Prendecki M and Pusey CD. Recent advances in understanding of the pathogenesis of ANCA-associated vasculitis [version 1; peer review: 2 approved]. F1000Research 2018, 7(F1000 Faculty Rev):1113 (https://doi.org/10.12688/f1000research.14626.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
1Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
Maria Prendecki
Roles:
Writing – Original Draft Preparation
Charles D. Pusey
Roles:
Writing – Review & Editing
OPEN PEER REVIEW
REVIEWER STATUS
Abstract
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are rare systemic autoimmune diseases characterised by inflammation of small blood vessels. Recent developments have been made in our understanding of the pathogenesis of these diseases, including the pathogenic role of ANCA, neutrophils and monocytes as mediators of injury, dysregulation of the complement system, and the role of T and B cells. Current treatment strategies for AAV are based on broad immunosuppression, which may have significant side effects. Advances in understanding of the pathogenesis of disease have led to the identification of new therapeutic targets which may lead to treatment protocols with less-toxic side effects. The aim of this review is to summarise current information and recent advances in understanding of the pathogenesis of AAV.
Corresponding author:
Maria Prendecki
Competing interests:
No competing interests were disclosed.
Grant information:
We acknowledge support from the NIHR Imperial Biomedical Research Centre.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a group of systemic autoimmune diseases characterised by inflammation of small blood vessels with multi-organ involvement, including the kidney, lung, nerves, gut, and ear, nose, and throat (ENT). Until 1979, it was assumed that rapidly progressive glomerulonephritis (RPGN) was caused by circulating immune complexes or anti-glomerular basement membrane (anti-GBM) antibodies. However, Stilmant et al. observed that many cases had no evidence of glomerular deposition of complement or immunoglobulin and were pauci-immune1. Subsequently, antibody binding to neutrophil cytoplasm was shown by using serum from patients with crescentic glomerulonephritis for indirect immunofluorescence2. The two main target antigens of ANCA were then identified as proteinase-3 (PR3) and myeloperoxidase (MPO), which are present in the granules of neutrophils and lysosomes of monocytes3–5. There are differing clinical syndromes associated with ANCA: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA), and renal limited vasculitis. Around 10% of patients are ANCA negative6. The aim of this review is to provide an overview of the current information and recent advances in understanding of the pathogenesis of AAV focussing on MPA and GPA rather than EGPA.
AAV is uncommon; its incidence in Europe is reported to be 13 to 20 cases per million7. There is a slight male preponderance, and incidence increases with age, although peak incidence has been reported variously as 55 to 64, 65 to 74, and more than 75 years7–9. AAV is rarer in non-Caucasian or non-Asian populations, and there are differences in the incidence of different clinical phenotypes between populations. When a Japanese and UK population were directly compared, the overall incidence of AAV was similar but GPA was much less common in Japan10. There is certainly a genetic basis for AAV, and this may explain some of the population differences. Two large genome-wide association studies showed an association between AAV and genetic factors, and there was a stronger genetic association with ANCA specificity than clinical syndrome, suggesting that MPO-ANCA and PR3-ANCA may be defining differing diseases. In anti-PR3 AAV, there were associations with HLA-DP, PRTN3 (the gene encoding proteinase-3), and SERPINA1 (the gene encoding a1-antitrypsin, a circulating inhibitor of PR3); anti-MPO AAV was associated mainly with HLA-DQ polymorphisms11,12. There are reports of an association between HLA-DRB1*15 and PR3-ANCA in African-Americans, and HLA DPB1*0401 has also been associated with PR3-ANCA disease13,14. Several studies have shown an association with a single-nucleotide polymorphism (SNP) in PTPN22 (the gene encoding a lymphoid-specific phosphatase which is involved in T-cell activation) and GPA, although whether this SNP is also associated with MPA is less clear15,16.
There are several reported environmental associations with AAV. Infection may precede disease relapse and nasal carriage of staphylococci correlates with disease relapse in patients with anti-PR3 AAV and ENT disease17. A mechanism of molecular mimicry whereby an immune response against microbial antigens cross-reacts with self tissue has been proposed18. An atypical ANCA, anti-human lysosome-associated membrane protein-2 (anti-LAMP-2) antibody, was first identified in patients with pauci-immune glomerulonephritis (GN) in 1995 and has 100% sequence homology with FimH, a bacterial adhesion protein on Gram-negative bacteria. Rats immunised with FimH develop GN and antibodies which react to human and rat LAMP-218. However, the clinical association has been reproduced in some but not other laboratories19,20. An alternative proposal involves complementary peptides of the auto-antigen. Patients with anti-PR3 AAV have been shown to have circulating antibodies to both PR3 and anti-sense complementary PR3 peptides (cPr3), suggesting that an initial immune response may be against the anti-sense peptide leading to the development of anti-idiotype antibodies which recognise PR321.
Other environmental risk factors identified include silica, heavy metal exposure and drugs which can induce ANCA, including propylthiouracil, hydralazine, and levamisole-contaminated cocaine22–24.
Pathogenicity of ANCA
ANCA have been shown to be pathogenic in several clinical and pre-clinical studies. There is a reported case of maternal–foetal transfer of anti-MPO ANCA resulting in neonatal renal disease and pulmonary haemorrhage shortly after birth25. Levels of ANCA have been shown to correlate with disease activity in some but not all case series with better correlation in patients with renal disease26. Removal of antibodies with plasma exchange has been shown to improve prognosis in severe AAV27, and depletion of B cells with rituximab has been shown to be effective in induction and maintenance of remission28–30.
Some of the best evidence for the pathogenesis of ANCA comes from a passive transfer model of anti-MPO AAV. MPO-deficient mice are immunised with mouse MPO and develop high-titre anti-MPO antibodies. Transfer of these antibodies into wild-type or Rag2 mice (which lack lymphocytes) results in the mice developing severe vasculitis with crescentic GN and pulmonary haemorrhage, demonstrating that MPO-ANCA alone are sufficient to induce disease31. Neutrophils were shown to have an essential role in disease pathogenesis in this model; depletion of neutrophils prior to transfer of antibodies prevented the development of disease32. ANCA have also been shown to be pathogenic in an autoimmune rat model of AAV, experimental autoimmune vasculitis in the susceptible WKY rat strain. Rats are immunised with human MPO in complete Freund’s adjuvant and also receive two doses of intraperitoneal pertussis toxin as an immune adjuvant. Animals develop polyclonal anti-MPO antibodies with pauci-immune vasculitis and pulmonary haemorrhage. Intra-vital imaging in this model showed increased leucocyte adhesion and transmigration at the endothelium in response to CXCL1, and this could also be observed in healthy animals following infusion of anti-MPO IgG isolated from rats with disease, supporting a role for the pathogenicity of ANCA33. The pathogenic role of PR3-ANCA is less well defined and this is owing, at least in part, to the difficulty in developing animal models of anti-PR3 AAV. An attempt to create a passive transfer model analogous to the one using anti-MPO antibodies resulted in no features of vasculitis and only a mild inflammatory response to tumour necrosis factor (TNF) in the skin34. This is potentially due to a lack of PR3 expression on the surface of unstimulated mouse neutrophils and a lesser degree of sequence homology between mouse and human PR3 than there is for MPO35.
Despite evidence for the pathogenicity of ANCA, the relationship between ANCA and active vasculitis is complex and ANCA are not always pathogenic. ANCA can persist in remission, can recur without evidence of clinical relapse, and have been identified in healthy individuals. Natural anti-MPO antibodies are of lower avidity and titre than are antibodies from patients with AAV36. The IgG subclass of ANCA may also be important. In vitro, IgG3-ANCA has been shown to be more effective than other IgG subclasses at activating neutrophils, although in other clinical studies the IgG subclass of ANCA did not correlate with disease severity37,38. Epitope mapping to identify the pathogenic epitopes of both PR3 and MPO have been carried out. One study using epitope excision and mass spectrometry identified a linear epitope on MPO at residue 447–459 that was limited to patients with disease; interestingly, when the three-dimensional structure of MPO was visualised, this epitope was close to epitopes seen in individuals with natural antibodies, leading the authors to suggest that pathogenic ANCA arise by a process of epitope spreading. In this study, IgG purified from patients with ANCA-negative vasculitis was able to bind to an MPO epitope, and it was suggested that competition for binding in immunoassays by a fragment of caeruloplasmin may be why ANCA cannot be detected in these patients39.
ANCA-induced activation of neutrophils and monocytes
The ability of ANCA to bind to and activate neutrophils causing degranulation and production of reactive oxygen species (ROS) was first shown nearly 30 years ago40. Since then, several in vitro studies have shown that neutrophils which have been primed with TNFα, lipopolysaccharide (LPS), or complement (C5a) undergo activation and degranulation and mediate endothelial cell damage when stimulated with MPO or PR3-ANCA41,42. ANCA binding to neutrophils has also been shown to activate intracellular signalling pathways leading to altered adhesion molecule expression and conformational changes which promote neutrophil adhesion and transmigration at the vascular endothelium43. Both the ANCA antigen-binding site and binding to Fcγ receptors on the surface of primed neutrophils and monocytes have been identified as mechanisms by which ANCA activates these cells.
ANCA have also been shown to be mediators of NETosis, a form of neutrophil cell death with release of neutrophil extracellular traps (NETs). NETs have a DNA backbone with a variety of pro-inflammatory proteins, including histones, high-mobility group box 1 (HMGB-1), neutrophil elastase, calprotectin, MPO, and PR344. NETs have been shown to be present at sites of tissue damage in AAV, and patients also have increased levels of NETs in the circulation45. NETs may play a pathogenic role in AAV; they can cause activation of dendritic cells and autoreactive B cells, endothelial damage, and complement activation46,47. NETs may also play a role in the loss of tolerance to ANCA antigens; one study has shown that dendritic cells activated by NETs induce loss of tolerance to both MPO and PR348. Neutrophils from patients with AAV undergo more spontaneous NETosis than those from healthy controls, but ANCA can also induce this process. The exact mechanism by which ANCA induce NETosis is unclear but is thought to require binding of both Fcγ receptors and the ANCA target antigen on the cell surface49.
Although many studies have focussed on neutrophils and their interactions with ANCA in the pathogenesis of disease, monocytes may also play a role in mediating AAV. Monocytes express ANCA antigens, and stimulation of monocytes in vitro with ANCA leads to cytokine production and generation of ROS50,51. Monocytes from patients with AAV have been shown to express higher levels of CD14, the LPS receptor, than monocytes from patients in remission or healthy controls, suggesting an increased cell activation state in patients with AAV52. Circulating monocytes from patients with active AAV have also been shown to express higher levels of cell surface markers which are essential for interaction between leucocytes and the endothelium53. Recent studies have shown that monocytes and macrophages are the predominant cells in glomeruli in renal biopsies from patients with AAV54,55. In one study using the passive transfer model of mouse anti-MPO AAV, depleting monocytes decreased glomerular crescent formation but had no effect on urinary abnormalities56.
Complement and AAV
There is increasing evidence for a role for complement in the pathogenesis of AAV. In the antibody transfer model of mouse anti-MPO AAV, mice deficient in C5 or those depleted of complement by pre-treatment with cobra venom did not develop disease. C4-deficient mice were not protected, suggesting a role for the alternative rather than the classic pathway57. Mice deficient in C5aR are protected from disease, and mice with knock-in of the human C5a receptor treated with an antagonist of human C5aR (CCX168; avacopan) showed decreased disease severity58,59. There is also evidence for a role for complement from in vitro studies; C5a can prime neutrophils to respond to stimulation by ANCA, and this may be due to its actions at the C5aR42. The interaction of C5a with its other receptor, C5L2, is more complex, and some studies report that it has a pro-inflammatory role in vitro but knockout of C5L2 resulted in more-severe disease in mouse anti-MPO AAV59,60. It has also been shown that both ANCA-stimulated neutrophils and NETs can activate the alternative pathway of the complement system, leading to a positive feedback loop47,57. There is evidence of complement deposition, such as C3d and factor B, at sites of tissue inflammation in patients with AAV and kidney deposition of Bb (a marker of activation of the alternative pathway) correlated with pathological severity of disease61. Plasma levels of C3a, C5a, soluble C5b-9, and Bb were higher in patients with active AAV than in those in remission62,63. In one study, patients with lower circulating C3 levels were shown to have poorer outcomes in terms of both patient and renal survival64. Blockade of C5 cleavage with eculizumab has been reported as treatment for AAV in one case report. It was used as add-on therapy to cyclophosphamide with good renal recovery, although unfortunately the patient developed non-Hodgkin lymphoma, thought to be unrelated to the eculizumab, and died from sepsis following chemotherapy65. A recently published phase II trial has shown that avacopan was effective in replacing high-dose glucocorticoids for induction of remission when added to cyclophosphamide or rituximab66. A phase III trial of this treatment approach is currently recruiting (ADVOCATE, ClinicalTrials.gov Identifier: NCT02994927).
B cells and AAV
B cells have a central role in AAV in that they produce ANCA, and levels of activated B cells have been shown to correlate with disease activity67. Depletion of B cells with rituximab has been shown to be effective in inducing and maintaining disease remission28,29. The return of B cells after rituximab may predict relapse of AAV, and it has been shown that following induction of remission with rituximab and cyclophosphamide, the return of B cells has a high negative predictive value for relapse but a poor positive predictive value68,69. It may be that the phenotype of the repopulating B cells is important in predicting relapse, and one study suggested that those who repopulate with a low percentage of CD5+ B cells have a shorter time to relapse70. Several studies have shown differences in B-cell subsets between patients with AAV and healthy controls. One study reported a memory B-cell subset with higher CD19 expression in patients with AAV, suggesting that these may represent autoreactive B cells71. Regulatory B (Breg) cells skew T-cell differentiation towards regulatory T (Treg) cells and away from T helper 1 (TH1) and TH17 phenotypes and decrease B cells which are producing ANCA72. Several studies have shown decreased Breg cells in patients with AAV as defined by cell surface markers such as CD5, CD24, and CD3873,74. In vitro, neutrophils stimulated with ANCA release B-cell survival factors such as B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). In one study, incubating B cells with supernatant from ANCA-stimulated neutrophils or with recombinant BLyS resulted in increased B-cell survival75. Several studies have reported higher levels of BLyS in patients with AAV, and some have shown that levels correlated with disease activity and ANCA titre and decreased following treatment76,77. Following rituximab treatment, serum BLyS levels have been shown to increase both in patients with AAV and in patients with other auto-immune diseases75,78. One study has shown that a SNP in BLyS predicted which patients were more likely to relapse following rituximab and had earlier return of B cells after treatment. The authors suggest that this SNP may result in higher baseline BLyS or increase in BLyS after B-cell depletion79. This may suggest a potential role for targeting BLyS as maintenance treatment of AAV following induction treatment with rituximab. A phase III trial which added anti-BLyS treatment with belimumab to azathioprine and steroids for maintenance of remission did not show any reduction in risk of relapse; however, in the subgroup of patients who received rituximab as an induction agent, belimumab did reduce relapse rate, although this was not significant80.
T-cell immunity and AAV
T cells are present in glomeruli and the tubulointerstitium in renal biopsy tissue from patients with AAV, suggesting that T-cell responses are pathogenic. Studies have shown that patients with AAV have defective Treg cell suppressive function81; one study has also shown increased frequency of a CD4+ T-cell subset that is resistant to the suppressor effects of Treg cells82. In a small group of patients, anti-thymocyte globulin was used as a successful treatment for refractory GPA83. Additionally, differential TH cell polarisation has been described in AAV, such that patients with active and systemic disease are more likely to have a TH2 response84.
In the mouse passive transfer model of anti-MPO AAV, CD4+ T cells have been used to transfer disease, demonstrating a role for T cells in pathogenesis. Mice pre-immunised with CD4+ T cells from MPO-immunised, B-cell-deficient, MPO-deficient mice developed greater severity of GN after induction of disease with MPO-ANCA compared with mice immunised with OVA-sensitised CD4+ cells85. In a model of anti-MPO AAV in which mice are immunised with MPO followed by a subnephritogenic dose of anti-GBM globulin, depletion of CD4+ cells decreased disease severity with no effect on ANCA titres86. This model of disease has been used to identify pathogenic epitopes for both CD4+ and CD8+ T cells, and these epitopes have been used to induce disease87,88.
The TH17 axis may also be involved in the development of ANCA; serum interleukin-23 (IL-23) and IL-17 are raised in the serum of patients with acute AAV, and in one study IL-23 levels correlated with disease activity89. IL-23 induces T-cell differentiation into the TH17 subset and enhances the production of IL-17 from these cells. Stimulation of neutrophils by ANCA has been shown to induce the production of IL-1790, and in one study IL-17-deficient mice were protected from MPO-ANCA-induced disease91.
Granuloma formation
Granulomatous disease is frequently seen in isolated and systemic GPA. Early granuloma formation is typified by activated neutrophils forming micro-abscesses and only scattered multinucleated giant cells. Later granulomas consist of a central necrotic area with multinucleated giant cells at the margin and surrounding dendritic cells, T lymphocytes, B lymphocytes, and plasma cells forming a follicular structure of ectopic lymphoid tissue92,93. The mechanisms initiating granuloma formation have not been fully identified, but there is some evidence that granulomatous inflammation is being driven by T cells producing TH1 cytokines94. It has also been shown that APRIL and BLyS are present in granulomas along with activated B cells, leading some authors to suggest that close association of B cells with PR3-positive cells within granulomas could lead to initiation or maintenance of anti-PR3 responses95. In an in vivo model of xenografted nasal mucosa from patients with GPA to mice, tissue damage was shown to be mediated by fibroblasts96.
Conclusions
The pathogenesis of AAV is complex and remains incompletely understood. Recent advances have been made in our understanding of the mechanisms of both the development of auto-immunity and inflammation leading to tissue damage. Our understanding of the generation of the auto-immune response is incomplete but may well involve molecular mimicry and dysregulation of both B and T cells. There is substantial evidence for the pathogenicity of ANCA, and neutrophils are both the target of ANCA and mediators of endothelial injury. NETs in particular have been shown to mediate tissue damage but also could be involved in the loss of tolerance to ANCA. Advances in understanding the role of the alternative pathway of the complement system in AAV have led to clinical trials of novel therapeutic agents. Further understanding of the mechanisms of disease may lead to the use of other novel therapeutics such as molecules to block NETosis, BLyS inhibitors, or monoclonal antibodies against IL-17 or IL-23.
Competing interests
No competing interests were disclosed.
Grant information
We acknowledge support from the NIHR Imperial Biomedical Research Centre.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
F1000 recommended
References
1.
Stilmant MM, Bolton WK, Sturgill BC, et al.:
Crescentic glomerulonephritis without immune deposits: clinicopathologic features.
Kidney Int.
1979; 15(2): 184–95. PubMed Abstract
| Publisher Full Text
2.
Davies DJ, Moran JE, Niall JF, et al.:
Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?
Br Med J (Clin Res Ed).
1982; 285(6342): 606. PubMed Abstract
| Publisher Full Text
| Free Full Text
3.
Falk RJ, Jennette JC:
Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis.
N Engl J Med.
1988; 318(25): 1651–7. PubMed Abstract
| Publisher Full Text
4.
Niles JL, McCluskey RT, Ahmad MF, et al.:
Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase.
Blood.
1989; 74(6): 1888–93. PubMed Abstract
5.
van der Woude FJ, Rasmussen N, Lobatto S, et al.:
Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis.
Lancet.
1985; 1(8426): 425–9. PubMed Abstract
| Publisher Full Text
6.
Eisenberger U, Fakhouri F, Vanhille P, et al.:
ANCA-negative pauci-immune renal vasculitis: histology and outcome.
Nephrol Dial Transplant.
2005; 20(7): 1392–9. PubMed Abstract
| Publisher Full Text
7.
Watts RA, Lane SE, Bentham G, et al.:
Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom.
Arthritis Rheum.
2000; 43(2): 414–9. PubMed Abstract
| Publisher Full Text
8.
Gonzalez-Gay MA, Garcia-Porrua C, Guerrero J, et al.:
The epidemiology of the primary systemic vasculitides in northwest Spain: implications of the Chapel Hill Consensus Conference definitions.
Arthritis Rheum.
2003; 49(3): 388–93. PubMed Abstract
| Publisher Full Text
9.
Mohammad AJ, Jacobsson LT, Westman KW, et al.:
Incidence and survival rates in Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and polyarteritis nodosa.
Rheumatology (Oxford).
2009; 48(12): 1560–5. PubMed Abstract
| Publisher Full Text
10.
Fujimoto S, Watts RA, Kobayashi S, et al.:
Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the U.K.
Rheumatology (Oxford).
2011; 50(10): 1916–20. PubMed Abstract
| Publisher Full Text
12.
Merkel PA, Xie G, Monach PA, et al.:
Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.
Arthritis Rheumatol.
2017; 69(5): 1054–66. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
13.
Cao Y, Schmitz JL, Yang J, et al.:
DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans.
J Am Soc Nephrol.
2011; 22(6): 1161–7. PubMed Abstract
| Publisher Full Text
| Free Full Text
14.
Hilhorst M, Arndt F, Joseph Kemna M, et al.:
HLA-DPB1 as a Risk Factor for Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Cohort Study.
Arthritis Rheumatol.
2016; 68(7): 1721–30. PubMed Abstract
| Publisher Full Text
15.
Carr EJ, Niederer HA, Williams J, et al.:
Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis.
BMC Med Genet.
2009; 10: 121. PubMed Abstract
| Publisher Full Text
| Free Full Text
16.
Martorana D, Maritati F, Malerba G, et al.:
PTPN22 R620W polymorphism in the ANCA-associated vasculitides.
Rheumatology (Oxford).
2012; 51(5): 805–12. PubMed Abstract
| Publisher Full Text
17.
Popa ER, Stegeman CA, Abdulahad WH, et al.:
Staphylococcal toxic-shock-syndrome-toxin-1 as a risk factor for disease relapse in Wegener's granulomatosis.
Rheumatology (Oxford).
2007; 46(6): 1029–33. PubMed Abstract
| Publisher Full Text
19.
Roth AJ, Brown MC, Smith RN, et al.:
Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis.
J Am Soc Nephrol.
2012; 23(3): 545–55. PubMed Abstract
| Publisher Full Text
| Free Full Text
21.
Pendergraft WF 3rd, Preston GA, Shah RR, et al.:
Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.
Nat Med.
2004; 10(1): 72–9. PubMed Abstract
| Publisher Full Text
22.
Pendergraft WF 3rd, Herlitz LC, Thornley-Brown D, et al.:
Nephrotoxic effects of common and emerging drugs of abuse.
Clin J Am Soc Nephrol.
2014; 9(11): 1996–2005. PubMed Abstract
| Publisher Full Text
| Free Full Text
23.
de Lind van Wijngaarden RA, van Rijn L, Hagen EC, et al.:
Hypotheses on the etiology of antineutrophil cytoplasmic autoantibody associated vasculitis: the cause is hidden, but the result is known.
Clin J Am Soc Nephrol.
2008; 3(1): 237–52. PubMed Abstract
| Publisher Full Text
24.
Yu F, Chen M, Gao Y, et al.:
Clinical and pathological features of renal involvement in propylthiouracil-associated ANCA-positive vasculitis.
Am J Kidney Dis.
2007; 49(5): 607–14. PubMed Abstract
| Publisher Full Text
25.
Bansal PJ, Tobin MC:
Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement.
Ann Allergy Asthma Immunol.
2004; 93(4): 398–401. PubMed Abstract
| Publisher Full Text
26.
Fussner LA, Hummel AM, Schroeder DR, et al.:
Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3.
Arthritis Rheumatol.
2016; 68(7): 1700–10. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
27.
Jayne DR, Gaskin G, Rasmussen N, et al.:
Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.
J Am Soc Nephrol.
2007; 18(7): 2180–8. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
31.
Xiao H, Heeringa P, Hu P, et al.:
Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.
J Clin Invest.
2002; 110(7): 955–63. PubMed Abstract
| Publisher Full Text
| Free Full Text
32.
Xiao H, Heeringa P, Liu Z, et al.:
The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies.
Am J Pathol.
2005; 167(1): 39–45. PubMed Abstract
| Publisher Full Text
| Free Full Text
33.
Little MA, Smyth CL, Yadav R, et al.:
Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo.
Blood.
2005; 106(6): 2050–8. PubMed Abstract
| Publisher Full Text
34.
Pfister H, Ollert M, Fröhlich LF, et al.:
Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo.
Blood.
2004; 104(5): 1411–8. PubMed Abstract
| Publisher Full Text
35.
Little MA:
L7. Animal models of PR3-ANCA vasculitis: approaches and controversies.
Presse Med.
2013; 42(4 Pt 2): 512–5. PubMed Abstract
| Publisher Full Text
36.
Xu PC, Cui Z, Chen M, et al.:
Comparison of characteristics of natural autoantibodies against myeloperoxidase and anti-myeloperoxidase autoantibodies from patients with microscopic polyangiitis.
Rheumatology (Oxford).
2011; 50(7): 1236–43. PubMed Abstract
| Publisher Full Text
37.
Nowack R, Grab I, Flores-Suarèz LF, et al.:
ANCA titres, even of IgG subclasses, and soluble CD14 fail to predict relapses in patients with ANCA-associated vasculitis.
Nephrol Dial Transplant.
2001; 16(8): 1631–7. PubMed Abstract
| Publisher Full Text
38.
Mulder AH, Heeringa P, Brouwer E, et al.:
Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fc gamma RII-dependent process.
Clin Exp Immunol.
1994; 98(2): 270–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
40.
Falk RJ, Terrell RS, Charles LA, et al.:
Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.
Proc Natl Acad Sci U S A.
1990; 87(11): 4115–9. PubMed Abstract
| Publisher Full Text
| Free Full Text
41.
Savage CO, Gaskin G, Pusey CD, et al.:
Anti-neutrophil cytoplasm antibodies can recognize vascular endothelial cell-bound anti-neutrophil cytoplasm antibody-associated autoantigens.
Exp Nephrol.
1993; 1(3): 190–5. PubMed Abstract
42.
Schreiber A, Xiao H, Jennette JC, et al.:
C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.
J Am Soc Nephrol.
2009; 20(2): 289–98. PubMed Abstract
| Publisher Full Text
| Free Full Text
43.
Radford DJ, Luu NT, Hewins P, et al.:
Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells.
Arthritis Rheum.
2001; 44(12): 2851–61. PubMed Abstract
| Publisher Full Text
46.
Villanueva E, Yalavarthi S, Berthier CC, et al.:
Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.
J Immunol.
2011; 187(1): 538–52. PubMed Abstract
| Publisher Full Text
| Free Full Text
48.
Sangaletti S, Tripodo C, Chiodoni C, et al.:
Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity.
Blood.
2012; 120(15): 3007–18. PubMed Abstract
| Publisher Full Text
49.
Kettritz R, Jennette JC, Falk RJ:
Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils.
J Am Soc Nephrol.
1997; 8(3): 386–94. PubMed Abstract
50.
Weidner S, Neupert W, Goppelt-Struebe M, et al.:
Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro.
Arthritis Rheum.
2001; 44(7): 1698–706. PubMed Abstract
| Publisher Full Text
52.
Tarzi RM, Liu J, Schneiter S, et al.:
CD14 expression is increased on monocytes in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis and correlates with the expression of ANCA autoantigens.
Clin Exp Immunol.
2015; 181(1): 65–75. PubMed Abstract
| Publisher Full Text
| Free Full Text
53.
Haller H, Eichhorn J, Pieper K, et al.:
Circulating leukocyte integrin expression in Wegener's granulomatosis.
J Am Soc Nephrol.
1996; 7(1): 40–8. PubMed Abstract
54.
Weidner S, Carl M, Riess R, et al.:
Histologic analysis of renal leukocyte infiltration in antineutrophil cytoplasmic antibody-associated vasculitis: importance of monocyte and neutrophil infiltration in tissue damage.
Arthritis Rheum.
2004; 50(11): 3651–7. PubMed Abstract
| Publisher Full Text
56.
Rousselle A, Kettritz R, Schreiber A:
Monocytes Promote Crescent Formation in Anti-Myeloperoxidase Antibody-Induced Glomerulonephritis.
Am J Pathol.
2017; 187(9): 1908–15. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
57.
Xiao H, Schreiber A, Heeringa P, et al.:
Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.
Am J Pathol.
2007; 170(1): 52–64. PubMed Abstract
| Publisher Full Text
| Free Full Text
58.
Huugen D, van Esch A, Xiao H, et al.:
Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice.
Kidney Int.
2007; 71(7): 646–54. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
60.
Hao J, Wang C, Yuan J, et al.:
A pro-inflammatory role of C5L2 in C5a-primed neutrophils for ANCA-induced activation.
PLoS One.
2013; 8(6): e66305. PubMed Abstract
| Publisher Full Text
| Free Full Text
61.
Xing GQ, Chen M, Liu G, et al.:
Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis.
J Clin Immunol.
2009; 29(3): 282–91. PubMed Abstract
| Publisher Full Text
62.
Gou SJ, Yuan J, Wang C, et al.:
Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN.
Clin J Am Soc Nephrol.
2013; 8(11): 1884–91. PubMed Abstract
| Publisher Full Text
| Free Full Text
63.
Manenti L, Vaglio A, Gnappi E, et al.:
Association of Serum C3 Concentration and Histologic Signs of Thrombotic Microangiopathy with Outcomes among Patients with ANCA-Associated Renal Vasculitis.
Clin J Am Soc Nephrol.
2015; 10(12): 2143–51. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
64.
Augusto JF, Langs V, Demiselle J, et al.:
Low Serum Complement C3 Levels at Diagnosis of Renal ANCA-Associated Vasculitis Is Associated with Poor Prognosis.
PLoS One.
2016; 11(7): e0158871. PubMed Abstract
| Publisher Full Text
| Free Full Text
65.
Manenti L, Urban ML, Maritati F, et al.:
Complement blockade in ANCA-associated vasculitis: an index case, current concepts and future perspectives.
Intern Emerg Med.
2017; 12(6): 727–31. PubMed Abstract
| Publisher Full Text
67.
Popa ER, Stegeman CA, Bos NA, et al.:
Differential B- and T-cell activation in Wegener's granulomatosis.
J Allergy Clin Immunol.
1999; 103(5 Pt 1): 885–94. PubMed Abstract
| Publisher Full Text
68.
Alberici F, Smith RM, Jones RB, et al.:
Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis.
Rheumatology (Oxford).
2015; 54(7): 1153–60. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
69.
McAdoo SP, Medjeral-Thomas N, Gopaluni S, et al.:
Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis.
Nephrol Dial Transplant.
2018. PubMed Abstract
| Publisher Full Text
70.
Bunch DO, Mendoza CE, Aybar LT, et al.:
Gleaning relapse risk from B cell phenotype: decreased CD5+ B cells portend a shorter time to relapse after B cell depletion in patients with ANCA-associated vasculitis.
Ann Rheum Dis.
2015; 74(9): 1784–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
71.
Culton DA, Nicholas MW, Bunch DO, et al.:
Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss.
J Clin Immunol.
2007; 27(1): 53–68. PubMed Abstract
| Publisher Full Text
73.
Todd SK, Pepper RJ, Draibe J, et al.:
Regulatory B cells are numerically but not functionally deficient in anti-neutrophil cytoplasm antibody-associated vasculitis.
Rheumatology (Oxford).
2014; 53(9): 1693–703. PubMed Abstract
| Publisher Full Text
| Free Full Text
74.
Wilde B, Thewissen M, Damoiseaux J, et al.:
Regulatory B cells in ANCA-associated vasculitis.
Ann Rheum Dis.
2013; 72(8): 1416–9. PubMed Abstract
| Publisher Full Text
75.
Holden NJ, Williams JM, Morgan MD, et al.:
ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process.
Ann Rheum Dis.
2011; 70(12): 2229–33. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
76.
Sanders JS, Huitma MG, Kallenberg CG, et al.:
Plasma levels of soluble interleukin 2 receptor, soluble CD30, interleukin 10 and B cell activator of the tumour necrosis factor family during follow-up in vasculitis associated with proteinase 3-antineutrophil cytoplasmic antibodies: associations with disease activity and relapse.
Ann Rheum Dis.
2006; 65(11): 1484–9. PubMed Abstract
| Publisher Full Text
| Free Full Text
77.
Krumbholz M, Specks U, Wick M, et al.:
BAFF is elevated in serum of patients with Wegener's granulomatosis.
J Autoimmun.
2005; 25(4): 298–302. PubMed Abstract
| Publisher Full Text
78.
Pollard RP, Abdulahad WH, Vissink A, et al.:
Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjogren's syndrome: data from a placebo-controlled clinical trial.
Ann Rheum Dis.
2013; 72(1): 146–8. PubMed Abstract
| Publisher Full Text
79.
Alberici F, Smith RM, Fonseca M, et al.:
Association of a TNFSF13B (BAFF) regulatory region single nucleotide polymorphism with response to rituximab in antineutrophil cytoplasmic antibody-associated vasculitis.
J Allergy Clin Immunol.
2017; 139(5): 1684–1687.e10. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
80.
Jayne D, Blockmans D, Luqmani R, et al.:
Efficacy and Safety of Belimumab in Combination with Azathioprine for Remission Maintenance in Granulomatosis with Polyangiitis and Microscopic Polyangiitis: A Multicenter Randomized, Placebo-Controlled Study (abstract).
Arthritis Rheumatol.
2017; 69(suppl 10). Reference Source
81.
Morgan MD, Day CJ, Piper KP, et al.:
Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells.
Immunology.
2010; 130(1): 64–73. PubMed Abstract
| Publisher Full Text
| Free Full Text
82.
Free ME, Bunch DO, McGregor JA, et al.:
Patients with antineutrophil cytoplasmic antibody-associated vasculitis have defective Treg cell function exacerbated by the presence of a suppression-resistant effector cell population.
Arthritis Rheum.
2013; 65(7): 1922–33. PubMed Abstract
| Publisher Full Text
| Free Full Text
83.
Schmitt WH, Hagen EC, Neumann I, et al.:
Treatment of refractory Wegener's granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients.
Kidney Int.
2004; 65(4): 1440–8. PubMed Abstract
| Publisher Full Text
84.
Schönermarck U, Csernok E, Trabandt A, et al.:
Circulating cytokines and soluble CD23, CD26 and CD30 in ANCA-associated vasculitides.
Clin Exp Rheumatol.
2000; 18(4): 457–63. PubMed Abstract
85.
Gan PY, Holdsworth SR, Kitching AR, et al.:
Myeloperoxidase (MPO)-specific CD4+ T cells contribute to MPO-anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis.
Cell Immunol.
2013; 282(1): 21–7. PubMed Abstract
| Publisher Full Text
86.
Ruth A, Kitching AR, Kwan RY, et al.:
Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis.
J Am Soc Nephrol.
2006; 17(7): 1940–9. PubMed Abstract
| Publisher Full Text
88.
Ooi JD, Chang J, Hickey MJ, et al.:
The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis.
Proc Natl Acad Sci U S A.
2012; 109(39): E2615–24. PubMed Abstract
| Publisher Full Text
| Free Full Text
89.
Nogueira E, Hamour S, Sawant D, et al.:
Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis.
Nephrol Dial Transplant.
2010; 25(7): 2209–17. PubMed Abstract
| Publisher Full Text
90.
Hoshino A, Nagao T, Nagi-Miura N, et al.:
MPO-ANCA induces IL-17 production by activated neutrophils in vitro via classical complement pathway-dependent manner.
J Autoimmun.
2008; 31(1): 79–89. PubMed Abstract
| Publisher Full Text
91.
Gan PY, Steinmetz OM, Tan DS, et al.:
Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis.
J Am Soc Nephrol.
2010; 21(6): 925–31. PubMed Abstract
| Publisher Full Text
| Free Full Text
92.
Mueller A, Holl-Ulrich K, Gross WL:
Granuloma in ANCA-associated vasculitides: another reason to distinguish between syndromes?
Curr Rheumatol Rep.
2013; 15(11): 376. PubMed Abstract
| Publisher Full Text
93.
Schönermarck U, Csernok E, Gross WL:
Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis: challenges and solutions 2014.
Nephrol Dial Transplant.
2015; 30 Suppl 1: i46–52. PubMed Abstract
| Publisher Full Text
94.
Csernok E, Trabandt A, Müller A, et al.:
Cytokine profiles in Wegener's granulomatosis: predominance of type 1 (Th1) in the granulomatous inflammation.
Arthritis Rheum.
1999; 42(4): 742–50. PubMed Abstract
| Publisher Full Text
95.
Zhao Y, Odell E, Choong LM, et al.:
Granulomatosis with polyangiitis involves sustained mucosal inflammation that is rich in B-cell survival factors and autoantigen.
Rheumatology (Oxford).
2012; 51(9): 1580–6. PubMed Abstract
| Publisher Full Text
96.
Kesel N, Köhler D, Herich L, et al.:
Cartilage destruction in granulomatosis with polyangiitis (Wegener's granulomatosis) is mediated by human fibroblasts after transplantation into immunodeficient mice.
Am J Pathol.
2012; 180(5): 2144–55. PubMed Abstract
| Publisher Full Text
We acknowledge support from the NIHR Imperial Biomedical Research Centre.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Prendecki M and Pusey CD. Recent advances in understanding of the pathogenesis of ANCA-associated vasculitis [version 1; peer review: 2 approved] F1000Research 2018, 7(F1000 Faculty Rev):1113 (https://doi.org/10.12688/f1000research.14626.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.
Share
Open Peer Review
Current Reviewer Status:
?
Key to Reviewer Statuses
VIEWHIDE
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
I confirm that I have read this submission and believe that I have an
... Continue reading
Competing Interests: No competing interests were disclosed.
Faculty Reviews are commissioned and written by members of the prestigious Faculty Opinions Faculty, and are edited as a service to our readers. In order to make these reviews as comprehensive and accessible as possible, we seek the reviewers’ input before publication. The reviewers’ names and any additional comments they may have are published alongside the review, as is usual on F1000Research.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
I confirm that I have read this submission and believe that I have an
... Continue reading
Competing Interests: No competing interests were disclosed.
Faculty Reviews are commissioned and written by members of the prestigious Faculty Opinions Faculty, and are edited as a service to our readers. In order to make these reviews as comprehensive and accessible as possible, we seek the reviewers’ input before publication. The reviewers’ names and any additional comments they may have are published alongside the review, as is usual on F1000Research.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations -
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
Adjust parameters to alter display
View on desktop for interactive features
Includes Interactive Elements
View on desktop for interactive features
Competing Interests Policy
Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
Examples of 'Non-Financial Competing Interests'
Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper.
You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors.
You are a close professional associate of any of the authors (e.g. scientific mentor, recent student).
You work at the same institute as any of the authors.
You hope/expect to benefit (e.g. favour or employment) as a result of your submission.
You are an Editor for the journal in which the article is published.
Examples of 'Financial Competing Interests'
You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements.
You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors.
You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on.
Stay Updated
Sign up for content alerts and receive a weekly or monthly email with all newly published articles
Comments on this article Comments (0)