophils [67, 68].

ANCA Pathogenicity

Since the discovery of ANCA there has been considerable debate as to whether or not it
has a direct pathogenic role with most authors now accepting that anti-myeloperoxidase
(MPO) antibodies are pathogenic based on the results of clinical, laboratory and animal
studies. Proteinase 3 (PR3) was found to be the target antigen of the cytoplasmic-ANCA
indirect immunofluorescence pattern while MPO is the target antigen of the perinuclear-
ANCA pattern, with the specificity of PR3-ANCA and MPO-ANCA for AAV as high as 98%
[69, 70].

Clinical Evidence

The most striking clinical evidence for the pathogenicity of ANCA was the report of a
neonate developing pulmonary haemorrhage and glomerulonephritis caused by transplacental
transfer of ANCA IgG from the mother who had anti-MPO antibody positive MPA [71].
There has, however, been a lack of clear consistent evidence of a relationship between the
serum ANCA titer and disease activity [72-75]. A meta-analysis of studies investigating the
association between ANCA and disease activity found a rise in the serum ANCA titer and
persistent presence of ANCA was only modestly predictive of future disease relapse
suggesting that serial ANCA measurements had a limited utility in guiding treatment
decisions in individual patients [76]. It is possible that there are subtle changes in ANCA such
as glycosylation state or change in the predominant subclass that is related to disease activity
and is undetected by routine assays [77-79].

Animal Models of AAV

Several murine and rat models of anti-MPO AAV have been created; unfortunately to
date there has not been a suitable animal model for anti-PR3 [80]. Xiao and colleagues [81]
immunized MPO-/- mice with purified MPO to generate high avidity anti-MPO antibodies.
Granulomatous inflammation, necrotizing and crescentic glomerulonephritis, and systemic
necrotising vasculitis developed when mouse splenocytes were transferred to Rag2-/- mice or
when anti-MPO containing IgG was transferred to wild-type mice. Levels of tumor necrosis
alpha (TNF-?) were increased and renal injury enhanced when lipopolysaccharide (LPS) was

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