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Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis.

ABSTRACT: The morbidity burden associated with anti-neutrophil cytoplasmic autoantibody-associated vasculitis is increasing, and many novel biological therapies are now entering the drug development pipeline. There is thus an urgent need to develop a representative animal model to facilitate testing of these agents. We previously examined the effect of antineutrophil cytoplasmic autoantibody on leukocyte-endothelial interactions in WKY rats via immunization with human myeloperoxidase. We now seek to extend this model so that all animals reliably develop crescentic glomerulonephritis and lung hemorrhage. We also wish to investigate whether there is a genetic contribution to vasculitis development in this rat strain. Using escalating doses of human myeloperoxidase, we found that a dose of 1600 microg/kg induced pauci-immune crescentic glomerulonephritis and lung hemorrhage in all immunized animals. We also found that the addition of pertussis toxin and killed Mycobacterium tuberculosis to the adjuvant when immunizing with 400 microg/kg of myeloperoxidase resulted in crescentic glomerulonephritis and lung hemorrhage in all animals. However, when Lewis, Wistar Furth, or Brown Norway rats were immunized using a similar protocol, no animals developed hematuria or glomerulonephritis, despite having identical levels of anti-human myeloperoxidase antibodies. We conclude that, by adjusting the immunization regimen, all WKY rats immunized with myeloperoxidase develop experimental autoimmune vasculitis, thus facilitating future therapeutic studies. The resistance of Lewis rats to experimental autoimmune vasculitis provides a genetic basis for future studies of anti-myeloperoxidase antibody-associated vasculitis.

SUBMITTER: Little MA

PROVIDER: S-EPMC2671354 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis.

Little Mark A MA Smyth Lucy L Salama Alan D AD Mukherjee Sriparna S Smith Jennifer J Haskard Dorian D Nourshargh Sussan S Cook H Terence HT Pusey Charles D CD

The American journal of pathology 20090305 4

The morbidity burden associated with anti-neutrophil cytoplasmic autoantibody-associated vasculitis is increasing, and many novel biological therapies are now entering the drug development pipeline. There is thus an urgent need to develop a representative animal model to facilitate testing of these agents. We previously examined the effect of antineutrophil cytoplasmic autoantibody on leukocyte-endothelial interactions in WKY rats via immunization with human myeloperoxidase. We now seek to exten ...[more]

PMID: 19264905

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Project description:IntroductionVenous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE.MethodsIn this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTEpos) were compared with patients without VTE (VTEneg, n = 29) and healthy controls (HC, n = 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed.ResultsVTEpos patients had higher MPTFa (peak median = 14.0, interquartile range = 4.3-36.6) than HC (0, 0-3.5) and VTEneg patients (0, 0-1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01-1.08) and remission (1.4; 1.11-1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03-1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5-12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE.ConclusionElevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.

Project description:BackgroundAnti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) are characterized by autoimmune small vessel inflammation. Eosinophils are multifunctional cells with both pro-inflammatory and immunoregulatory properties. Tissue activated eosinophils secrete cyto- and chemokines and form extracellular traps (EETs), they release free granules and produce reactive oxygen species. The role of eosinophils is well established in eosinophilic granulomatosis with polyangiitis (EGPA) but very little is known about their role in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).MethodsThe expression of surface markers CD11c, CD11b, CD16, CD35, CD62L, CD64, CD88, Siglec-8 and CD193 and reactive oxygen species production by peripheral blood eosinophils were studied using flow cytometry. Fluorescence microscopy was used to visualize the release of eosinophil extracellular DNA traps (EETs). 98 GPA and MPA patients and 121 healthy controls were included in the study.ResultsBoth GPA and MPA patients had decreased frequency of eosinophils in peripheral blood compared with healthy controls (p < 0.0001), which could not solely be explained by corticosteroid treatment. The patient's eosinophils showed increased surface expression of the Fc receptors CD16 (p < 0.0001) and CD64 (p = 0.0035) as well as CCR3 (CD193) (p = 0.0022). Decreased expression was found of the complement receptors CD35 (p = 0.0022), CD88 (p < 0,0001) as well as CD11c (p < 0,0001), CD11b (p = 0.0061) and Siglec-8 (p = 0,0015). Moreover, GPA and MPA eosinophils, showed decreased capacity to produce ROS (p < 0.0001). ANCA stimulation of eosinophils from GPA and MPA patients after C5a priming enhanced EETosis (p = 0,0088).ConclusionsThe percentage of eosinophils were decreased in peripheral blood in GPA and MPA patients and showed altered surface marker expression and function. The enhanced EETosis after ANCA stimulation, suggests that eosinophil can contribute to the autoantibody driven inflammatory process.

Project description:BACKGROUND:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Myeloperoxidase (MPO) and proteinase 3 (PR3) are the main antigens for ANCA. AAV is a common multisystem autoimmune disease and most of the studies on AAV have been conducted in Western countries. Nowadays in China many efforts are made to investigate this disease. SUMMARY:This review highlights the progress in the prevalence, management and outcomes of AAV in Chinese patients. With respect to the prevalence of AAV, though there are no precise data, AAV is not rare in the Chinese population. In Chinese patients with AAV there is a striking preponderance of MPA, and MPO-ANCA is much more common than PR3-ANCA. Even in patients with GPA there is a predominance of MPO-ANCA over PR3-ANCA. Propylthiouracil-induced AAV and ANCA-negative pauci-immune glomerulonephritis are stated in this review as well. With respect to the management of AAV, glucocorticoids in combination with cyclophosphamide remain the mainstay of induction therapy. Besides, we describe predictors of different outcomes in Chinese patients, including mortality, relapse, treatment resistance and end-stage renal disease. KEY MESSAGES:AAV is not rare in the Chinese population. The disease spectrum and subtypes of ANCA are different between patients with AAV in China and Western countries. The treatment strategy for AAV in China is in consistency with that in Western countries. Predictors of different clinical outcomes are provided. FACTS FROM EAST AND WEST:Treatment options for AAV 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.

Project description:IntroductionThe complement system is crucial for the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In particular, C5a plays a central role. In this study, plasma and urinary levels of C5a as well as renal C5a receptors (CD88 and C5L2) expression were investigated in patients with AAV.MethodsTwenty-four patients with AAV in the active phase, 19 patients with AAV in the remission phase, and 20 patients with lupus nephritis (LN) were included. Plasma and urinary levels of C5a were measured with enzyme-linked immunosorbent assay (ELISA). The staining of CD88 and C5L2 in renal specimens was detected with immunohistochemistry.ResultsThe level of plasma C5a was significantly higher in patients with AAV in the active phase than that in patients in remission, that in patients with LN, and that in normal controls. The urinary C5a level was significantly higher in patients with AAV in the active phase than that in patients in remission and that in normal controls, but not significantly different between patients with active AAV and patients with LN. The mean optical density of CD88 staining in the tubulointerstitium was significantly lower in AAV patients than that in normal controls (0.0052 ± 0.0011 versus 0.029 ± 0.0042; P = 0.005). The mean optical density of C5L2 in glomeruli was significantly higher in AAV patients than that in normal controls (0.013 ± 0.0027 versus 0.0032 ± 0.0006; P < 0.001). The mean optical density of CD88 staining closely correlated with the initial eGFR (r = 0.835; P < 0.001) in AAV patients. Double-labeling immunofluorescence assay suggested that CD88 did not express on neutrophils, monocytes, or macrophages, but C5L2 expressed on neutrophils (or monocytes) and macrophages.ConclusionThe elevated plasma and urinary C5a levels indicated complement activation in human AAV. The level of renal CD88 expression could reflect the disease severity of ANCA-associated glomerulonephritis. CD88 expression was downregulated, and C5L2 was upregulated in ANCA-associated glomerulonephritis.

Dataset Information

Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis.

Publications

Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis.

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