Page 210 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

186 Constantina Yiannakis, Lorna Ward and Matthew David Morgan

endothelial transmigration but not adhesion which may increase contact with endothelium and
promote intra-vascular retention of activated neutrophils [111]. The actions of endothelial
cells inhibit the neutrophil production of superoxide and therefore granule content release
may be a more important pathogenic mechanism in AAV [82-84].

ANCA and Neutrophil Apoptosis

Neutrophil apoptosis does not normally result in the release of the intracellular contents
thus preventing inflammation. ANCA-activated neutrophils were shown to undergo
dysregulated and accelerated apoptosis which may lead to increased inflammation associated
with the release of granule contents, increased surface expression of MPO and PR3, and
macrophage-mediated uptake of ANCA opsonized neutrophils [67, 112, 113].

Cell-Mediated Immunity

Both B-and T-cells have important roles in the pathogenesis of AAV and are important in
the development of autoimmunity and the development of tissue inflammation.
The production of autoantibodies, implying a loss of self-tolerance to PR3, MPO and possibly
LAMP-2, could occur via several possible mechanisms. The presence of low levels of
specific autoantibodies (SAA) to MPO and PR3 in the healthy population has led to the
theory that ANCA form part of the natural repertoire [114]. One explanation for the non-
pathogenic nature of SAA is that compared to MPO-ANCA derived from patients with AAV,
significantly lower titers of SAA MPO are found with lower avidity suggesting that high
affinity autoantibodies underlying the autoimmune pathology of AAV may result from
dysregulation of SAA-producing B-cells. However, the precise mechanism remains unknown
and larger cohort studies are required [114]. One intriguing suggestion has been the role of
complementary peptides in the production of anti-PR3 ANCA. These peptides are produced
by the transcription and translation of the DNA complementary to the PR3 gene. The peptides
so produced generate an anti-complementary PR3 (cPR3) response which leads to an anti-
idiotype response producing anti-PR3 antibodies [115]. It has also been suggested that cPR3
shows homology with proteins from staphylococcal bacteria. T-cells specific for cPR3 have
also been identified in AAV patients [116]. T-cells are required to allow IgG subclass
switching, a process which has been shown to be essential in the pathogenesis of AAV [117].
The importance of T-cells in the disease process is further supported by the presence of high
levels of soluble IL-2 receptors and activated CD4+ cells in patient blood and sera, as well as
soluble CD4 and CD8 [118]. MPO and PR3 have been shown to promote the proliferation of
autoreactive T-cells [119-121].

Regulatory CD4+ T-cells (Treg) important in the maintenance of self-tolerance have
functional defects in patients with GPA in remission [122, 123]. The percentage of Treg cells
was found to be inversely related to the disease relapse rate in patients with GPA and was
associated with both functional and numerical defects in PR3-specific Treg cells [124]. There
has been increasing interest in the role of IL-17 producing helper T-cells (Th17) in
autoimmune disease in which higher proportions of Th17 cells were found in the peripheral
blood of AAV patients compare to controls [125] with MPO-specific Th17 cells identified in

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