Role Of Antineutrophil Cytoplasmic Autoantibodies Research Articles

Anti‐Neutrophil Cytoplasmic Autoantibodies: A Renewed Paradigm in Periodontal Disease Pathogenesis?

In the past, various models including the autoimmunity model have been proposed to explain the pathogenesis of periodontal diseases. The aim of this review is to introduce the pathogenic role of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in various autoimmune diseases and compare these conditions with periodontal disease to elucidate common pathogenic mechanisms. Also, a novel model to explain the pathogenesis of periodontal disease based on the concept of ANCA-associated autoimmunity is proposed. This encompasses a wide array of biochemical mediators that range from direct and indirect initiators of ANCA production and eventual release of proinflammatory mediators and free radicals, all of which have been implicated in periodontal tissue destruction in the past. In addition, specific links between the typical ANCA-associated diseases and periodontal disease are discussed. Finally, a new paradigm in the periodontal disease-associated destruction is proposed that includes the currently accepted mechanism, namely, the genetic-microbial-host interactions.

Human anti-neutrophil cytoplasm autoantibodies to proteinase 3 (PR3-ANCA) bind to neutrophils

Recently, the in vivo pathogenic role of anti-neutrophil cytoplasm autoantibodies (ANCA) in ANCA-associated vasculitis has been challenged by Abdel-Salam et al. In their report, they observed that ANCA directed against proteinase 3 (PR3) cannot bind to their target autoantigen PR3 on circulating neutrophils (PMN). Here we present evidence that human PR3-ANCA do specifically bind to PMN that express PR3 on their membrane. PMN were isolated from donors showing bimodal membrane PR3 expression on their PMN (N= 3). TNFalpha-primed PMN or PMA-stimulated PMN were incubated with serum or plasma from PR3-ANCA-positive patients with Wegener's granulomatosis (WG) (N= 8) or healthy controls (N= 8). Binding of IgG in serum or plasma samples to PMN was assessed by indirect immunofluorescence. Binding of IgG in undiluted plasma or serum from PR3-ANCA-positive WG-patients to PMN was significantly increased compared to plasma or serum from healthy controls. Dilution of plasma and serum showed concentration-dependent binding of IgG. Double staining for PR3 and IgG demonstrated that IgG in plasma or serum from PR3-ANCA-positive patients only bound to those PMN that expressed PR3, and not to PMN that lacked PR3 expression on their membrane. PR3-ANCA in undiluted serum or plasma from PR3-ANCA-positive WG patients bind to TNFalpha- primed and PMA-stimulated PMN that express PR3 on their membrane. Therefore, the hypothesis that PR3-ANCA can bind and activate primed PMN is still the most attractive explanation for the contribution of PR3-ANCA to the pathogenesis of Wegener's granulomatosis.

Occupational exposure in ANCA-positive patients: A case-control study

Antineutrophil cytoplasmic autoantibodies (ANCA) are valuable biomarkers for the diagnosis and follow-up of small vessel vasculitis. The role of ANCA has not yet been fully established, but genetic, infectious, and/or environmental factors may increase susceptibility to these diseases. We performed an epidemiologic study to investigate whether the presence of ANCA was associated with silica or any other form of occupational exposure, regardless of the underlying disease. All consecutive ANCA-positive patients recorded at the institution's Laboratory of Immunology between 1990 and 2000 were included. Patients hospitalized in a unit of internal medicine matched for age and gender were selected as controls (two controls/case). Qualitative and semiquantitative professional exposure and smoking habits were analyzed by five experts blind to the diagnosis. Univariate analysis showed that patients who reported dust exposure had a 2.6 greater risk of being ANCA-positive (P= 0.007) (odds ratio 2.6; 95% CI 1.3 to 5.3) and individuals with professional exposure to silica had a 3.4 higher risk of being ANCA-positive (P= 0.03) (odds ratio 3.4; 95% CI 1.1 to 9.9). None of the other environmental factors or smoking habits were different between ANCA-positive patients and controls. There was no difference in silica exposure between patients with cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), or atypical ANCA. Semiquantitative analysis showed a dose effect of silica exposure with a nearly sevenfold greater risk of being ANCA-positive compared to controls (P= 0.02) (odds ratio 6.9; 95% CI 1.3 to 35.1). These results support the hypothesis that the presence of ANCA in plasma might at least partially be related to occupational exposure.

Peripheral neuropathy in systemic vasculitides

Peripheral nervous system (PNS) involvement is of great diagnostic value in systemic vasculitides, because it occurs frequently and often early during the course of these diseases, despite the supposed blood-nerve barrier that should prevent or at least minimize PNS damage. However, it carries no poor prognostic value in vasculitides. Recent advances have been made in understanding the pathogenetic mechanisms of PNS involvement. Vasculitic neuropathy may result from primary or secondary systemic vasculitides, or may be restricted to the PNS, in a form that is now also considered to be a systemic vasculitis. The blood-nerve barrier is not as efficient as the blood-brain barrier. Inflammatory cell infiltration into the vasa nervorum and epineurial arteries leads to ischemic axonal nerve injury and is facilitated by additional breaches in the blood-nerve barrier, induced by proinflammatory cytokines, oxidative stress-derived molecules, and matrix metalloproteinases. Although animal models of myeloperoxidase or, now, proteinase 3-antineutrophil cytoplasmic autoantibody-inducing vasculitis have been developed, they do not support a role for antineutrophil cytoplasmic autoantibodies in PNS involvement. Treatment should be chosen based on the other organ involvement and the patient's general condition. When PNS involvement is isolated, corticosteroids alone should be used as first-line treatment. Apart from the so-called nonsystemic nerve vasculitis, PNS involvement is rarely the sole clinical sign of systemic necrotizing vasculitis, and its association with other typical manifestations is often suggestive of the diagnosis of vasculitis. Herein are summarized recent advances that have clarified but not yet fully elucidated the pathogenesis of peripheral neuropathy in systemic vasculitides, together with the latest clinical findings and therapeutic strategies.

Pathogenesis of Pulmonary Vasculitis

Vasculitis is inflammation of blood vessels and can affect any type of vessel in any organ. Pulmonary vasculitis usually is a component of a systemic small vessel vasculitis. Three major forms of small vessel vasculitis that often affect the lungs are Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. These forms of vasculitis are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA) directed against enzymes contained in the primary granules of neutrophils and peroxidase-positive lysosomes of monocytes. This review discusses the evidence for a pathogenic role of ANCA. In vitro, ANCAs can activate cytokine-primed neutrophils and monocytes resulting in oxygen radical formation and release of lysosomal enzymes. In vivo, antimyeloperoxidase ANCA has been shown to induce crescentic glomerulonephritis and systemic vasculitis. Overall, the available data suggest that ANCA are indeed a pathogenic factor in the development of small-vessel vasculitis. Antiglomerular basement membrane (anti-GBM) disease also causes pulmonary vasculitis through immune attack on alveolar capillaries and glomerulonephritis through antibody mediated injury to glomerular capillaries. Thus, there is evidence that antibodies are important pathogenic factors in both ANCA disease and anti-GBM disease, however, there are also indications that T cells may play important pathogenic roles in both categories of disease as well.

New insights into the immunopathogenesis and treatment of small vessel vasculitis of the kidney.

Glomerulonephritis is an important manifestation of small vessel vasculitides such as Wegener granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Renal involvement in these diseases is characterized by a pauci-immune segmental necrotizing and crescentic glomerulonephritis that is strongly associated with circulating antineutrophil cytoplasmic autoantibodies. We will review recent advances in understanding the pathogenesis of antineutrophil cytoplasmic autoantibody-related renal vasculitides and innovative approaches to their treatment. An experimental milestone in antineutrophil cytoplasmic autoantibody research has been reached in the past year. Using an innovative mouse model, investigators from the University of North Carolina in Chapel Hill have recently acquired robust data supporting the pathogenic role of antineutrophil cytoplasmic autoantibodies in the glomerulonephritis and small vessel vasculitis, analogous to those seen in microscopic polyangiitis and Wegener granulomatosis. Novel immunosuppressive approaches have been examined including preliminary studies using biologic agents, such as antagonists of tumor necrosis factor and monoclonal antibodies to B lymphocytes. Recent insights into the pathogenesis of antineutrophil cytoplasmic autoantibody-related vascular injury and the availability of new biologic, immune response modifiers to complement standard chemical immunosuppressive agents offer exciting new prospects for investigation in the management of patients with small vessel renal vasculitides.

Diagnostic and pathogenetic role of antineutrophil cytoplasmic autoantibodies

Anti-neutrophil cytoplasmic antibodies (ANCA) are mostly known as a useful diagnostic tool in patients with small-vessel vasculitides. With the accumulating knowledge of these autoantibodies, however, it becomes clear that the role of ANCA may not be only limited to a diagnosis of such disorders. The current review addresses, in addition to classical diagnostic associations, other diseases connected with ANCA positivity, both in adults and in children. The etiology of ANCA remains unknown, but still, the importance of both genetic and environmental factors is undoubted. The role of infection and chemicals in the etiology of ANCA-associated diseases is stressed in particular. A pathogenetic role of ANCA is suggested because of clinical observations based on the correlation of the vasculitis activity and the titer of ANCA. Many experiments show the effects of ANCA in various steps of an inflammatory process, particularly on leukocyte microbicidal activity and oxidative burst. Recent findings are analyzed in the experimental field and they are correlated with clinical significance.

Seroprevalence and disease association of antineutrophil cytoplasmic autoantibodies and antigens in HIV infection.

This prospective study was designed to determine the role of antineutrophil cytoplasmic autoantibodies (ANCA) in HIV-infected patients. Immunofluorescence tests (IFT) and enzyme-linked immunosorbent assays (ELISA) were applied to sera of 199 consecutive outpatients. In the IFT 20% were positive. An atypical ANCA pattern was demonstrated in 67% of these, 33% revealed a perinuclear staining (pANCA). Specific ELISA revealed proteinase 3 (n = 2), myeloperoxidase (n = 1), lysozyme (n = 2), lactoferrin (n = 1), cathepsin G (n = 1), and human leukocyte elastase (HLE, n = 6). The target antigen remained unidentified in 26 patients. Perinuclear ANCA-positive patients showed atypical antigens in eight of 13 cases; all six patients with anti-HLE revealed a pANCA pattern. The antigens of atypical ANCA-positive patients remained unidentified in 21 of 26 (81%) cases. No signs of vasculitis were present in the ANCA-positive patients. ANCA are frequently found in the sera of HIV-positive patients. They bind to a variety of antigens. No correlation was found between ANCA positivity and autoimmune or opportunistic diseases.

Evolving concepts about the role of antineutrophil cytoplasm autoantibodies in systemic vasculitides.

This review discusses the main issues of antineutrophil cytoplasm autoantibodies (ANCA) that have emerged from the literature. From January 1997 to August 1998, 216 papers were published on ANCA. Two major themes seem to be evolving from these articles. The first theme concerns the specificity and sensitivity of ANCA testing in clinical practice in relation to diagnosing systemic vasculitic syndromes. We focus on immunofluorescence patterns, ANCA antigens, testing methodology, and the (predictive) value of ANCA in clinical practice. Second, there is the unsolved question of how ANCA are etiologically involved in the development of the vasculitic lesion. Ongoing research questions the role of ANCA in stimulating granulocytes, monocytes, and the endothelium.

Antineutrophil cytoplasmic autoantibodies interact with primary granule constituents on the surface of apoptotic neutrophils in the absence of neutrophil priming.

The pathogenic role of antineutrophil cytoplasmic autoantibodies (ANCA) remains controversial because of the difficulty in explaining how extracellular ANCA can interact with intracellular primary granule constituents. It has been postulated that cytokine priming of neutrophils (PMN), as may occur during a prodromal infection, is an important trigger for mobilization of granules to the cell surface, where they may interact with ANCA. We show by electron microscopy that apoptosis of unprimed PMN is also associated with the translocation of cytoplasmic granules to the cell surface and alignment just beneath an intact cell membrane. Immunofluorescent microscopy and FACS analysis demonstrate reactivity of ANCA-positive sera and antimyeloperoxidase antibodies with apoptotic PMN, but not with viable PMN. Moreover, we show that apoptotic PMN may be divided into two subsets, based on the presence or absence of granular translocation, and that surface immunogold labeling of myeloperoxidase occurs only in the subset of PMN showing translocation. These results provide a novel mechanism that is independent of priming, by which ANCA may gain access to PMN granule components during ANCA-associated vasculitis.

The Pathogenic Role of Antineutrophil Cytoplasmic Autoantibodies

Antineutrophil cytoplasmic autoantibodies (ANCA) are found in the sera of patients with systemic necrotizing vasculitis and glomerulonephritis. Their role in the pathogenesis of these diseases is not clearly understood; however, there is a growing body of data that supports a pathogenic function for these antibodies. In vitro they can activate neutrophils and monocytes to produce reactive oxygen species (ROS), degranulate, and damage target cells. The antigens to which they are directed stimulate T lymphocytes from patients with these diseases. The ANCA directed against proteinase 3 (PR3) may also play a role in growth regulation of monocytes by inactivating the enzymatic function of its antigen. The proposed model of ANCA-induced disease takes into account both the in vitro data and the natural history of these diseases.