ANCA-Associated Vasculitides—An Update

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are characterized by destruction of small vessels, granulomatous inflammation of the respiratory tract and necrotizing glomerulonephritis. This review describes the clinical diagnosis and therapy as well as the patho-physiology of ANCA-associated vasculitides with a specific focus on the interplay of ANCAs with activated neutrophils and the deleterious pathophysiological consequences of neutrophil-endothelium interaction.

Share and Cite:

Kegel, J. and Kirsch, T. (2014) ANCA-Associated Vasculitides—An Update. Health, 6, 1767-1779. doi: 10.4236/health.2014.614209.

1. Introduction

Vasculitides are defined by the presence of inflammatory leukocytes in vessel walls with reactive damage to mural structures. This leads to the loss of vessel wall integrity, compromise of the lumen with downstream tissue ischemia and necrosis. Vasculitis may occur as a primary auto-inflammatory process or may be secondary to another underlying disease such as inflammatory bowel disease, rheumatoid arthritis, neoplasia or viral infections [1] [2] . Classically, the vasculitides have been categorized by the sizes and types of blood vessels most commonly affected leading to a distinction between large-, medium sizedand small vessel vasculitis [3] . The presence or absence of anti-neutrophil cytoplasmic antibodies (ANCA) is an addition to proposed classification criteria [4] . Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) comprise granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome). These diseases are characterized by Pauci-immune necrotizing small-vessel vasculitis and glomerulonephritis, combined with granulomatous inflammation, particularly in the airways, in GPA and EGPA [5] . The annual incidence of AAV as a group is 10 - 20/million/year with regional differences. In northern Europe including Germany GPA is more common whereas in Southern Europe MPA has a higher occurrence [6] . The peak incidence is at 65 to 74 years of age, with a greater incidence in men, and the mortality ratio is 2.6 compared to the general population with most deaths related to infection due to the immunosuppressive therapy [7] [8] .

2. Classification of Granulomatosis with Polyangiitis

In January 2011 the Boards of Directors of the American College of Rheumatology, the American Society of Nephrology, and the European League against Rheumatism recommended that the name Wegener’s granulomatosis be changed to granulomatosis with polyangiitis, abbreviated as GPA [9] . The hallmark of GPA is a necrotizing granulomatous inflammation of the upper and/or lower respiratory tract, systemic small-vessel necrotizing vasculitis and necrotizing glomerulonephritis in conjunction with the occurrence of ANCA directed to the neutrophils’ proteinase 3 (PR3).

3. ACR Criteria

The 1990 ACR criteria include:

• Nasal or oral inflammation (painful or painless oral ulcers or purulent or bloody nasal discharge);

• Abnormal chest radiograph showing nodules, fixed infiltrates or cavities;

• Abnormal urinary sediment (microhematuria or red cell cast);

• Granulomatous inflammation on biopsy of an artery or perivascular area.

It should be noted that these criteria have less value in separating MPA from GPA [10] .

4. Chapel Hill Consensus Conference Criteria (CHCC)

According to the 1992 Chapel Hill Consensus Conference Criteria GPA, MPA and CSS are distinguished from other vasculitides by the absence of immune deposits. The potential value of ANCA serology was noted but not included as a criterion for diagnosis. GPA is characterized by [11] :

• Granulomatous inflammation involving the respiratory tract;

• Necrotizing vasculitis affecting small to medium-sized vessels;

• Necrotizing glomerulonephritis is common.

5. Clinical Presentation, Diagnosis and Therapy

Reliable and validated diagnostic criteria for ANCA-associates vasculitides are still not available, although a large prospective international study aimed at establishing these criteria (Diagnosis and Classification of Vasculitis Study [DCVAS]) is underway. [12] Patients often present with prodromal symptoms such as fever, migratory arthralgias, malaise, anorexia and weight loss. These might last for weeks or months without the evidence of specific organ involvement listed in Table 1 [13] -[19] .

The clinical presentation may be a first hint towards the diagnosis of GPA. Routine laboratory tests should be performed. Common abnormalities include leukocytosis, thrombocytosis, an elevation in the erythrocyte sedimentation rate and C-reactive protein levels and normochromic, normocytic anemia [16] . Approximately 90% of patients with active, generalized GPA are ANCA-positive. In limited forms of the disease ANCA may only be

Table 1 . Organ manifestation of Granulomatosis with polyangiitis. 

found in 60%. Thus a positive ANCA test strongly suggests the diagnosis of vasculitis but the absence of ANCA does not exclude the diagnosis of GPA [20] . Serum-creatinine, a calculated estimated filtration rate and a urine analysis help to determine the presence of kidney injury. A chest x-ray and CT disclose pulmonary lesions.

The diagnosis should be confirmed by a tissue biopsy at a site of active disease. Biopsies are most commonly obtained from the kidney or skin and less commonly from the nose or the lung. Therapy of GPA has two components: The induction of remission and maintenance immunosuppressive therapy to prevent relapse. The standard of care for patients with organ-threatening disease is cyclophosphamide in combination with glucocorticoids, although two randomized studies have shown that rituximab was as effective as cyclophosphamide in inducing remission of patients with newly diagnoses or relapsing GPA [21] [22] . Maintenance therapy includes methotrexate, azathioprine, leflunomide, mycophenolate mofetil, and in refractory cases also IVIg, infliximab and anti-thymocyte globulin [23] .

6. Pathophysiology of GPA

Both innate and adaptive immune mechanisms are involved in the pathogenesis of GPA. There are several hints that the antigen-driven immune response is initiated in the upper respiratory tract with involvement of endonasal B cells [24] [25] .

In a first step macrophages are stimulated by microbial products in a Toll-like receptor way to release proinflammatory cytokines [5] . Tadema et al. demonstrated increased expression of Toll-like receptors by monocytes and natural killer cells of patients with GPA. [26] Cytokines then prime and activate neutrophils to release Proteinase-3 and endothelial cells to express adhesion molecules, thus recruiting inflammatory cells like monocytes and macrophages. These cells, in response to TLR ligands, secrete more proinflammatory cytokines, including interleukin 23, driving T-cells towards a T helper cell 17 phenotype. Secreted IL-17 then attracts neutrophils and stimulates granuloma formation. Neutrophils adhere to the endothelium and release the auto-antigen PR3. IL-21 derived from follicular T helper cells and B-cell activating factor (BAFF) released from activated neutrophils activate B-cells to produce PR3-ANCAs. PR3-ANCAs then fully activate primed neutrophils resulting in degranulation and the production and release of reactive oxygen species leading to leukocytoclastic vasculitis. PR3-ANCA formation is perpetuated by the lack of function of regulatory T cells (Treg) and regulatory B cells (Breg) [5] . Treg cell frequency is increased in patients with active disease, but the Treg cells have a decreased suppressive function. These patients also carry CD4+ T cell populations that are resistant to Treg cell suppression and produce inflammatory cytokines [27] . In GPA an expansion of CD4 T cells occurs in the CD4+ effector memory population. The generation of CD4 TEM cells requires a strong and persistent trigger, suggesting that, also during remission, T cells in GPA are in a persistent state of ongoing immunological trigger [28] . At the functional level CD4+ TEM cells mimic NK cells by their cytotoxicity and surface expression of NKG2D [29] . One of the NKG2D ligands is the major histocompatibility complex class I chain-related molecule A (MICA), which is absent on normal cells, but expressed upon cellular injury and stress [30] .

The formation of granulomatous lesions differs from T cell mediated granulomatous inflammation known from tuberculosis or sarcoidosis. Here the initial step is the formation of a micro-abscess by neutrophils due to neutrophil activation by ANCA and accumulation in the extravascular tissue. This tissue injury leads to an immune response attracting monocytes. They transform into macrophages, which in turn recruit T-cells [31] . It has been speculated that local antigen presentation is maintained by such macrophages [32] . Consistent with these findings, a purulent neutrophil reaction with the formation of micro-abscesses is present in respiratory tract lesions of initial GPA [33] . Furthermore, granulomatous lesions in GPA contain clusters of PR3 surrounded by antigen-presenting cells, Th1-type CD4+CD28− T cells, maturing B and plasma cells suggestive of a neoformation of lymphoid like structures in GPA [34] .

7. Characteristics of ANCAs

It was in 1985, when the presence of antineutrophil cytoplasmic antibodies (ANCA) was linked to Granulomatosis with Polyangiitis for the first time [35] . Within several years, a relationship among ANCA, GPA, microscopic polyangiitis (MPA), and “renal-limited” vasculitis (pauci-immune glomerulonephritis without evidence of extra-renal disease) had been established [36] [37] . When incubated with ethanol-fixed human neutrophils, two major ANCA immunofluorescence patterns are observed. With the C-ANCA pattern, the staining is diffuse throughout the cytoplasm. In most cases, antibodies directed against PR3 cause this pattern [38] , but MPOANCA can occasionally be responsible. The perinuclear or P-ANCA pattern results from a staining pattern around the nucleus, which represents an artefact of ethanol fixation. Among vasculitis patients, the antibody responsible for this pattern is usually directed against MPO (and only occasionally PR3) [36] . Indirect immunofluorescence has a high sensitivity whereas enzyme-linked immunoassays have a higher specificity. Specific ELISAs for antibodies to PR3 and MPO are commercially available, and should be part of any standardized approach to the testing for ANCA [39] .

PR3, also called myeloblastin, is specifically expressed by neutrophils and monocytes and belongs to the neutrophil serine protease family. It is classically localized in azurophilic granules with its homologs: elastase, cathepsin G and azurocidin. After phagocytosis of pathogens, PR3 is secreted in the phagolysosome to exert its microbicidal function [40] . Upon priming neutrophils express PR3 on their surface, usually in co-expression with CD177 although CD177 independent ways of expression have been described [41] [42] .

The question whether ANCA themselves play a pathogenic role in the development of vasculitis has been discussed extensively. Mice injected with anti-MPO developed focal necrotizing crescentic glomerulonephritis [43] [44] . Chimeric mice with a human immune system also exhibited clinical and histological signs of systemic vasculitis affecting the kidneys and lungs after injection of anti PR3 containing IgG [45] . Transfusion of anti MPO containing blood via the cord can induce pulmonary hemorrhage and kidney involvement in a neonate [46] . Epigenetic changes associated with gene silencing of the ANCA auto-antigen-encoding genes and inappropriate expression of PR3 and MPO in ANCA vasculitis indirectly support a pathogenic role for ANCA [47] . Also an increase in ANCA titers can be a predictor of relapse and the successful treatment of with the B-cell depleting agent Rituximab supports a pathogenic role for ANCA [48] [49] . As described in more detail below ANCA can induce the respiratory burst of primed and unprimed neutrophils [42] [50] -[52] . However even in healthy individuals natural autoantibodies against MPO and PR3 can be detected, although in much lower titers than those of MPO/PR3 ANCA from patients with vasculitis. It is speculated that these natural autoantibodies are kept under control by anti-idiotype antibodies [53] . In addition, nearly half of the patients with localized disease are ANCA negative and not in all cases conventional serological assays correlate with disease activity although this might be due to differences in ANCA epitope specificity [54] [55] .

8. Interaction of ANCA and Polymorphonuclear Leukocytes (PMN)—The Role of Apoptotic PMN

Polymorphonuclear cells (PMN) are professional phagocytic cells of the innate immune system that act as the first line of defence against invading pathogens. PMNs, especially neutrophils, play a pivotal role in the acute injury of ANCA associated vasculitis since they are both effector cells responsible for endothelial damage and targets of autoimmunity [40] . Although some authors suggest that unprimed neutrophils express the ANCA antigen Proteinase-3 and neutrophilic respiratory burst can be stimulated by binding of ANCA, it is generally accepted, that an initial priming step is required for their pathophysiological function in AAV [40] [50] . Priming can be induced by inflammatory cytokines, adhesion, bacterial products (lipopolysaccharide), or lipid mediators. In their primed state, exposure to a second stimulus results in faster and stronger responses of the PMN [40] . In AAV, priming induces membrane expression of PR3 and MPO and subsequent binding of ANCA triggering PMN activation [42] . Primed neutrophils incubated with IgG purified from sera containing anti-PR3 ANCA or anti-MPO ANCA are able to produce superoxide anion and release lytic granular proteins in vitro [42] [51] [52] . ANCA-induced neutrophil activation requires both, antigen binding via Fc receptors (FcγRIIa or FcγRIIIb) as well as β2-integrin engagement [40] [56] . The size and subset of PMN that display PR3 on their surface seems to be a stable feature of an individual, most likely genetically controlled. Witko-Sarsat et al. defines three types of phenotypes with low, intermediate and high expression of membrane-located PR3 (mPR3). The mPR3 high phenotype occurs significantly more often in patients with ANCA vasculitis [57] [58] . PMN from AAV patients also re-express genes coding for PR3, despite the fact that these genes are normally restricted to the promyelocytic stage during granulocytic differentiation [59] .

PMN are not simple terminal effector cells but also show immuno-modulating features. By secreting a great variety of cytokines and chemokines they instruct all immune cells (monocytes, dendritic cells (DC), T cells and B cells) through an active cross-talk [40] . PMN traffic immature and mature DC to mucosal surfaces and lymphoid organs, produce chemoattractants for DC, modulate DC maturation and function and act as a transport vehicle for antigens to DC, thus playing an important role in the activation of T-cell responses controlled by DC [60] . In addition PMN crosstalk with T-cells and exhibit a significant chemotactic effect toward Th1 and Th17 cell subsets by releasing CCL2, CXCL9, CXCL10, CCL20 and CCL2 [61] . Moreover, PMN are a major source of B-cell-Activating Factor (BAFF) and A Proliferating-Inducing Ligand (APRIL), which are both members of the TNF superfamily and implicated in fundamental processes of B lymphocytes homeostasis. Notably, serum levels of BAFF are elevated in GPA compared to controls [62] . In addition, ANCA primed PMN produce BLyS, a protein which promotes B-cell survival, and patients with ANCA vasculitis show increased serum levels of BLyS [63] .

PMN from patients with AAV showed enhanced apoptosis compared to controls when activated by ANCA [64] . Apoptosis is a genetically programmed cell suicide, characterized by the condensation of cytoplasm and intracellular organelles, cleavage of nuclear chromatin, formation of apoptotic bodies with or without nuclear remnants and exposure of phosphatidylserine on the outer leaflet of the plasma membrane. All of these changes are related to the activation of caspases, an evolutionary conserved family of proteins that irreversibly commit a cell to die [65] [66] . The efficient clearance of apoptotic cells is crucial for tissue homeostasis. Otherwise, postapoptotic necrosis leads to loss of membrane integrity and leakage of potentially cytotoxic and antigenic intracellular contents into the surrounding environment. Clearance is a process of engulfment and digestion of apoptotic cells by phagocytes and is mainly executed by tissue macrophages. Apoptotic cells display different so called eat-me signals on their surface, including externalized phosphatidylserine, oxidized LDL or Thrombospondin-1 binding sites as well as so called find-me signals like lysophosphatidylcholine to attract monocytes. The complex process of apoptotic cell clearance actively suppresses the initiation of inflammation and immune responses, in part through the release of anti inflammatory cytokines such as TGF-β, PGE2 or PAF through autocrine and paracrine mechanisms. In higher organisms non-ingested apoptotic cells might be a reservoir for autoantigens presented to the adaptive immune system and thus initiate and drive systemic autoimmunity. For example, mice lacking certain proteins involved in the bridging process between the apoptotic cell and the phagocyte develop auto-immune diseases resembling human lupus erythematosus [67] . ANCA-opsonized PMN develop the morphologic features of apoptosis without cell surface changes that normally accompany apoptosis, including phosphatidylserine expression. These ANCA primed PMN are less well cleared by phagocytic macrophages and eventually disintegrate, releasing cytotoxic contents [68] [69] . ANCA-opsonized PMN also show higher rates of apoptosis and increased ROS production, and their clearance by phagocytic cells triggers the production of proinflammatory cytokines. In addition, ANCA-opsonized apoptotic PMN translocate PR3 to their membrane leading to increased ANCA binding [51] [64] [70] -[74] . Immunization of rats with late apoptotic PMN leads to a break of tolerance against PMN and the production of ANCA [75] [76] .

Another quite recently described pathway of neutrophil death is the formation of NETs (neutrophil extracellular traps). NETs are webs formed by chromatin and granule proteins that provide a high local concentration of antimicrobial molecules including PR3 [77] . ANCA binding to primed PMN induces the formation of NETs expressing the auto-antigen PR3. This may activate plasmacytoid dendritic cells, thus breaking the tolerance against self DNA and promoting auto immunity by production of interferon-α and the activation of auto-reactive B cells to the production of ANCA [78] [79] .

9. Endothelium-Neutrophil Interactions in GPA

Endothelium-neutrophil interactions are essential to allow neutrophils to move toward inflammatory sites and to perform innate immune responses [80] . The transmigration of neutrophils through the endothelium includes a number of steps. The initial attachment of neutrophils to endothelial cells is termed rolling. Rolling is generally mediated by interactions between selectins on the endothelial cells and glycosylated ligands of the neutrophil and leads to a slowing down of the cells in the bloodstream. Endothelial selectins are upregulated in response to stimuli such TNF-α, interleukin-1β (IL-1β) or IL-17. These stimuli are generated during infection or inflammation and result in upregulation of P-selectin and E-selectin on the luminal surface of ECs. The neutrophil ligands, L-selectin and P-selectin ligand-1 (PSGL-1), are constitutively expressed on the tips of neutrophil microvilli. Selectin-mediated neutrophil-EC interaction only lasts seconds and is reversible. This step is followed by firm adhesion mediated by the β2-integrins, LFA-1 (αLα2), Mac-1 (αMβ2) and VLA-4 on neutrophils and their ligands on endothelial cells including ICAM-1, ICAM-2 and VCAM-1. Various chemokines have been found inducing integrin activation on neutrophils, such as platelet-activating factor (PAF), IL-8, fMLP, TNF-α, RANTES or bacterial products, like LPS. Two routes have been described for neutrophil migration through the endothelium: transcellular migration, whereby neutrophils penetrate the body of ECs, and paracellular migration used by the majority of neutrophils, whereby they squeeze between two adjacent ECs. Paracellular migration of neutrophils is controlled by endothelial ICAM-1, ICAM-2, junctional adhesion molecule-A (JAM-A) and platelet endothelial cell adhesion molecule-1 (PECAM-1). Blocking or depletion of ICAM-1or ICAM-2 revealed that they are both involved in guiding neutrophils to enter the EC-junctions. JAM-A is associated with further penetration of neutrophils, and finally PECAM-1 performs the last step of neutrophil transendothelial migration, which is demonstrated by the observation that in PECAM-1−/− mice neutrophils are trapped between ECs and basement membrane [81] [82] .

In AAV levels of circulating TNF-α and IL-8 are elevated creating an inflammatory environment that triggers β2-integrin activation and adherence of circulating neutrophils to the endothelium [83] [84] . The rolling of ANCA-opsonized PMN is converted into firm adhesion even at minimal TNF-α concentration [85] -[87] . Indeed, increased glomerular endothelial ICAM-1 and VCAM-1 concentrations and increased levels of neutrophil β2 and β1-integrins are described in active AAV [88] [89] . Consistent with these findings, Cockwell et al. have located infiltrated PMN during acute vasculitis at or within the glomerular capillary loops with rather poor penetration into the interstitial tissue [90] . Adhesion leads to the expression of high levels of mPR3 that is accessible to plasma-derived ANCA [91] . Synergy of β2-integrin outside signaling, TNF-α induced signaling and FcγR signaling of ANCA binding leads to an explosive oxidative burst and subsequent endothelial damage [92] [93] . Complement activation further amplifies the proinflammatory response of adherent PMN in the presence of ANCA. PMN-bound ANCA trigger the complement classic pathway exclusively on adherent PMN, a condition allowing access of ANCA to their antigens in plasma [80] .

As described above, PR3 and CD177 are co-expressed on the membrane of a subset of PMN, and the proportion of mPR3+/CD177+ PMN is increased in patients with ANCA vasculitis. Anti-PR3 ANCA trigger degranulation and extracellular superoxide release from the CD177+ PMN subsets [94] [95] . Moreover mPR+/CD177+ PMN show a higher transendothelial migration probably due to CD177-triggered PECAM-1 signaling [94] [96] .

Although PMN binding sites and the area of protein leakage are uncoupled, hence suggesting that the adhesion process is not the main inductor of vascular permeability, the close proximity of activated, ROS and proteases releasing PMNs to the endothelium may contribute to vascular permeability [97] -[101] . Moreover, interaction of PMN and endothelial cells in the phase of firm adhesion leads to cytoskeletal changes and disturbed integrity of the endothelial barrier. Altered barrier function facilitates diapedesis followed by endothelial apoptosis and detachment promoted by PMN-derived proteases and oxidants [80] [102] -[106] . One of the cellular markers for endothelial cell damage is the number of circulating endothelial cells which is significantly higher in patients with ANCA vasculitis and decreases with remission [107] .

In conclusion, ANCA antibodies lower the threshold of neutrophil responses to inflammatory cytokines and result in a vigorous response in the vascular bed even before any diapedesis or migration [80] .

10. What Triggers GPA and Its Relapse?

Staphylococcus aureus seems to play an important role in the stimulation of immune responses in patients with GPA. Carriers of nasal S. aureus express increased levels of intracellular TLR9, which are stimulated by bacterial CpG dinucleotide motifs. The latter, together with IL-2, have been reported to trigger autoreactive B-cells to the in vitro production of PR3-ANCA [26] [108] . Chronic nasal carriage of S. aureus is an independent risk factor for relapse [109] . Also, peptides from S. aureus can induce the production of antibodies to complimentary PR3, which, in turn, could induce antibodies to PR3 via idiotypic-anti-idiotypic interactions [110] . However, an increase of antibodies to complementary PR3 could not be observed in all cohorts of patients with GPA [111] . It is speculated that S. aureus might directly prime neutrophils to translocate PR3 to the surface, thus increasing the susceptibility for PR-ANCA. Moreover, S. aureus may also activate B-Cells polyclonally by its cell-wall components, resulting in persistence of ANCA. Other known risk factors are the exposure to silica, which might evoke an immune response and inflammatory reactions via various pathways and accelerate the apoptosis of neutrophils [112] -[115] . Drugs, in particular propylthiouracil, hydralazine, anti TNF-α agents, sulfasalazine, D-penicillamine and minocycline, have also been described to be associated with an increased risk for developing GPA [116] .

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Watts, R.A. and Scott, D.G. (2009) Recent Developments in the Classification and Assessment of Vasculitis. Best Practice & Research Clinical Rheumatology, 23, 429-443.
http://dx.doi.org/10.1016/j.berh.2008.12.004
[2] Hoffman, G.S. (1998) Classification of the Systemic Vasculitides: Antineutrophil Cytoplasmic Antibodies, Consensus and Controversy. Clinical and Experimental Rheumatology, 16, 111-115.
[3] Hunder, G.G., Arend, W.P., Bloch, D.A., Calabrese, L.H., Fauci, A.S., Fries, J.F., Leavitt, R.Y., Lie, J.T., Lightfoot Jr., R.W., Masi, A.T., et al. (1990) The American College of Rheumatology 1990 Criteria for the Classification of Vasculitis. Introduction. Arthritis & Rheumatology, 33, 1065-1067.
http://dx.doi.org/10.1002/art.1780330802
[4] Watts, R., Lane, S., Hanslik, T., Hauser, T., Hellmich, B., Koldingsnes, W., Mahr, A., Segelmark, M., Cohen-Tervaert, J.W. and Scott, D. (2007) Development and Validation of a Consensus Methodology for the Classification of the ANCA-Associated Vasculitides and Polyarteritis Nodosa for Epidemiological Studies. Annals of the Rheumatic Diseases, 66, 222-227.
http://dx.doi.org/10.1136/ard.2006.054593
[5] Kallenberg, C.G., Stegeman, C.A., Abdulahad, W.H. and Heeringa, P. (2013) Pathogenesis of ANCA-Associated Vasculitis: New Possibilities for Intervention. American Journal of Kidney Diseases, 62, 1176-1187.
http://dx.doi.org/10.1053/j.ajkd.2013.05.009
[6] Watts, R.A. and Scott, D.G. (2003) Epidemiology of the Vasculitides. Current Opinion in Rheumatology, 15, 11-16.
http://dx.doi.org/10.1097/00002281-200301000-00003
[7] Flossmann, O., Berden, A., de Groot, K., Hagen, C., Harper, L., Heijl, C., Hoglund, P., Jayne, D., Luqmani, R., Mahr, A., Mukhtyar, C., Pusey, C., Rasmussen, N., Stegeman, C., Walsh, M. and Westman, K. (2011) Long-Term Patient Survival in ANCA-Associated Vasculitis. Annals of the Rheumatic Diseases, 70, 488-494.
http://dx.doi.org/10.1136/ard.2010.137778
[8] Watts, R.A., Lane, S.E., Bentham, G. and Scott, D.G. (2000) Epidemiology of Systemic Vasculitis: A Ten-Year Study in the United Kingdom. Arthritis & Rheumatology, 43, 414-419.
http://dx.doi.org/10.1002/1529-0131(200002)43:2<414::AID-ANR23>3.0.CO;2-0
[9] Falk, R.J., Gross, W.L., Guillevin, L., Hoffman, G., Jayne, D.R., Jennette, J.C., Kallenberg, C.G., Luqmani, R., Mahr, A.D., Matteson, E.L., Merkel, P.A., Specks, U. and Watts, R. (2011) Granulomatosis with Polyangiitis (Wegener’s): An Alternative Name for Wegener’s Granulomatosis. Journal of the American Society of Nephrology, 22, 587-588.
http://dx.doi.org/10.1681/ASN.2011010081
[10] Leavitt, R.Y., Fauci, A.S., Bloch, D.A., Michel, B.A., Hunder, G.G., Arend, W.P., Calabrese, L.H., Fries, J.F., Lie, J.T., Lightfoot Jr., R.W., et al. (1990) The American College of Rheumatology 1990 Criteria for the Classification of Wegener’s Granulomatosis. Arthritis & Rheumatology, 33, 1101-1107.
http://dx.doi.org/10.1002/art.1780330807
[11] Jennette, J.C., Falk, R.J., Andrassy, K., Bacon, P.A., Churg, J., Gross, W.L., Hagen, E.C., Hoffman, G.S., Hunder, G.G., Kallenberg, C.G., et al. (1994) Nomenclature of Systemic Vasculitides. Proposal of an International Consensus Conference. Arthritis & Rheumatology, 37, 187-192.
http://dx.doi.org/10.1002/art.1780370206
[12] Luqmani, R.A., Suppiah, R., Grayson, P.C., Merkel, P.A. and Watts, R. (2011) Nomenclature and Classification of Vasculitis—Update on the ACR/EULAR Diagnosis and Classification of Vasculitis Study (DCVAS). Clinical & Experimental Immunology, 164, 11-13.
http://dx.doi.org/10.1111/j.1365-2249.2011.04358.x
[13] Jennette, J.C. and Falk, R.J. (1997) Small-Vessel Vasculitis. New England Journal of Medicine, 337, 1512-1523.
http://dx.doi.org/10.1056/NEJM199711203372106
[14] Seo, P. and Stone, J.H. (2004) The Antineutrophil Cytoplasmic Antibody-Associated Vasculitides. The American Journal of Medicine, 117, 39-50.
http://dx.doi.org/10.1016/j.amjmed.2004.02.030
[15] Falk, R.J., Hogan, S., Carey, T.S. and Jennette, J.C. (1990) Clinical Course of Anti-Neutrophil Cytoplasmic Autoanti-body-Associated Glomerulonephritis and Systemic Vasculitis. The Glomerular Disease Collaborative Network. Annals of Internal Medicine, 113, 656-663.
http://dx.doi.org/10.7326/0003-4819-113-9-656
[16] Hoffman, G.S., Kerr, G.S., Leavitt, R.Y., Hallahan, C.W., Lebovics, R.S., Travis, W.D., Rottem, M. and Fauci, A.S. (1992) Wegener Granulomatosis: An Analysis of 158 Patients. Annals of Internal Medicine, 116, 488-498.
http://dx.doi.org/10.7326/0003-4819-116-6-488
[17] Jayne, D. (2009) The Diagnosis of Vasculitis. Best Practice & Research Clinical Rheumatology, 23, 445-453.
http://dx.doi.org/10.1016/j.berh.2009.03.001
[18] Gomez-Puerta, J.A., Hernandez-Rodriguez, J., Lopez-Soto, A. and Bosch, X. (2009) Antineutrophil Cytoplasmic Antibody-Associated Vasculitides and Respiratory Disease. Chest, 136, 1101-1111.
http://dx.doi.org/10.1378/chest.08-3043
[19] Jennette, J.C. and Falk, R.J. (1994) The Pathology of Vasculitis Involving the Kidney. American Journal of Kidney Diseases, 24, 130-141.
http://dx.doi.org/10.1016/S0272-6386(12)80171-5
[20] Hoffman, G.S. and Specks, U. (1998) Antineutrophil Cytoplasmic Antibodies. Arthritis & Rheumatology, 41, 1521-1537.
http://dx.doi.org/10.1002/1529-0131(199809)41:9<1521::AID-ART2>3.0.CO;2-A
[21] Jones, R.B., Tervaert, J.W., Hauser, T., Luqmani, R., Morgan, M.D., Peh, C.A., Savage, C.O., Segelmark, M., Tesar, V., van Paassen, P., Walsh, D., Walsh, M., Westman, K. and Jayne, D.R. (2010) Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis. New England Journal of Medicine, 363, 211-220.
http://dx.doi.org/10.1056/NEJMoa0909169
[22] Stone, J.H., Merkel, P.A., Spiera, R., Seo, P., Langford, C.A., Hoffman, G.S., Kallenberg, C.G., St Clair, E.W., Turkiewicz, A., Tchao, N.K., Webber, L., Ding, L., Sejismundo, L.P., Mieras, K., Weitzenkamp, D., Ikle, D., Seyfert-Margolis, V., Mueller, M., Brunetta, P., Allen, N.B., Fervenza, F.C., Geetha, D., Keogh, K.A., Kissin, E.Y., Monach, P.A., Peikert, T., Stegeman, C., Ytterberg, S.R. and Specks, U. (2010) Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. New England Journal of Medicine, 363, 221-232.
http://dx.doi.org/10.1056/NEJMoa0909905
[23] Holle, J.U. (2013) ANCA-Associated Vasculitis. Zeitschrift für Rheumatologie, 72, 445-456.
http://dx.doi.org/10.1007/s00393-013-1211-0
[24] Voswinkel, J., Mueller, A., Kraemer, J.A., Lamprecht, P., Herlyn, K., Holl-Ulrich, K., Feller, A.C., Pitann, S., Gause, A. and Gross, W.L. (2006) B Lymphocyte Maturation in Wegener’s Granulomatosis: A Comparative Analysis of VH Genes from Endonasal Lesions. Annals of the Rheumatic Diseases, 65, 859-864.
http://dx.doi.org/10.1136/ard.2005.044909
[25] Muller, A., Trabandt, A., Gloeckner-Hofmann, K., Seitzer, U., Csernok, E., Schonermarck, U., Feller, A.C. and Gross, W.L. (2000) Localized Wegener’s Granulomatosis: Predominance of CD26 and IFN-Gamma Expression. The Journal of Pathology, 192, 113-120.
http://dx.doi.org/10.1002/1096-9896(2000)9999:9999<::AID-PATH656>3.0.CO;2-M
[26] Tadema, H., Abdulahad, W.H., Stegeman, C.A., Kallenberg, C.G. and Heeringa, P. (2011) Increased Expression of Toll-Like Receptors by Monocytes and Natural Killer Cells in ANCA-Associated Vasculitis. PLoS ONE, 6, e24315.
http://dx.doi.org/10.1371/journal.pone.0024315
[27] Bunch, D.O., McGregor, J.G., Khandoobhai, N.B., Aybar, L.T., Burkart, M.E., Hu, Y., Hogan, S.L., Poulton, C.J., Berg, E.A., Falk, R.J. and Nachman, P.H. (2013) Decreased CD5+ B Cells in Active ANCA Vasculitis and Relapse after Rituximab. Clinical Journal of the American Society of Nephrology, 8, 382-391.
http://dx.doi.org/10.2215/CJN.03950412
[28] Abdulahad, W.H., De Souza, A.W. and Kallenberg, C.G. (2013) L3. Are Mononuclear Cells Predominant Actors of Endothelial Damage in Vasculitis? La Presse Médicale, 42, 499-503.
http://dx.doi.org/10.1016/j.lpm.2013.02.305
[29] Appay, V. (2004) The Physiological Role of Cytotoxic CD4(+) T-Cells: The Holy Grail? Clinical Experimental Immunology, 138, 10-13.
http://dx.doi.org/10.1111/j.1365-2249.2004.02605.x
[30] Zwirner, N.W., Dole, K. and Stastny, P. (1999) Differential Surface Expression of MICA by Endothelial Cells, Fibroblasts, Keratinocytes, and Monocytes. Human Immunology, 60, 323-330.
http://dx.doi.org/10.1016/S0198-8859(98)00128-1
[31] Charles Jennette, J. and Falk, R.J. (2013) L1. Pathogenesis of ANCA-Associated Vasculitis: Observations, Theories and Speculations. La Presse Médicale, 42, 493-498.
http://dx.doi.org/10.1016/j.lpm.2013.01.003
[32] Jennette, J.C. (2011) Nomenclature and Classification of Vasculitis: Lessons Learned from Granulomatosis with Polyangiitis (Wegener’s Granulomatosis). Clinical & Experimental Immunology, 164, 7-10.
http://dx.doi.org/10.1111/j.1365-2249.2011.04357.x
[33] Mark, E.J., Matsubara, O., Tan-Liu, N.S. and Fienberg, R. (1988) The Pulmonary Biopsy in the Early Diagnosis of Wegener’s (Pathergic) Granulomatosis: A Study Based on 35 Open Lung Biopsies. Human Pathology, 19, 1065-1071.
http://dx.doi.org/10.1016/S0046-8177(88)80088-1
[34] Lamprecht, P. and Gross, W.L. (2007) Current Knowledge on Cellular Interactions in the WG-Granuloma. Clinical and Experimental Rheumatology, 25, S49-S51.
[35] van der Woude, F.J., Rasmussen, N., Lobatto, S., Wiik, A., Permin, H., van Es, L.A., van der Giessen, M., Van Der Hem, G.K. and The, T.H. (1985) Autoantibodies against Neutrophils and Monocytes: Tool for Diagnosis and Marker of Disease Activity in Wegener’s Granulomatosis. The Lancet, 1, 425-429.
http://dx.doi.org/10.1016/S0140-6736(85)91147-X
[36] Falk, R.J. and Jennette, J.C. (1988) Anti-Neutrophil Cytoplasmic Autoantibodies with Specificity for Myeloperoxidase in Patients with Systemic Vasculitis and Idiopathic Necrotizing and Crescentic Glomerulonephritis. The New England Journal of Medicine, 318, 1651-1657.
http://dx.doi.org/10.1056/NEJM198806233182504
[37] Tervaert, J.W., Goldschmeding, R., Elema, J.D., van der Giessen, M., Huitema, M.G., van der Hem, G.K., The, T.H., von dem Borne, A.E. and Kallenberg, C.G. (1990) Autoantibodies against Myeloid Lysosomal Enzymes in Crescentic Glomerulonephritis. Kidney International, 37, 799-806.
http://dx.doi.org/10.1038/ki.1990.48
[38] Jennette, J.C., Wilkman, A.S. and Falk, R.J. (1998) Diagnostic Predictive Value of ANCA Serology. Kidney International, 53, 796-798.
http://dx.doi.org/10.1038/ki.1998.36
[39] Hagen, E.C., Daha, M.R., Hermans, J., Andrassy, K., Csernok, E., Gaskin, G., Lesavre, P., Ludemann, J., Rasmussen, N., Sinico, R.A., Wiik, A. and van der Woude, F.J. (1998) Diagnostic Value of Standardized Assays for Anti-Neutrophil Cytoplasmic Antibodies in Idiopathic Systemic Vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney International, 53, 743-753.
http://dx.doi.org/10.1046/j.1523-1755.1998.00807.x
[40] Witko-Sarsat, V. (2013) L34. Neutrophils in ANCA-Associated Vasculitis: Still under Investigation. La Presse Médicale, 42, 595-597.
http://dx.doi.org/10.1016/j.lpm.2013.01.034
[41] Hu, N., Westra, J., Huitema, M.G., Bijl, M., Brouwer, E., Stegeman, C.A., Heeringa, P., Limburg, P.C. and Kallenberg, C.G. (2009) Coexpression of CD177 and Membrane Proteinase 3 on Neutrophils in Antineutrophil Cytoplasmic Autoantibody-Associated Systemic Vasculitis: Anti-Proteinase 3-Mediated Neutrophil Activation Is Independent of the Role of CD177-Expressing Neutrophils. Arthritis Rheumatology, 60, 1548-1557.
http://dx.doi.org/10.1002/art.24442
[42] Yang, J.J., Tuttle, R.H., Hogan, S.L., Taylor, J.G., Phillips, B.D., Falk, R.J. and Jennette, J.C. (2000) Target Antigens for Anti-Neutrophil Cytoplasmic Autoantibodies (ANCA) Are on the Surface of Primed and Apoptotic but Not Unstimulated Neutrophils. Clinical Experimental Immunology, 121, 165-172.
http://dx.doi.org/10.1046/j.1365-2249.2000.01228.x
[43] Huugen, D., Xiao, H., van Esch, A., Falk, R.J., Peutz-Kootstra, C.J., Buurman, W.A., Tervaert, J.W., Jennette, J.C. and Heeringa, P. (2005) Aggravation of Anti-Myeloperoxidase Antibody-Induced Glomerulonephritis by Bacterial Lipo-polysaccharide: Role of Tumor Necrosis Factor-Alpha. American Journal of Pathology, 167, 47-58.
http://dx.doi.org/10.1016/S0002-9440(10)62952-5
[44] Xiao, H., Heeringa, P., Hu, P., Liu, Z., Zhao, M., Aratani, Y., Maeda, N., Falk, R.J. and Jennette, J.C. (2002) Antineutrophil Cytoplasmic Autoantibodies Specific for Myeloperoxidase Cause Glomerulonephritis and Vasculitis in Mice. Journal of Clinical Investigation, 110, 955-963.
http://dx.doi.org/10.1172/JCI0215918
[45] Little, M.A., Al-Ani, B., Ren, S., Al-Nuaimi, H., Leite Jr., M., Alpers, C.E., Savage, C.O. and Duffield, J.S. (2012) Anti-Proteinase 3 Anti-Neutrophil Cytoplasm Autoantibodies Recapitulate Systemic Vasculitis in Mice with a Humanized Immune System. PLoS ONE, 7, e28626.
http://dx.doi.org/10.1371/journal.pone.0028626
[46] Bansal, P.J. and Tobin, M.C. (2004) Neonatal Microscopic Polyangiitis Secondary to Transfer of Maternal Myeloperoxidase-Antineutrophil Cytoplasmic Antibody Resulting in Neonatal Pulmonary Hemorrhage and Renal Involvement. Annals of Allergy, Asthma Immunology, 93, 398-401.
http://dx.doi.org/10.1016/S1081-1206(10)61400-7
[47] Ciavatta, D.J., Yang, J., Preston, G.A., Badhwar, A.K., Xiao, H., Hewins, P., Nester, C.M., Pendergraft 3rd, W.F., Magnuson, T.R., Jennette, J.C. and Falk, R.J. (2010) Epigenetic Basis for Aberrant Upregulation of Autoantigen Genes in Humans with ANCA Vasculitis. Journal of Clinical Investigation, 120, 3209-3219.
http://dx.doi.org/10.1172/JCI40034
[48] Tomasson, G., Grayson, P.C., Mahr, A.D., Lavalley, M. and Merkel, P.A. (2012) Value of ANCA Measurements during Remission to Predict a Relapse of ANCA-Associated Vasculitis—A Meta-Analysis. Rheumatology (Oxford), 51, 100-109.
http://dx.doi.org/10.1093/rheumatology/ker280
[49] Cartin-Ceba, R., Golbin, J.M., Keogh, K.A., Peikert, T., Sanchez-Menendez, M., Ytterberg, S.R., Fervenza, F.C. and Specks, U. (2012) Rituximab for Remission Induction and Maintenance in Refractory Granulomatosis with Polyangiitis (Wegener’s): Ten-Year Experience at a Single Center. Arthritis & Rheumatism, 64, 3770-3778.
http://dx.doi.org/10.1002/art.34584
[50] Keogan, M.T., Esnault, V.L., Green, A.J., Lockwood, C.M. and Brown, D.L. (1992) Activation of Normal Neutrophils by Anti-Neutrophil Cytoplasm Antibodies. Clinical Experimental Immunology, 90, 228-234.
http://dx.doi.org/10.1111/j.1365-2249.1992.tb07934.x
[51] Preston, G.A. and Falk, R.J. (2001) ANCA Signaling: Not Just a Matter of Respiratory Burst. Kidney International, 59, 1981-1982.
http://dx.doi.org/10.1046/j.1523-1755.2001.0590051981.x
[52] Savage, C.O., Pottinger, B.E., Gaskin, G., Pusey, C.D. and Pearson, J.D. (1992) Autoantibodies Developing to Myeloperoxidase and Proteinase 3 in Systemic Vasculitis Stimulate Neutrophil Cytotoxicity toward Cultured Endothelial Cells. American Journal of Pathology, 141, 335-342.
[53] Cui, Z., Zhao, M.H., Segelmark, M. and Hellmark, T. (2010) Natural Autoantibodies to Myeloperoxidase, Proteinase 3, and the Glomerular Basement Membrane Are Present in Normal Individuals. Kidney International, 78, 590-597.
http://dx.doi.org/10.1038/ki.2010.198
[54] Holle, J.U., Gross, W.L., Holl-Ulrich, K., Ambrosch, P., Noelle, B., Both, M., Csernok, E., Moosig, F., Schinke, S. and Reinhold-Keller, E. (2010) Prospective Long-Term Follow-Up of Patients with Localised Wegener’s Granulomatosis: Does It Occur as Persistent Disease Stage? Annals of the Rheumatic Diseases, 69, 1934-1939.
http://dx.doi.org/10.1136/ard.2010.130203
[55] Roth, A.J., Ooi, J.D., Hess, J.J., van Timmeren, M.M., Berg, E.A., Poulton, C.E., McGregor, J., Burkart, M., Hogan, S.L., Hu, Y., Winnik, W., Nachman, P.H., Stegeman, C.A., Niles, J., Heeringa, P., Kitching, A.R., Holdsworth, S., Jennette, J.C., Preston, G.A. and Falk, R.J. (2013) Epitope Specificity Determines Pathogenicity and Detectability in ANCA-Associated Vasculitis. Journal of Clinical Investigation, 123, 1773-1783.
http://dx.doi.org/10.1172/JCI65292
[56] Mulder, A.H., Heeringa, P., Brouwer, E., Limburg, P.C. and Kallenberg, C.G. (1994) Activation of Granulocytes by Anti-Neutrophil Cytoplasmic Antibodies (ANCA): A Fc Gamma RII-Dependent Process. Clinical Experimental Immunology, 98, 270-278.
http://dx.doi.org/10.1111/j.1365-2249.1994.tb06137.x
[57] Witko-Sarsat, V., Lesavre, P., Lopez, S., Bessou, G., Hieblot, C., Prum, B., Noel, L.H., Guillevin, L., Ravaud, P., Sermet-Gaudelus, I., Timsit, J., Grunfeld, J.P. and Halbwachs-Mecarelli, L. (1999) A Large Subset of Neutrophils Expressing Membrane Proteinase 3 Is a Risk Factor for Vasculitis and Rheumatoid Arthritis. Journal of the American Society of Nephrology, 10, 1224-1233.
[58] Schreiber, A., Busjahn, A., Luft, F.C. and Kettritz, R. (2003) Membrane Expression of Proteinase 3 Is Genetically Determined. Journal of the American Society of Nephrology, 14, 68-75.
http://dx.doi.org/10.1097/01.ASN.0000040751.83734.D1
[59] Yang, J.J., Pendergraft, W.F., Alcorta, D.A., Nachman, P.H., Hogan, S.L., Thomas, R.P., Sullivan, P., Jennette, J.C., Falk, R.J. and Preston, G.A. (2004) Circumvention of Normal Constraints on Granule Protein Gene Expression in Peripheral Blood Neutrophils and Monocytes of Patients with Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis. Journal of the American Society of Nephrology, 15, 2103-2114.
http://dx.doi.org/10.1097/01.ASN.0000135058.46193.72
[60] Cassatella, M.A. (2013) L33. Neutrophil in Immunity: A Key Modulator. La Presse Médicale, 42, 594-595.
http://dx.doi.org/10.1016/j.lpm.2013.01.033
[61] Pelletier, M., Maggi, L., Micheletti, A., Lazzeri, E., Tamassia, N., Costantini, C., Cosmi, L., Lunardi, C., Annunziato, F., Romagnani, S. and Cassatella, M.A. (2010) Evidence for a Cross-Talk between Human Neutrophils and Th17 Cells. Blood, 115, 335-343.
http://dx.doi.org/10.1182/blood-2009-04-216085
[62] Krumbholz, M., Specks, U., Wick, M., Kalled, S.L., Jenne, D. and Meinl, E. (2005) BAFF Is Elevated in Serum of Patients with Wegener’s Granulomatosis. Journal of Autoimmunity, 25, 298-302.
http://dx.doi.org/10.1016/j.jaut.2005.08.004
[63] Holden, N.J., Williams, J.M., Morgan, M.D., Challa, A., Gordon, J., Pepper, R.J., Salama, A.D., Harper, L. and Savage, C.O.S. (2011) ANCA-Stimulated Neutrophils Release BLyS and Promote B Cell Survival: A Clinically Relevant Cellular Process. Annals of the Rheumatic Diseases, 70, 2229-2233.
http://dx.doi.org/10.1136/ard.2011.153890
[64] Harper, L., Cockwell, P., Adu, D. and Savage, C.O. (2001) Neutrophil Priming and Apoptosis in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis. Kidney International, 59, 1729-1738.
http://dx.doi.org/10.1046/j.1523-1755.2001.0590051729.x
[65] van Rossum, A.P., Limburg, P.C. and Kallenberg, C.G. (2005) Activation, Apoptosis, and Clearance of Neutrophils in Wegener’s Granulomatosis. Annals of the New York Academy of Sciences, 1051, 1-11.
http://dx.doi.org/10.1196/annals.1361.041
[66] Cabrini, M., Nahmod, K. and Geffner, J. (2010) New Insights into the Mechanisms Controlling Neutrophil Survival. Current Opinion in Hematology, 17, 31-35.
http://dx.doi.org/10.1097/MOH.0b013e3283333b29
[67] Lauber, K., Blumenthal, S.G., Waibel, M. and Wesselborg, S. (2004) Clearance of Apoptotic Cells: Getting Rid of the Corpses. Molecular Cell, 14, 277-287.
http://dx.doi.org/10.1016/S1097-2765(04)00237-0
[68] Harper, L., Ren, Y., Savill, J., Adu, D. and Savage, C.O. (2000) Antineutrophil Cytoplasmic Antibodies Induce Reactive Oxygen-Dependent Dysregulation of Primed Neutrophil Apoptosis and Clearance by Macrophages. American Journal of Pathology, 157, 211-220.
http://dx.doi.org/10.1016/S0002-9440(10)64532-4
[69] Fernandez-Boyanapalli, R., McPhillips, K.A., Frasch, S.C., Janssen, W.J., Dinauer, M.C., Riches, D.W., Henson, P.M., Byrne, A. and Bratton, D.L. (2010) Impaired Phagocytosis of Apoptotic Cells by Macrophages in Chronic Granulomatous Disease Is Reversed by IFN-Gamma in a Nitric Oxide-Dependent Manner. The Journal of Immunology, 185, 4030-4041.
http://dx.doi.org/10.4049/jimmunol.1001778
[70] Gilligan, H.M., Bredy, B., Brady, H.R., Hebert, M.J., Slayter, H.S., Xu, Y., Rauch, J., Shia, M.A., Koh, J.S. and Levine, J.S. (1996) Antineutrophil Cytoplasmic Autoantibodies Interact with Primary Granule Constituents on the Surface of Apoptotic Neutrophils in the Absence of Neutrophil Priming. The Journal of Experimental Medicine, 184, 2231-2241.
http://dx.doi.org/10.1084/jem.184.6.2231
[71] Moosig, F., Csernok, E., Kumanovics, G. and Gross, W.L. (2000) Opsonization of Apoptotic Neutrophils by Anti-Neutrophil Cytoplasmic Antibodies (ANCA) Leads to Enhanced Uptake by Macrophages and Increased Release of Tumour Necrosis Factor-Alpha (TNF-Alpha). Clinical Experimental Immunology, 122, 499-503.
http://dx.doi.org/10.1046/j.1365-2249.2000.01410.x
[72] Csernok, E., Moosig, F. and Gross, W.L. (2008) Pathways to ANCA Production: From Differentiation of Dendritic Cells by Proteinase 3 to B Lymphocyte Maturation in Wegener’s Granuloma. Clinical Reviews in Allergy Immunology, 34, 300-306.
http://dx.doi.org/10.1007/s12016-007-8056-8
[73] Deutsch, M., Guejes, L., Zurgil, N., Shovman, O., Gilburd, B., Afrimzon, E. and Shoenfeld, Y. (2004) Antineutrophil Cytoplasmic Autoantibodies Penetrate into Human Polymorphonuclear Leukocytes and Modify Their Apoptosis. Clinical and Experimental Rheumatology, 22, S35-S40.
[74] Hsieh, S.C., Yu, H.S., Cheng, S.H., Li, K.J., Lu, M.C., Wu, C.H., Tsai, C.Y. and Yu, C.L. (2007) Anti-Myeloperoxidase Antibodies Enhance Phagocytosis, IL-8 Production, and Glucose Uptake of Polymorphonuclear Neutrophils Rather than Anti-Proteinase 3 Antibodies Leading to Activation-Induced Cell Death of the Neutrophils. Clinical Rheumatology, 26, 216-224.
http://dx.doi.org/10.1007/s10067-006-0285-3
[75] Patry, Y.C., Trewick, D.C., Gregoire, M., Audrain, M.A., Moreau, A.M., Muller, J.Y., Meflah, K. and Esnault, V.L. (2001) Rats Injected with Syngenic Rat Apoptotic Neutrophils Develop Antineutrophil Cytoplasmic Antibodies. Journal of the American Society of Nephrology, 12, 1764-1768.
[76] Rauova, L., Gilburd, B., Zurgil, N., Blank, M., Guegas, L.L., Brickman, C.M., Cebecauer, L., Deutsch, M., Wiik, A. and Shoenfeld, Y. (2002) Induction of Biologically Active Antineutrophil Cytoplasmic Antibodies by Immunization with Human Apoptotic Polymorphonuclear Leukocytes. Clinical Immunology, 103, 69-78.
http://dx.doi.org/10.1006/clim.2002.5194
[77] Fuchs, T.A., Abed, U., Goosmann, C., Hurwitz, R., Schulze, I., Wahn, V., Weinrauch, Y., Brinkmann, V. and Zychlinsky, A. (2007) Novel Cell Death Program Leads to Neutrophil Extracellular Traps. The Journal of Cell Biology, 176, 231-241.
http://dx.doi.org/10.1083/jcb.200606027
[78] Lande, R., Gregorio, J., Facchinetti, V., Chatterjee, B., Wang, Y.H., Homey, B., Cao, W., Su, B., Nestle, F.O., Zal, T., Mellman, I., Schroder, J.M., Liu, Y.J. and Gilliet, M. (2007) Plasmacytoid Dendritic Cells Sense Self-DNA Coupled with Antimicrobial Peptide. Nature, 449, 564-569.
http://dx.doi.org/10.1038/nature06116
[79] Kessenbrock, K., Krumbholz, M., Schonermarck, U., Back, W., Gross, W.L., Werb, Z., Grone, H.J., Brinkmann, V. and Jenne, D.E. (2009) Netting Neutrophils in Autoimmune Small-Vessel Vasculitis. Nature Medicine, 15, 623-625.
http://dx.doi.org/10.1038/nm.1959
[80] Halbwachs, L. and Lesavre, P. (2012) Endothelium-Neutrophil Interactions in ANCA-Associated Diseases. Journal of the American Society of Nephrology, 23, 1449-1461.
http://dx.doi.org/10.1681/ASN.2012020119
[81] Hu, N., Westra, J. and Kallenberg, C.G. (2011) Dysregulated Neutrophil—Endothelial Interaction in Antineutrophil Cytoplasmic Autoantibody (ANCA)-Associated Vasculitides: Implications for Pathogenesis and Disease Intervention. Autoimmunity Reviews, 10, 536-543.
http://dx.doi.org/10.1016/j.autrev.2011.04.004
[82] Johnson-Leger, C., Aurrand-Lions, M. and Imhof, B.A. (2000) The Parting of the Endothelium: Miracle, or Simply a Junctional Affair? Journal of Cell Science, 113, 921-933.
[83] Zeng, M., Zhang, H., Lowell, C. and He, P. (2002) Tumor Necrosis Factor-Alpha-Induced Leukocyte Adhesion and Microvessel Permeability. American Journal of Physiology-Heart and Circulatory Physiology, 283, H2420-H2430.
[84] Carvalho-Tavares, J., Hickey, M.J., Hutchison, J., Michaud, J., Sutcliffe, I.T. and Kubes, P. (2000) A Role for Platelets and Endothelial Selectins in Tumor Necrosis Factor-Alpha-Induced Leukocyte Recruitment in the Brain Microvasculature. Circulation Research, 87, 1141-1148.
http://dx.doi.org/10.1161/01.RES.87.12.1141
[85] Radford, D.J., Savage, C.O. and Nash, G.B. (2000) Treatment of Rolling Neutrophils with Antineutrophil Cytoplasmic Antibodies Causes Conversion to Firm Integrin-Mediated Adhesion. Arthritis Rheumatology, 43, 1337-1345.
http://dx.doi.org/10.1002/1529-0131(200006)43:6<1337::AID-ANR16>3.0.CO;2-M
[86] Radford, D.J., Luu, N.T., Hewins, P., Nash, G.B. and Savage, C.O. (2001) Antineutrophil Cytoplasmic Antibodies Stabilize Adhesion and Promote Migration of Flowing Neutrophils on endothelial Cells. Arthritis Rheumatology, 44, 2851-2861.
http://dx.doi.org/10.1002/1529-0131(200112)44:12<2851::AID-ART473>3.0.CO;2-2
[87] Calderwood, J.W., Williams, J.M., Morgan, M.D., Nash, G.B. and Savage, C.O. (2005) ANCA Induces Beta2 Integrin and CXC Chemokine-Dependent Neutrophil-Endothelial Cell Interactions That Mimic Those of Highly Cytokine-Activated Endothelium. Journal of Leukocyte Biology, 77, 33-43.
[88] Haller, H., Eichhorn, J., Pieper, K., Gobel, U. and Luft, F.C. (1996) Circulating Leukocyte Integrin Expression in Wegener’s Granulomatosis. Journal of the American Society of Nephrology, 7, 40-48.
[89] Arrizabalaga, P., Sole, M., Iglesias, C., Escaramis, G. and Ascaso, C. (2006) Renal Expression of ICAM-1 and VCAM-1 in ANCA-Associated Glomerulonephritis—Are There Differences among Serologic Subgroups? Clinical Nephrology, 65, 79-86.
http://dx.doi.org/10.5414/CNP65079
[90] Cockwell, P., Brooks, C.J., Adu, D. and Savage, C.O. (1999) Interleukin-8: A Pathogenetic Role in Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis. Kidney International, 55, 852-863.
http://dx.doi.org/10.1046/j.1523-1755.1999.055003852.x
[91] Brachemi, S., Mambole, A., Fakhouri, F., Mouthon, L., Guillevin, L., Lesavre, P. and Halbwachs-Mecarelli, L. (2007) Increased Membrane Expression of Proteinase 3 during Neutrophil Adhesion in the Presence of Anti Proteinase 3 Antibodies. Journal of the American Society of Nephrology, 18, 2330-2339.
http://dx.doi.org/10.1681/ASN.2006121309
[92] Porges, A.J., Redecha, P.B., Kimberly, W.T., Csernok, E., Gross, W.L. and Kimberly, R.P. (1994) Anti-Neutrophil Cytoplasmic Antibodies Engage and Activate Human Neutrophils via Fc Gamma RIIa. The Journal of Immunology, 153, 1271-1280.
[93] Reumaux, D., Vossebeld, P.J., Roos, D. and Verhoeven, A.J. (1995) Effect of Tumor Necrosis Factor-Induced Integrin Activation on Fc Gamma Receptor II-Mediated Signal Transduction: Relevance for Activation of Neutrophils by Anti-Proteinase 3 or Anti-Myeloperoxidase Antibodies. Blood, 86, 3189-3195.
[94] Schreiber, A., Luft, F.C. and Kettritz, R. (2004) Membrane Proteinase 3 Expression and ANCA-Induced Neutrophil Activation. Kidney International, 65, 2172-2183.
http://dx.doi.org/10.1111/j.1523-1755.2004.00640.x
[95] Jerke, U., Rolle, S., Dittmar, G., Bayat, B., Santoso, S., Sporbert, A., Luft, F. and Kettritz, R. (2011) Complement Receptor Mac-1 Is an Adaptor for NB1 (CD177)-Mediated PR3-ANCA Neutrophil Activation. The Journal of Biological Chemistry, 286, 7070-7081.
http://dx.doi.org/10.1074/jbc.M110.171256
[96] Bayat, B., Werth, S., Sachs, U.J., Newman, D.K., Newman, P.J. and Santoso, S. (2010) Neutrophil Transmigration Mediated by the Neutrophil-Specific Antigen CD177 Is Influenced by the Endothelial S536N Dimorphism of Platelet Endothelial Cell Adhesion Molecule-1. The Journal of Immunology, 184, 3889-3896.
http://dx.doi.org/10.4049/jimmunol.0903136
[97] McDonald, D.M. (1994) Endothelial Gaps and Permeability of Venules in Rat Tracheas Exposed to Inflammatory Stimuli. American Journal of Physiology, 266, L61-L83.
[98] Valeski, J.E. and Baldwin, A.L. (1999) Effect of Early Transient Adherent Leukocytes on Venular Permeability and Endothelial Actin Cytoskeleton. American Journal of Physiology, 277, H569-H575.
[99] DiStasi, M.R. and Ley, K. (2009) Opening the Flood-Gates: How Neutrophil-Endothelial Interactions Regulate Permeability. Trends in Immunology, 30, 547-556.
http://dx.doi.org/10.1016/j.it.2009.07.012
[100] Berden, A.E., Ferrario, F., Hagen, E.C., Jayne, D.R., Jennette, J.C., Joh, K., Neumann, I., Noel, L.H., Pusey, C.D., Waldherr, R., Bruijn, J.A. and Bajema, I.M. (2010) Histopathologic Classification of ANCA-Associated Glomerulonephritis. Journal of the American Society of Nephrology, 21, 1628-1636.
http://dx.doi.org/10.1681/ASN.2010050477
[101] Falk, R.J., Terrell, R.S., Charles, L.A. and Jennette, J.C. (1990) Anti-Neutrophil Cytoplasmic Autoantibodies Induce Neutrophils to Degranulate and Produce Oxygen Radicals in Vitro. Proceedings of the National Academy of Sciences of the United States of America, 87, 4115-4119.
http://dx.doi.org/10.1073/pnas.87.11.4115
[102] Westlin, W.F. and Gimbrone Jr., M.A. (1993) Neutrophil-Mediated Damage to Human Vascular Endothelium. Role of Cytokine Activation. American Journal of Pathology, 142, 117-128.
[103] Yang, J.J., Kettritz, R., Falk, R.J., Jennette, J.C. and Gaido, M.L. (1996) Apoptosis of Endothelial Cells Induced by the Neutrophil Serine Proteases Proteinase 3 and Elastase. American Journal of Pathology, 149, 1617-1626.
[104] Preston, G.A., Zarella, C.S., Pendergraft 3rd, W.F., Rudolph, E.H., Yang, J.J., Sekura, S.B., Jennette, J.C. and Falk, R.J. (2002) Novel Effects of Neutrophil-Derived Proteinase 3 and Elastase on the Vascular Endothelium Involve in Vivo Cleavage of NF-Kappab and Proapoptotic Changes in JNK, ERK, and p38 MAPK Signaling Pathways. Journal of the American Society of Nephrology, 13, 2840-2849.
http://dx.doi.org/10.1097/01.ASN.0000034911.03334.C3
[105] Pendergraft 3rd, W.F., Rudolph, E.H., Falk, R.J., Jahn, J.E., Grimmler, M., Hengst, L., Jennette, J.C. and Preston, G.A. (2004) Proteinase 3 Sidesteps Caspases and Cleaves p21Waf1/Cip1/Sdi1 to Induce Endothelial Cell Apoptosis. Kidney International, 65, 75-84.
http://dx.doi.org/10.1111/j.1523-1755.2004.00364.x
[106] Rahman, A. and Fazal, F. (2009) Hug Tightly and Say Goodbye: Role of Endothelial ICAM-1 in Leukocyte Transmigration. Antioxidants Redox Signaling, 11, 823-839.
http://dx.doi.org/10.1089/ars.2008.2204
[107] Woywodt, A., Streiber, F., de Groot, K., Regelsberger, H., Haller, H. and Haubitz, M. (2003) Circulating Endothelial Cells as Markers for ANCA-Associated Small-Vessel Vasculitis. The Lancet, 361, 206-210.
http://dx.doi.org/10.1016/S0140-6736(03)12269-6
[108] Tadema, H., Abdulahad, W.H., Lepse, N., Stegeman, C.A., Kallenberg, C.G. and Heeringa, P. (2011) Bacterial DNA Motifs Trigger ANCA Production in ANCA-Associated Vasculitis in Remission. Rheumatology (Oxford), 50, 689-696.
http://dx.doi.org/10.1093/rheumatology/keq375
[109] Stegeman, C.A., Tervaert, J.W., Sluiter, W.J., Manson, W.L., de Jong, P.E. and Kallenberg, C.G. (1994) Association of Chronic Nasal Carriage of Staphylococcus aureus and Higher Relapse Rates in Wegener Granulomatosis. Annals of Internal Medicine, 120, 12-17.
http://dx.doi.org/10.7326/0003-4819-120-1-199401010-00003
[110] Pendergraft 3rd, W.F., Preston, G.A., Shah, R.R., Tropsha, A., Carter Jr., C.W., Jennette, J.C. and Falk, R.J. (2004) Autoimmunity Is Triggered by cPR-3(105-201), a Protein Complementary to Human Autoantigen Proteinase-3. Nature Medicine, 10, 72-79.
http://dx.doi.org/10.1038/nm968
[111] Tadema, H., Kallenberg, C.G., Stegeman, C.A. and Heeringa, P. (2011) Reactivity against Complementary Proteinase-3 Is Not Increased in Patients with PR3-ANCA-Associated Vasculitis. PLoS ONE, 6, e17972.
http://dx.doi.org/10.1371/journal.pone.0017972
[112] Hogan, S.L., Cooper, G.S., Savitz, D.A., Nylander-French, L.A., Parks, C.G., Chin, H., Jennette, C.E., Lionaki, S., Jennette, J.C. and Falk, R.J. (2007) Association of Silica Exposure with Anti-Neutrophil Cytoplasmic Autoantibody Small-Vessel Vasculitis: A Population-Based, Case-Control Study. Clinical Journal of the American Society of Nephrology, 2, 290-299.
http://dx.doi.org/10.2215/CJN.03501006
[113] Hogan, S.L., Satterly, K.K., Dooley, M.A., Nachman, P.H., Jennette, J.C. and Falk, R.J. (2001) Silica Exposure in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis and Lupus Nephritis. Journal of the American Society of Nephrology, 12, 134-142.
[114] Kallenberg, C.G. (1995) Overlapping Syndromes, Undifferentiated Connective Tissue Disease, and Other Fibrosing Conditions. Current Opinion in Rheumatology, 7, 568-573.
http://dx.doi.org/10.1097/00002281-199511000-00017
[115] Leigh, J., Wang, H., Bonin, A., Peters, M. and Ruan, X. (1997) Silica-Induced Apoptosis in Alveolar and Granulomatous Cells in Vivo. Environmental Health Perspectives, 105, 1241-1245.
http://dx.doi.org/10.1289/ehp.97105s51241
[116] Chen, M. and Kallenberg, C.G.M. (2010) The Environment, Geoepidemiology and ANCA-Associated Vasculitides. Autoimmunity Reviews, 9, A293-A298.
http://dx.doi.org/10.1016/j.autrev.2009.10.008

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.