The Role of Neutrophils in the Induction of Glomerulonephritis by Anti-Myeloperoxidase Antibodies

Abstract

In humans, circulating anti-neutrophil cytoplasm autoantibodies (ANCAs) with specificity for myeloperoxidase (MPO) are strongly associated with the development of pauci-immune necrotizing and crescentic glomerulonephritis (NCGN). In mice, we have demonstrated that intravenous injection of mouse antibodies specific for mouse MPO induces NCGN that closely mimics the human disease. We now report that the development of NCGN in this experimental model is accompanied by glomerular accumulation of neutrophils and macrophages. Neutrophil infiltration was most conspicuous at sites of glomerular necrosis and crescent formation, with macrophages also most numerous in crescents. Lymphocytes, however, were sparse in acute lesions. Importantly, mice that were depleted of circulating neutrophils with NIMP-R14 rat monoclonal antibodies were completely protected from anti-MPO IgG-induced NCGN. These findings provide direct evidence that neutrophils play a major role in the pathogenesis of anti-MPO-induced NCGN in this animal model and implicate neutrophils in the induction of human ANCA disease. This raises the possibility that therapeutic strategies to reduce circulating neutrophils could be beneficial to patients with ANCA-induced NCGN.

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

“…Although the pathophysiological significance of these cells during atherogenesis has not yet been well documented, it is suggested that these cells are pro-atherogenic [73]. Neutrophils play a major role in the development of many forms of vasculitis [74,75]. In particular, MPO, an important enzyme from myeloid granules, has been implicated in the pathogenesis of atherosclerosis [76,77].…”

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.…”

Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt

“…Recently, the passive transfer of anti-MPO mAb from MPO-deficient mice into wild-type mice resulted in systemic vasculitis, and the clinical manifestations included necrotizing pauciimmune glomerulonephritis (25). Moreover, neutrophil depletion completely prevented this disease in another mouse model, thus firmly establishing the role of ANCAs and neutrophils in the induction of vasculitis (12). The findings from animal models regarding PR3-specific ANCAs are currently less clear, although in one mouse model, anti-PR3 antibodies accelerated TNF␣-mediated dermal inflammation (26).…”

“…The ANCA-activated neutrophils generate reactive oxygen species and release tissue-toxic granule proteins, both of which are functions that mediate endothelial cell damage and ultimately lead to vasculitis (3)(4)(5)(6)(7)(8)(9)(10)(11). Recently, the central role of neutrophils in the induction of ANCA-mediated vasculitis was shown by neutrophil depletion in a mouse model of glomerulonephritis (12). Investigations of the underlying signal transduction pathways that control this cytokine-mediated priming and ANCA-induced activation of neutrophils identified the participation of p38 MAPK, ERK, protein kinase C, Syk, p21 ras , and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt (9,10,(13)(14)(15)(16).…”