Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis

Primo, Valeria; Marušić, Suzana; Franklin, Corinna C.; Goldmann, Wolfgang H.; Achaval, C. G.; Smith, Rex Neal; Arnaout, M. Amin; Nikolic, Boris

doi:10.1111/j.1365-2249.2009.04072.x

Cited by 69 publications

(42 citation statements)

References 42 publications

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“…In fact, vasculitis could only be induced when splenocytes from these immunized NOD mice were transferred into NOD-SCID mice. 81 A more recent study using humanized NOD-SCID-IL-2Rg 2/2 mice injected with LPS and human IgG containing anti-PR3 antibodies showed the development of lung hemorrhage and mild kidney disease, characterized by mesangial hypercellularity and leukocyte influx. This supports the pathogenicity of PR3-ANCA.…”

Section: Animal Modelsmentioning

confidence: 99%

Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis

Hilhorst

Paassen

Tervaert

2015

Journal of the American Society of Nephrology

171

137

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In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacific, with the exception of New Zealand and Australia. A genetic contribution has been extensively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele in patients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy controls. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differences when analyzed carefully. Clinically, both serotypes are difficult to distinguish, but quantitative differences are present. More organs are affected in PR3-AAV, whereas renal limited vasculitis occurs more often in patients with MPO-AAV. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classification.

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Section: Animal Modelsmentioning

confidence: 99%

Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis

Hilhorst

Paassen

Tervaert

2015

Journal of the American Society of Nephrology

171

137

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“…138 Similar studies implicate an immune response to PR3 in pathogenesis. 139 Other models have utilized transfer of MPO + bone marrow, 140 adjuvants that enhance the immune response and increase cytokine levels, 141 and mice with subclinical GN immunized to human MPO in which the crescentic GN that follows is mediated by the immune response to endogenous MPO. 142 Studies of the Xaio model confirm neutrophil dependence and, despite the absence of antibody deposits, a requirement for alternative complement pathway activation involving C5a and C5a receptors.…”

Section: T Cellsmentioning

confidence: 99%

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

Couser

2012

Journal of the American Society of Nephrology

176

155

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Genetically modified immune responses to infections and self-antigens initiate most forms of GN by generating pathogen-and danger-associated molecular patterns that stimulate Toll-like receptors and complement. These innate immune responses activate circulating monocytes and resident glomerular cells to release inflammatory mediators and initiate adaptive, antigen-specific immune responses that collectively damage glomerular structures. CD4 T cells are needed for B cell-driven antibody production that leads to immune complex formation in glomeruli, complement activation, and injury induced by both circulating inflammatory and resident glomerular effector cells. Th17 cells can also induce glomerular injury directly. In this review, information derived from studies in vitro, well characterized experimental models, and humans summarize and update likely pathogenic mechanisms involved in human diseases presenting as nephritis (postinfectious GN, IgA nephropathy, antiglomerular basement membrane and antineutrophil cytoplasmic antibodymediated crescentic GN, lupus nephritis, type I membranoproliferative GN), and nephrotic syndrome (minimal change/FSGS, membranous nephropathy, and C3 glomerulopathies). Advances in understanding the immunopathogenesis of each of these entities offer many opportunities for future therapeutic interventions.

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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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Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis

Cited by 69 publications

References 42 publications

Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis

Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

Updates in ANCA-associated vasculitis

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