Pathogenesis of ANCA-associated vasculitis

Timmeren, Mirjan M. van; Heeringa, Peter

doi:10.1097/bor.0b013e32834bde57

Cited by 44 publications

(18 citation statements)

References 40 publications

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“…On this line, TLRs have been consistently involved in the pathogenesis of SLE and SVV. [42][43][44] However, in necrotic PMNs, proteins undergo structural changes that altering epitope conformation render MPO and PR3 unsuitable for DC cross-presentation of relevant epitopes. In NETtosis, the cytoplasmic proteins are extruded in association with a nucleic acid thread that preserves their conformation to grants their antimicrobial activity.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Sangaletti

Tripodo

Chiodoni

et al. 2012

Blood

361

314

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Antineutrophil cytoplasmic antibodies (ANCAs) target proteins normally retained within neutrophils, indicating that cell death is involved in the autoimmunity process. Still, ANCA pathogenesis remains obscure. ANCAs activate neutrophils inducing their respiratory burst and a peculiar form of cell death, named NETosis, characterized by formation of neutrophil extracellular traps (NETs), decondensed chromatin threads decorated with cytoplasmic proteins endorsed with antimicrobial activity. NETs have been consistently detected in ANCA-associated small-vessel vasculitis, and this association prompted us to test whether the peculiar structure of NET favors neutrophil proteins uploading into myeloid dendritic cells and the induction of ANCAs and associated autoimmunity. Here we show that myeloid DCs uploaded with and activated by NET components induce ANCA and autoimmunity when injected into naive mice. DC uploading and autoimmunity induction are prevented by NET treatment with DNAse, indicating that NET structural integrity is needed to maintain the antigenicity of cytoplasmic proteins. We found NET intermingling with myeloid dendritic cells also positive for neutrophil myeloperoxidase in myeloperoxidase-ANCA-associated microscopic poliangiitis providing a potential correlative picture in human pathology. These data provide the first demonstration that NET structures are highly immunogenic such to trigger adaptive immune response relevant for autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Sangaletti

Tripodo

Chiodoni

et al. 2012

Blood

361

314

View full text Add to dashboard Cite

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“…First, considering the pathologic features of TMA, endothelial damage has long been regarded as an important disease mechanism in TMAs (24). On the other hand, ANCA-mediated activation of neutrophils that results in endothelial injury is the basic pathophysiologic mechanism involved in AAV (25). It seems that TMA and AAV share the same target cells, namely, endothelial cells, which may contribute to the development of renal TMA in ANCA-associated GN.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Characteristics and Outcomes of Renal Thrombotic Microangiopathy in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis

Chen

Wang

Huang

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Thrombotic microangiopathy (TMA) in ANCA-associated vasculitis (AAV) has been mainly reported in isolated case reports. The aim of this study was to analyze clinical and pathologic characteristics and prognosis of patients with renal TMA in ANCA-associated GN in a large cohort of Chinese patients.Design, setting, participants, & measurements Clinical and renal histopathologic data of 220 patients with biopsy-proven ANCA-associated GN from 1996 to 2013 were retrospectively analyzed. Patients were followed up for a median period of 32 (interquartile range [IQR], 12-65) months, and outcomes of patients were analyzed.Results Among the 220 patients with ANCA-associated GN, 30 were identified having concomitant renal TMA by pathologic evaluation. Compared with the non-TMA group, patients with renal TMA presented with more severe renal injury, as evidenced clinically by a higher level of serum creatinine at diagnosis (5.0 [IQR, 3.5-9.0] versus 3.2 [IQR, 1.7-6.8] mg/dl; P=0.02) and pathologically by a higher percentage of cellular crescents (15.0% [IQR, 6.9%-34.9%] versus 6.9% [IQR, 0%-21.1%]; P=0.04) and more severe interstitial infiltration (2 [IQR, 2-2] versus 2 [IQR, 1-2]; P=0.03) in renal biopsies. Furthermore, multivariate analysis showed that renal TMA was independently associated with mortality of patients with AAV after adjusting for age, sex, initial serum creatinine, tubular atrophy, and interstitial fibrosis (hazard ratio, 1.92; 95% confidence interval, 1.08 to 3.41; P=0.03) or for age, sex, the histopathologic classification scheme proposed by Berden et al. (J Am Soc Nephrol 21: 1628-1636, tubular atrophy, and interstitial fibrosis (hazard ratio, 1.95; 95% confidence interval, 1.07 to 3.55; P=0.03).Conclusions Renal TMA in ANCA-associated GN is not rare and presents with more severe renal injury. Renal TMA is independently associated with all-cause mortality in patients with AAV.

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“…First, homology between human and murine PR3 is less than that for MPO. Hence, animal models are more difficult to generate, and complex alterations in mice are required before achieving some vasculitic changes close to those seen in GPA (52)(53)(54). Second, only a fraction of ANCAs are pathogenic in an individual, i.e., only those ANCAs directed toward one or a few specific epitope(s) are pathogenic.…”

Section: Clinical and Biological Findings Diagnosismentioning

confidence: 99%

Updates in ANCA-associated vasculitis

2016

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Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated. Moreover, some MPO-ANCA subsets, which are directed against a few specific MPO epitopes, have recently been found to be better associated with disease activity, but a different method than the one presently used in routine detection is required to detect them. B cells possibly play a major role in the pathogenesis because they produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes [T helper (Th)1, Th2, Th17, regulatory cluster of differentiation (CD)4+ CD25+ forkhead box P3 (FoxP3)+ T cells] and/or cytokine-chemokine networks. The alternative complement pathway is also involved, and its blockade has been shown to prevent renal disease in an MPO-ANCA murine model. Other recent studies suggested strongest genetic associations by ANCA type rather than by clinical diagnosis. The induction treatment for severe granulomatosis with polyangiitis and microscopic polyangiitis is relatively well codified but does not (yet) really differ by precise diagnosis or ANCA type. It comprises glucocorticoids combined with another immunosuppressant, cyclophosphamide or rituximab. The choice between the two immunosuppressants must consider the comorbidities, past exposure to cyclophosphamide for relapsers, plans for pregnancy, and also the cost of rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate. The optimal maintenance strategy following rituximab-based induction therapy remains to be determined. Preliminary results on rituximab for maintenance therapy appear promising. Efforts are still under way to determine the optimal duration of maintenance therapy, ideally tailored according to the characteristics of each patient and the previous treatment received.Keywords: Antineutrophil cytoplasmic antibody-associated vasculitis, granulomatosis with polyangiitis (Wegener's granulomatosis), microscopic polyangiitis, Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis), cyclophosphamide, rituximab IntroductionAntineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA; al...

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Pathogenesis of ANCA-associated vasculitis

Cited by 44 publications

References 40 publications

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Clinicopathologic Characteristics and Outcomes of Renal Thrombotic Microangiopathy in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis

Updates in ANCA-associated vasculitis

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