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Published online before print May 22, 2003
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Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Luebeck, and Rheumaklinik Bad Bramstedt, Luebeck, Germany
Correspondence: Bernhard Hellmich, M.D., Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Luebeck, and Rheumaklinik Bad Bramstedt, Ratzeburger Allee 160, 23538 Luebeck, Germany. E-mail: hellmich{at}rheuma-zentrum.de
Key Words: Wegener’s granulomatosis • proteinase 3 • myeloperoxidase • ANCA
EDITORIAL COMMENTARY
From the first identification of antineutrophil cytoplasmic antibodies (ANCA), 20 years ago to date, growing evidence suggests that ANCA are not only a valuable diagnostic tool in entities now termed the "ANCA-associated vasculitides" [Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome] but are also pathogenic by activating neutrophils, which finally leads to endothelial cell damage and vasculitis. The first evidence for a possible role of ANCA in vasculitis arose in 1982, when Davies and coworkers [1
] from Australia reported the presence of an "antineutrophil autoantibody" in patients with necrotizing glomerulonephritis and suggested a possible link to viral infections. Two years later, Hall et al. [2
] found the same autoantibodies in four patients with unclassified vasculitis. In 1985, a group of Dutch and Danish researchers [3
] were the first to show a strong association of a distinct fluorescence type of antineutrophil antibodies termed anticytoplasmic autoantibodies and a more distinct form of vasculitis (WG), a finding that was confirmed by our group a few months later [4
]. Then it was found that certain types of small vessel vasculitides—the so-called pauci-immune vasculitides—were associated with a different fluorescence pattern, a cytoplasmic pattern (C-ANCA) in WG [5
] and a perinuclear pattern (P-ANCA) in MPA [6
]. Soon after this first period of immunodiagnostic progress, the target antigen of C-ANCA in WG, proteinase 3 (PR3; synonym, "Wegener’s autoantigen") was detected [7
, 8
], and Falk and Jennette [6
] identified myeloperoxidase (MPO) as the main target antigen of P-ANCA in MPA. To date, many studies have confirmed that testing C-ANCA plus PR3-ANCA and P-ANCA plus MPO-ANCA are major steps in proving the clinical diagnosis of one of the ANCA-associated vasculitides. In addition, the initial impression that ANCA titers correlate with disease activity has been confirmed at least partially [9
]. Thus, from a clinical point of view, there is a strong belief in the pathogenic capability of PR3- or MPO-ANCA. Therefore, over the last decade, the ANCA scientific community pushed forward the observations that ANCA participate in the pathogenesis of the associated diseases. Among the number of hypotheses describing how ANCA may cause vasculitis, the most accepted ("ANCA-cytokine-sequence theory") is based on the observations that the cytokine-induced expression of granule proteins (i.e., PR3) on the surface of neurophils and monocytes allows ANCA an interaction with surface antigens. This interaction results in an activation of neutrophils (i.e., respiratory burst, degranulation, etc.) and interaction with the endothelium, resulting in its damage [10
, 11
]. In their excellent review in the current issue of Journal of Leukocyte Biology, Rarok et al. [12
] describe the in vitro evidence for the pathogenic role of ANCA in vasculitis focusing on the neutrophil-activating capabilities of ANCA. Neutrophils play an important role in the pathogenesis of pauci-immune vasculitis (i.e., those without immune deposits in situ in contrast to the immune complex-induced forms): They predominate at the site of tissue injury (necrotizing vasculitis and granuloma), and they are the main target cell associated with the ANCA antigens. How neutrophils become activated by ANCA—in particular, which signal-transduction pathways are used—is still a matter of investigation. The authors evaluate the molecular mechanisms by which ANCA perturb neutrophils and support the concept that both parts of the immunoglobulin molecule result in a signal for leukocyte activation. ANCA signaling is most likely a consolidation of signals produced by ANCA-F(ab')2 and ANCA-Fc engagement. Furthermore, ANCA-induced signaling can synergize with arachidonic acid- and tumor-necrosis factor 
(TNF-)-signaling pathways. Increased interest in ANCA as a signaling molecule has been fueled by findings that neutrophils respond to the physical cues of ANCA by up-regulating transcription of genes such as interleukin (IL)-1ß, IL-8, cyclooxygenase 2, and differentiation-dependent gene 2 [13
]. The consequence of neutrophil activation for endothelium and tissue is an inflammatory process that becomes dysregulated. In contrast to regular uptake of apoptotic cells by macrophages, which is noninflammatory, interaction of ANCA with apoptotic neutrophils expressing PR3 enhances clearance by macrophages and induces a proinflammatory response with release of IL-1, IL-8, and TNF- [14
, 15
]. These observations may help to explain the amplification and perpetuation of inflammation associated with severe necrotizing vascular injury. Furthermore, a recent study showed the development of ANCA, albeit of undefined specificity, in rats after multiple injections of apoptotic neutrophils [16
]. So, theoretically, accumulation of apoptotic neutrophils may boost the PR3-specific autoimmune response.
Very recently, Xiao et al. [17 ], from the laboratories of Charles Jennette and Ronald J. Falk, provided evidence for the first time that ANCA can in fact be pathogenic in vivo and that this involves the activation of neutrophils. They transferred autoantibodies directed against murine MPO into recombinase-activating gene 2-deficient knockout mice, which lack functional T and B cells, and observed the development of vasculitic lesions that resemble those seen in MPA, thus fulfilling Witebsky’s postulate for autoimmunity [17 ]. In summary, we now know that a passive transfer of MPO-ANCA is sufficient to induce disease, but it remains to be discovered how the production of ANCA is triggered. Furthermore, a satisfactory animal model for PR3-ANCA-induced vasculitis has yet to be developed.
Today, these findings are of major interest with regard to new treatment modalities. The recent observation from a controlled trial that the removal of antibodies by plasmapheresis is superior to conventional immunosuppressive treatment with methylprednisolone further alienates the importance of ANCA in the development of vasculitis [18
]. In addition, the knowledge about the key role of cytokines in the pathogenesis of vasculitides has opened avenues for therapeutic interventions (e.g., TNF--blocking agents) [19
, 20
]. Finally, the effectiveness of anti-CD20 antibodies in patients with refractory WG points toward a possible role of B cells in WG, which warrants further investigation [21
].
Thus, after 20 years of extensive research, we have learned that activation of neutrophils by ANCA is central for the pathogenesis of the ANCA-associated vasculitides. In the future, a better understanding of the underlying mechanisms that lead to the generation and production of ANCA may open new ways for treatment of these formerly incurable diseases.
Received April 4, 2003; accepted April 4, 2003.
REFERENCES
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