Elsevier

Journal of Autoimmunity

Volume 30, Issues 1–2, February–March 2008, Pages 29-36
Journal of Autoimmunity

Review
Pathogenesis of PR3-ANCA associated vasculitis

https://doi.org/10.1016/j.jaut.2007.11.005Get rights and content

Abstract

Wegener's Granulomatosis (WG) is closely associated with antineutrophil cytoplasmic autoantibodies (ANCA), particularly those directed to proteinase 3 (PR3). ANCA directed to myeloperoxidase (MPO) are associated with microscopic polyangiitis (MPA) and the Churg Strauss syndrome. PR3-ANCA associated vasculitis differs from MPO-ANCA associated vasculitis particularly in the occurrence of granulomatous inflammation and more widespread disease in the former condition. Studies in experimental animals strongly suggest a pathogenic role for MPO-ANCA, but this is less clear for PR3-ANCA. Here, we review pathogenic pathways in PR3-ANCA associated vasculitis focussing on unique patterns of PR3 expression on the neutrophil membrane in WG, as surface expression of PR3 is a prerequisite for stimulation by PR3-ANCA; (PR3-specific) cellular immunity in WG; and the role of Staphylococcus aureus carriage in this disease. These factors, together, may explain, at least in part, differences in clinical expression between MPO-ANCA and PR3-ANCA associated vasculitis.

Introduction

The antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides comprise a group of diseases characterized by necrotizing vasculitis of small vessels with frequent involvement of the kidneys, lack or paucity of immune deposits in the vessel wall, and presence (in the majority of cases) of autoantibodies to neutrophil constituents, in particular myeloperoxidase (MPO) and proteinase 3 (PR3) [1]. Disease entities in this group are Wegener's Granulomatosis (WG), microscopic polyangiitis (MPA) and its renal limited form, and the vasculitic variant of Churg Strauss syndrome (CSS) [1], [2].

MPA and “vasculitic” CSS are primarily associated with ANCA directed to MPO (MPO-ANCA), whereas WG is primarily associated with ANCA directed to PR3 (PR3-ANCA) [1], [2]. PR3-ANCA associated vasculitis clearly differs in its clinical presentation from MPO-ANCA vasculitis [3]. Patients with PR3-ANCA have, in comparison with patients positive for MPO-ANCA, more organs involved, a faster decline in renal function, more frequent relapses of the disease, and, particularly, granulomatous necrotizing inflammation in the airways [3]. PR3-ANCA vasculitis shares necrotizing small-vessel vasculitis, manifested in the kidney as necrotizing crescentic glomerulonephritis, with MPO-ANCA vasculitis. Nevertheless, these observations suggest that the pathogenetic pathways involved in PR3-ANCA vasculitis differ from those in MPO-ANCA vasculitis. Studies in experimental animals have shed light on the pathogenesis of MPO-ANCA vasculitis and suggest that MPO-ANCA are directly involved in its pathogenesis [4]. In PR3-ANCA vasculitis, many questions as to the pathogenetic role of PR3-ANCA are still open. In this review I will briefly discuss current thoughts about the pathogenesis of MPO-ANCA vasculitis. I will more extensively discuss current views on the pathogenesis of PR-ANCA associated vasculitis, in particular Wegener's Granulomatosis, as a clear unifying view on this latter condition is still lacking.

Section snippets

Pathogenesis of MPO-ANCA vasculitis

As mentioned, MPO-ANCA vasculitis is characterized by necrotizing small-vessel vasculitis, particularly including kidneys and lungs but other organ systems may be involved as well. In the right clinical context their specificity for small-vessel vasculitis is high (98.6% [5]) although MPO-ANCA have been described in patients with other systemic autoimmune inflammatory diseases such as SLE, rheumatoid arthritis, scleroderma and inflammatory bowel disease, as well as during use of antithyroid

Pathogenesis of PR3-ANCA vasculitis

Whereas MPO-ANCA associated microscopic polyangiitis is characterized by necrotizing leukocytoclastic small-vessel vasculitis, PR3-ANCA associated WG demonstrates, besides small-vessel vasculitis, granulomatous inflammation, particularly in the airways [3]. This suggests that, besides autoantibodies, cellular immune mechanisms are operative in this disease as well. What evidence is currently available for a pathogenic role of the PR3-directed immune response in WG?

In vivo evidence for a pathogenic role of PR3-ANCA

Original studies in patients with WG showed a high sensitivity (93% in active disease) and specificity (97%) of c-ANCA in this disease [9], [10]. Rising titers of c-ANCA were shown to predict a relapse of the disease [10] and pre-emptive treatment with cyclophosphamide and steroids based on rising titers of c-ANCA was able to prevent the occurrence of relapses (9 out of 11 patients relapsing without pre-emptive treatment, no relapses in the 9 patients with pre-emptive treatment) [11]. Others,

Neutrophil activation by PR3-ANCA

PR3-ANCA in vitro are able to activate neutrophils to produce reactive oxygen species and release lytic enzymes such as elastase and PR3 itself. In order to get activated by PR3-ANCA, neutrophils must be in a state of pre-activation called “priming” (Table 1). During priming PR3 is expressed on the cell surface and available for interaction with PR3-ANCA. Different scenarios have been proposed in order to explain how neutrophils are activated by PR3-ANCA and which signal transduction pathways

In vivo experimental evidence for a pathogenic role of PR3-ANCA

In analogy to the model of MPO-ANCA associated vasculitis in mice [7], Pfister et al. have tried to develop a comparable model for PR3-ANCA associated vasculitis [23]. They immunized PR3-deficient mice with recombinant murine PR3. Immunized mice developed anti-mouse PR3 antibodies that were able to recognize mouse PR3 on the surface of mouse PMN. Passive transfer of the IgG fraction of immunized mice, containing anti-mouse PR3 antibodies, did, however, not result in vasculitis in kidneys or

Cellular immunity in PR3-ANCA associated vasculitis

As mentioned granulomatous inflammation in PR3-AAV suggests the involvement of cellular immunity. Indeed, activated T-cells, both CD4+ and CD8+, are present in the peripheral blood of patients with PR3-AAV, both during active disease as during remission (although to a lower extent) [26]. Th1 CD4-positive T-cells predominate although conflicting results have been reported [27]. More recent studies have shown that, particularly, effector memory CD4-positive T-cells, characterized as being CD45

Staphylococcus aureus and PR3-ANCA associated vasculitis

Stegeman et al. were the first to describe the association between nasal carriage of S. aureus and the occurrence of relapses of PR3-AAV [33]. Nasal carriage of S. aureus proved a strong risk factor (relative risk 9.0) for relapse. Furthermore, prophylactic treatment with co-trimoxazole resulted in a 60% reduction in relapses [34]. Mechanistically, the role of S. aureus carriage can be explained in different ways (Fig. 5). Carriage may induce low-grade infection in the upper airways resulting

Conclusion

Experimental studies have convincingly shown the pathogenic role of anti-MPO autoantibodies in MPO-ANCA associated vasculitis. This is less clear for anti-PR3 autoantibodies. PR3-ANCA associated vasculitis differs from MPO-ANCA vasculitis by the predominance of granulomatous lesions. Current data demonstrate that, besides autoantibodies, cellular immunity plays an important role in the pathogenesis of PR3-ANCA associated vasculitis, in particular Wegener's Granulomatosis. In addition, carriage

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