Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo

Abstract

Systemic small vessel vasculitis is associated with antineutrophil cytoplasm antibodies (ANCAs). While there is mounting in vitro evidence to suggest that ANCAs are capable of enhancing leukocyte-endothelial interactions, no in vivo evidence for this has been provided. In this study a novel rat model of ANCA-associated experimental autoimmune vasculitis (EAV), induced by immunization with human myeloperoxidase (MPO), was used to analyze directly the potential effect of ANCAs on leukocyte-venular wall interactions in vivo as observed by intravital microscopy. These rats developed anti-MPO antibodies directed against rat leukocytes, showed pathologic evidence of small vessel vasculitis, and had enhanced leukocyte adhesion and transmigration in response to the chemokine Gro␣ ( IntroductionSystemic small vessel vasculitis (SVV) results in rapidly progressive glomerulonephritis and lung hemorrhage in humans and is usually fatal if untreated. 1 It is characterized by microvascular inflammation and necrosis in a variety of organs. The 2 organs that are most extensively injured in this manner are the kidney, through the development of pauci-immune crescentic glomerulonephritis, and the lung, with consequent alveolar hemorrhage. The association between antineutrophil cytoplasm antibodies (ANCAs) and SVV, initially described in the 1980s, 2 has attracted considerable interest over the past decade. These autoantibodies are principally directed against myeloperoxidase (MPO) and proteinase-3. 3,4 At first, ANCAs were regarded only as clinical markers of disease activity, but it is now apparent that they have direct biologic effects on neutrophils 5,6 and monocytes. 7 The binding of ANCAs to antigen expressed on the leukocyte cell surface following cytokine priming is followed by the activation of an array of intracellular signaling pathways, 8 with resultant degranulation and dysregulated apoptosis. 9 Granulocyte infiltration and fibrinoid necrosis of the vessel wall are the pathologic hallmarks of SVV. For this reason, investigative efforts have focused on the influence that ANCAs have on the interaction between leukocytes and the vascular endothelium, specifically with reference to the inflammatory cascade of leukocyte rolling, adhesion, and transmigration. In this context, in vitro studies using flow chamber models have shown that ANCAs can cause rolling neutrophils to arrest on platelet monolayers 10 and to promote firm adhesion and migration of rolling neutrophils on endothelial cells. 11,12 Despite growing in vitro evidence implicating ANCAs as an inducer of leukocyte-endothelial cell interactions, there has been no evidence to date demonstrating such an effect of these antibodies in vivo. The ability of ANCAs to induce systemic small vessel vasculitis and crescentic glomerulonephritis, however, has been demonstrated by transfer of anti-MPO antibodies in a mouse model of vasculitis. 13 Crescent formation in these animals occurred secondary to fibrinoid necrosis of the glomerular tuft, which was induced by necrosis and...

Clinical analysis of patients with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis

“…According to Millet et al (2013) MPO-AAV and PR3-AAV may be two independent diseases and should be studied separately. Existing evidence supports MPO-ANCA, rather than PR3-ANCA, as the pathogenic antibody of AAV (Xiao et al, 2002;Little et al, 2005;Schlieben et al, 2005;Roth et al, 2013). In China, MPO-ANCA-associated MPA is the main type of AAV.…”

“…According to previous studies, the incidence of GPA in the European population is >60% (Reinhold-Keller et al, 2005), that of MPA in China and Japan is 79-83% (Chen et al, 2005;Fujimoto et al, 2011), and that of MPO-ANCA is as high as 59-94% (Oh et al, 2009;Ahn et al, 2012). Inducing AAV in an immunized animal model with MPO-ANCA or MPO antigen in a previous study (Xiao et al, 2002;Little et al, 2005;Roth et al, 2013) suggested that MPO-ANCA may play a pathogenic role in AAV. Therefore, MPO-ANCA may be the main antibody associated with AAV in Chinese patients.…”

Complement Receptor Mac-1 Is an Adaptor for NB1 (CD177)-mediated PR3-ANCA Neutrophil Activation

“…PR3-and MPO-ANCA binding to their target antigens on the membrane of neutrophils and monocytes leads to cell activation (3,4). ANCA pathogenicity and the pivotal role of the ANCA-neutrophil interaction were established in several animal models (5)(6)(7)(8)(9). In contrast to MPO, membrane-PR3 (mPR3) has a bimodal expression pattern resulting in distinct mPR3 low and mPR3 high subsets.…”

Microscopic Polyangiitis: from Pathogenesis to Treatment

“…In the majority of the cases MPO-ANCA has been detected but autoantibodies against Proteinase 3 (PR3) have also been reported in MPO patients [20]. Data from animal studies, reported that ANCAs may activate (primed) neutrophils to produce reactive oxygen species and several lytic enzymes resulting in endothelial detachment and lysis [21][22][23]. In accordance, passage of MPO-ANCA from mother to fetus may cause pulmonary hemorrhage and renal failure to newborn [24].…”