Wegener's granulomatosis (WG) is a form of systemic vasculitis that predominantly affects small- and medium-sized blood vessels. Frequently commencing with general, aspecific symptoms, the disease is frequently hallmarked by the presence of autoantibodies (anti neutrophil cytoplasmic antibodies [ANCA]) [1,2] directed predominantly against the myeloid enzyme proteinase 3 (in 80% of WG patients) and, in a minority of cases, against myeloperoxidase [3,4]. Manifestations of granulomatous inflammation in the upper and lower airways, vasculitis and necrotizing glomerulonephritis characterize the classical clinical picture of WG [5].

In WG, respiratory tract infections frequently precede or accompany initial symptoms [6,7]. Moreover, treatment of WG limited to the airways with the antibiotic co-trimoxazole often leads to achievement of stable remission [8] and prophylactic treatment with this drug reduced the incidence of disease relapses [9]. Although the beneficial effect of co-trimoxazole may also be explained by its immunosuppressive effect [10] and although a bacterial agent was originally not pinpointed [9,11], these findings were taken as indications that bacterial infections may be essentially implicated in the pathogenesis of WG. In search of a specific pathogenic bacterial agent we have shown that chronic nasal carriage of Staphylococcus aureus is approximately three times higher in WG patients than in healthy individuals [11], which may, at least in part, be due to hospitalization and/or immunosuppressive treatment. In contrast to healthy individuals who are frequently exposed to S. aureus (e.g. hospital personnel), but for whom carriage of this bacterium remains inconsequential, in WG patients S. aureus constitutes a risk factor for disease exacerbation [11]. This may possibly be due to a dysregulated immune system and frequent nasal lesions present in these patients. Thus, these data ask for exploration of the potential mechanisms mediating staphylococcal pathogenicity. Recently obtained data supporting various pathogenic mechanisms related to S. aureus will be reviewed below.

In vitro and in animal models S. aureus acts as a potent immunostimulator, effecting polyclonal proliferation of T and B cells, secretion of immunoglobulins, and cytokine production. The main influence of S. aureus on immunocompetent cells is exerted by its exotoxins. Three classes of staphylococcal exotoxins have been described so far: the staphylococcal enterotoxins, exfoliative toxins, and the toxic-shock-syndrome-toxin-1 (TSST-1) [12]. Based on their exceptionally strong capacity to stimulate T cells in a non antigen specific way, exotoxins were termed 'super-antigens' (SAg) [13]. Moreover, staphylococcal protein A (SpA), a common component of the staphylococcal cell wall, has been recognized as a B-cell SAg [14].

In patients with S. aureus-associated glomerulonephritis, high levels of circulating immune complexes are present which decrease during antibiotic treatment [22,23]. These findings raise the possibility that specific staphylococcal molecules may be nephritogenic. One of these molecules is the cationic acid phosphatase, SAcP [24], which has a high affinity for the glomerular basement membrane and can induce glomerulonephritis when perfused in the kidney of naïve rats [25] or rats immunized with SAcP [26]. Based on these data, we hypothesized that, in WG, SAcP may act as a planted antigen by binding to glomerular basement membrane and vascular endothelium, thus initiating glomerulonephritis and vasculitis. We found that SAcP can bind to human umbilical vein endothelial cells and glomerular endothelial cells in vitro [27] in a charge-dependent manner, since binding can be blocked by the negatively charged heparin. Moreover, sera of WG patients were able to bind SAcP bound to endothelial cells in vitro [27]. Together with our finding that antibodies to SAcP are present in WG patients who are S. aureus carriers, these data suggest that, in vivo, the presence of SAcP in conjunction with anti-SAcP antibodies may be nephritogenic and vasculitogenic in WG patients. Moreover, in the presence of SAcP–anti-SAcP immune complexes in the kidney, ANCA may be able to aggravate glomerulonephritis, as suggested by our studies on the effect of myeloperoxidase-specific autoantibodies on anti-glomerular-basement-membrane-mediated glomerular injury in the rat [28].

To date, despite clinical evidence suggesting that S. aureus may be implicated in the pathophysiology of WG, laboratory investigation of the possible mechanisms by which S. aureus is involved in WG is still scarce. Besides staphylococcal SAg and SAcP, which have received some attention, other staphylococcal molecules, such as hemolysins, teichoic acid, proteoglycans and DNA-containing CpG motifs, to name only a few, are currently known as immunomodulators and certainly deserve further investigation in the context of vasculitis. Moreover, there are ample in vitro and in vivo data available on the effect of S. aureus on immunocompetent cells, such as B and T cells, monocytes and neutrophillic granulocytes, but also on other cell types, such as endothelial and epithelial cells. Keeping in mind that in WG, immune dysbalance can eventually lead to vascular damage, S. aureus as a trigger and mediator of various pathophysiologic mechanisms is a very attractive target for investigation.

ANCA = anti neutrophil cytoplasmic antibody; SAcP = staphylococcal acid phosphatase; SAg = superantigen; SpA = staphylococcal protein A; TCR Vβ = T-cell receptor V-beta chains; TSST = toxic-shock-syndrome-toxin; WG = Wegener's granulomatosis.