Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases in which the small vessels are inflamed. Clinical observations suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data and animal models, particularly for myeloperoxidase-ANCA. An in vivo pathogenic role of ANCA directed to proteinase 3 has, however, not been fully substantiated. Additionally, the pathogenic role of B cells, T cells, and the alternative pathway of complement in AAV have been elucidated. Insight into these pathogenic pathways involved in AAV has opened and will further open new ways for targeted biologic treatment. In this review the pathogenesis of AAV and potential targets for biologic treatment are discussed.

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“…Xiao et al [17] immunized MPO-deficient mice with mouse MPO. As a result, these mice developed an immune response to mouse MPO.…”

Section: Arguments For a Pathogenic Role Of Ancamentioning

confidence: 99%

Pathogenesis of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis and Potential Targets for Biologic Treatment

et al. 2014

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“…Several animal models of disease caused by ANCA have been described [40]. The first described, and most extensively studied, is a mouse model developed by Xiao et al [41]. MPO knockout mice were immunized with murine MPO to produce high titers of anti-murine MPO antibodies.…”

Section: Animal Model Evidence Supporting and Elucidating The Pathogementioning

confidence: 99%

“…Intravenous injection of the purified anti-MPO IgG into wild-type or immunodeficient Rag2-/- mice (lacking immune-competent B and T cells) induced pauci-immune NCGN and systemic small vessel vasculitis which closely mimic human ANCA disease (fig. 1) [41]. Depending on modulating factors such as infection or modification of innate immune capabilities, mice can be induced to have more or less pulmonary alveolar hemorrhagic capillaritis or necrotizing granulomatosis [unpubl.…”

Section: Animal Model Evidence Supporting and Elucidating The Pathogementioning

confidence: 99%

Overview of the Pathogenesis of ANCA-Associated Vasculitis

Xiao

Falk

et al. 2015

Kidney Dis

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Background: Antineutrophil cytoplasmic autoantibodies (ANCA) are associated with a spectrum of necrotizing vasculitis including granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited necrotizing and crescentic glomerulonephritis. Clinical observations and in vitro and in vivo experimental evidence strongly indicate that ANCA are pathogenic. Summary: The etiology and pathogenesis of ANCA-associated vasculitis (AAV) are multifactorial, with contributions from genetic factors, environmental exposures, infections, characteristics of the innate and adaptive immune system, and the intensity and duration of the injury. Acute vascular inflammation is induced when resting neutrophils that have ANCA autoantigens sequestered in cytoplasmic granules are exposed to priming factors - for example, cytokines induced by infection or phlogogenic factors released by complement activation - that cause the release of ANCA antigens on the surface of neutrophils and in the microenvironment around the neutrophils. ANCA bind to these ANCA antigens, which activates neutrophils by Fcγ receptor engagement and F(ab′)₂ binding at the neutrophil cell surface. ANCA-activated neutrophils release factors that activate the alternative complement pathway, which generates C5a, a chemoattractant for neutrophils; C5a also primes the arriving neutrophils for activation by ANCA. Activated neutrophils adhere to and penetrate vessel walls, and they release toxic oxygen radicals and destructive enzymes that cause apoptosis and necrosis of the neutrophils as well as of the adjacent vessel wall cells and matrix. Key Messages: Patients with active AAV have ongoing asynchronous onsets of countless acute lesions, with each lesion evolving through stereotypical phases within 1 or 2 weeks. Induction of remission results in termination of new waves of acute lesions and allows all lesions to progress to scarring or resolution.

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“…Xiao et al [28] developed a model in which intravenous administration of anti-MPO IgG into either immune-competent mice or Rag2-/- mice that have no functioning T or B cells causes pauci-immune crescentic glomerulonephritis and small-vessel vasculitis, remarkably similar to human disease. Within 6 days of the intravenous injection, all mice develop glomerular lesions while some develop systemic vasculitis, including leukocytoclastic angiitis, necrotizing arteritis, pulmonary capillaritis and necrotizing granulomatosis inflammation [28,29,30,31]. Similarly, severe crescentic glomerulonephritis and systemic vasculitis can be induced by passive transfer of splenocytes from MPO-/- mice that have been immunized with murine MPO.…”

Section: The Role Of Anca In Disease Recognition and Pathogenesismentioning

confidence: 99%

The Prevalence and Management of Pauci-Immune Glomerulonephritis and Vasculitis in Western Countries

Lionaki¹,

Boletis²

2015

Kidney Dis

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Background: Pauci-immune glomerulonephritis is the most common cause of aggressive glomerulonephritis and occurs as a renal-limited disease or as a component of systemic necrotizing small-vessel vasculitis. It is characterized by paucity of staining for immunoglobulins, by immunofluorescence along with fibrinoid necrosis and crescent formation by light microscopy, while the vast majority of patients have anti-neutrophil cytoplasmic antibodies (ANCA) in their circulation, which also participate in the pathogenesis of the disease. Summary: Pauci-immune glomerulonephritis often manifests with rapidly deteriorating kidney function, which may be accompanied by distinctive clinical features of systemic necrotizing small-vessel vasculitis of one the following clinical phenotypes: microscopic polyangiitis, granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis. These are associated with a wide spectrum of vasculitic manifestations in different organ systems at clinical presentation and during the course of the disease. ANCA specificity is associated with distinct clinical syndromes and different prognostic profiles among patients. The key element of the management of patients with pauci-immune glomerulonephritis, with or without systemic vasculitis, is the clinical acumen, which results in timely diagnosis. Speed in diagnosis is crucial for the quick institution of immunosuppressive therapy aimed at removing circulating autoantibodies and quelling the inflammatory process. Key Messages: The introduction of ANCA testing in routine clinical practice has increased the ability of disease suspicion and recognition, resulting in earlier establishment of diagnosis by seeking a tissue confirmation of pauci-immune vasculitis. ANCA specificity is associated with distinct clinical syndromes and different prognostic profiles among patients. The management of patients with ANCA glomerulonephritis and/or vasculitis includes two major elements: prompt diagnosis and institution of immunosuppressive therapy to avoid irreversible kidney damage or death, and consideration of the predictors, which are associated with relapsing disease for planning of therapy in the long term. Facts from East and West: Treatment options for ANCA-associated vasculitis are shared between the East and West, with corticosteroid combined with cyclophosphamide being the standard regimen for inductive therapy and switching to azathioprine after remission. The major cause of death in treated patients is infection related to immunosuppressive therapy within the first year after diagnosis, and this rate might be higher in China than in Western countries. Western studies demonstrated the efficacy and safety of rituximab for induction of remission in cases with relatively mild disease and maintenance therapy, but this agent is rarely used in China.

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Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice

Cited by 918 publications

References 19 publications

Pathogenesis of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis and Potential Targets for Biologic Treatment

Pathogenesis of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis and Potential Targets for Biologic Treatment

Overview of the Pathogenesis of ANCA-Associated Vasculitis

The Prevalence and Management of Pauci-Immune Glomerulonephritis and Vasculitis in Western Countries

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