Page 211 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Classification and Pathogenicity of ANCA-Associated Vasculitis 187

AAV patients with MPO-ANCA suggesting a pathogenic role [126]. Mice deficient in IL-
17A were almost completely protected from developing GN in an anti-MPO model of
vasculitis.

T-cells are prominent at sites of inflammation in AAV particularly in the kidney where
they are the predominant infiltrating cell type [127]. Four major subtypes, Th1, Th2, Th17
and Treg, were identified in inflamed AAV tissue [128-131].

The presence of interstitial Foxp3-positive Treg predicted renal survival in patients with
MPO ANCA-associated glomerulonephritis suggesting a beneficial role in suppression of
inflammation [132].

Large populations of T cells and macrophages have been found in the granulomatous and
vasculitic lesions in AAV and studies have demonstrated the involvement of CD4+ T cells in
AAV disease manifestation, particularly effector memory T cells [133]. The theory that
CD4+ cells migrate to sites of inflammation in AAV was supported by the observation of
decreased levels of peripheral blood CD4 TEM in patients with GPA with active disease
compared to those in remission [133]; moreover, the observation that T-cell depletion is
effective in controlling disease in therapy resistant patients supports their role in inflammation
[134]. One particularly interesting population of Th cells in AAV is the frequently reported
expanded population of CD4+CD28- cells which has been associated with increased disease
severity [133, 135-139]. CD4+CD28- cells have potent effector functions and are a major
source of Th-1 type cytokine secretion, predominantly IFN? and TNF? and express perforin
and granzyme B [140].

The expansion of this cell population is driven by cytomegalovirus infection in AAV, and
was no different between AAV patients and controls matched for CMV-specific IgG
seropositivity. Further, the expansion of this population in AAV patients was associated with
a reduced number of naive helper T-cells and an increased risk of infection and mortality
[141].

B-cells are responsible for the production of ANCA and are thus vital in the pathogenesis
of AAV. Tissues affected by GPA, such as nasal lesions, contain B-cells [127, 142], and the
proportion of activated B-cells is increased in active GPA [136].

Treatment with the B-cell depleting anti-CD20 monoclonal antibody rituximab has been
shown to induce disease remission and reduce ANCA titers in AAV, supporting a role for B-
cells in the pathogenesis of the disease [143, 144]. The theory that the breakdown of the
normal mechanisms that ensure tolerance to self-antigens is important in the disease process
is further supported by the presence of autoreactive B-cells which may persist due to low
surface expression of CD19 resulting in decreased signaling strength allowing them to evade
normal tolerance mechanisms [145].

The selection and maturation of B-cells that produce anti-PR3 ANCA may occur in sites
of early granulomatous inflammation as histological examination of granulomata in GPA
show B-cell clusters closely associated with numerous PR3-positive cells [142].
The proteasome inhibitor bortezomib was studied in a murine model of AAV noting that
treatment with bortezomib was associated with MPO-specific plasma cell depletion and a
reduction in anti-MPO titers that prevented GN formation [146]. Although further
investigation into timing of treatment and adverse effects is needed, bortezomib represents an
attractive potential treatment.

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