Antineutrophil cytoplasmic autoantibodies, autoantigens, and systemic vasculitis

Abstract

Antineutrophil cytoplasmic antibodies (ANCA) encompass a heterogeneous group of autoantibodies targeting antigens in neutrophils (PMN), monocytes, and endothelial cells. ANCA are routinely detected by the indirect immunofluorescence technique (IFT) and at least three different patterns of fluorescence can be distinguished which have been assigned the acronyms cANCA, pANCA and aANCA. cANCA is mostly induced by proteinase 3 (PR3) antibodies (PR3‐ANCA), and pANCA by myeloperoxidase (MPO) antibodies (MPO‐ANCA), while aANCA has unidentified subspecificity. Over the past decade, ANCA have been the subject of extensive investigation. They have proved to be of significant value both as diagnostic tools and for follow‐up in several forms of systemic vasculitis (e.g. Wegener's granulomatosis, WG; microscopic polyarteritis, MPA; Churg‐Strauss syndrome, CSS) which are now termed ‘ANCA‐associated vasculitides’. Furthermore, it is suspected that the presence of ANCA is an important factor in the pathogenesis of these disease groups. Data regarding the detection of ANCA and their diagnostic value and role in the pathogenesis of vasculitic disorders will be discussed in this review. Growing evidence points to a pathophysiological and diagnostic relevance of the distribution of the ANCA target antigens PR3 and MPO (presence in the circulation, on cellmembranes, and in tissue extracellularly). An autoimmune process has been implicated in the pathogenesis of ANCA‐associated vasculitis, but it is uncertain which mechanism underlies the induction of the ANCA‐related immunoresponse. In this paper mechanisms such as antigenic cross‐reactivity between human PMN proteins and extrinsic antigens by molecular mimicry, idiotypic immunoglobulin regulation, and T‐cell reactivity to PR3 and MPO will be discussed.

Recombinant human proteinase 3, the Wegener's autoantigen, expressed in HMC‐1 cells is enzymatically active and recognized by c‐ANCA

“…The data confirm that routine c-ANCA testing by IIF using neutrophil substrates may detect cytoplasmic fluorescence even in patients without any ANCA associated disease [10,15]. The two sera for which this was the case did not contain antibodies against PR3 as indicated by the test results using HMC-1/PR3 cells as substrate.…”

“…emphysema [4,9] and Wegener's granulomatosis (WG) [10]. WG is a specific form of vasculitis associated with circulating anti-neutrophil cytoplasmic autoantibodies directed against PR3 (c-ANCA) [3].…”

“…WG is a specific form of vasculitis associated with circulating anti-neutrophil cytoplasmic autoantibodies directed against PR3 (c-ANCA) [3]. The interaction of c-ANCA with PR3 exposed on the surface of cytokine stimulated neutrophils is felt to be significant for the pathogenesis of the disease [10].…”

Recent Advances in the Diagnosis of Churg-Strauss Syndrome

“…CSS is associated with a positive ANCA in some reports in as many as 70% of cases (10 -15); this is usually p-(myeloperoxidase) ANCA, although c-ANCA-positive patients have also been reported, and sometimes the proportion of positive cases is much smaller (see Reference 11). Microscopic polyangiitis, one of the morphologic differentials of CSS, is also typically p-ANCA positive in about 40 -80% of cases, whereas Wegener's granulomatosis, another morphologic differential, is generally c-(proteinase 3) ANCA positive, in some studies in up to 90% of cases (11)(12)(13)(14)(15)). There appears to be a consensus that a properly performed ANCA test, which must include an ELISA to show proteinase 3 or myeloperoxidase specificity, provides strong support for a diagnosis of CSS, even if overt vasculitis cannot be found.…”

“…Systemic vasculitides of this type can progress rapidly, and some argue that on this basis, the vasculitic phase should always be treated with both steroids and cyclophosphamide (5). The role of serum ANCA in monitoring disease activity is presently a controversial topic (11)(12)(13)(14)(15).…”