Animal models of anti-neutrophil cytoplasmic antibody-associated vasculitis

Abstract

SummaryAntibodies against neutrophil proteins myeloperoxidase (MPO) and proteinase 3 are thought to cause disease in anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. There have been a number of recent developments in the animal models of ANCA vasculitis in both mice and rats. These include models based on an immune response to MPO generated in MPO-deficient mice, with other models using MPO-sufficient mice and rats. In addition, there is a report of the use of humanized mice where immunodeficient mice have been engrafted with human haematopoietic stem cells and injected with patient ANCA. Antibodies to another protein lysosomal-associated protein-2 have been found in patients with ANCA vasculitis, and evidence from a rat model suggests that they are also pathogenic. These models all have advantages and disadvantages, which are discussed. We also consider what these models have taught us about the pathogenesis of ANCA vasculitis. Experiments using genetically modified mice and pharmacological inhibition have given insights into disease mechanisms and have identified potential therapeutic targets. Toll-like receptor stimulation modifies disease by acting both at the level of tissue injury and in the generation of the autoimmune response. Complement is also potentially important with data to support the role of the alternative pathway and C5a in particular. Intracellular pathways have been examined, with a role showing p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase g. Serine proteases are now known to contribute to disease by release of interleukin-1b in ANCA-activated neutrophils and monocytes. Other potential therapies studied in these models include the use of bortezemib and strategies to modify antibody glycosylation.

Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis

“…75 The development of an animal model for AAV was most successful for MPO-AAV. Initially, Brown-Norway rats were immunized with MPO and their kidneys were perfused with H 2 O 2 and a lysosomal extract containing MPO and elastinolytic enzymes.…”

Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development

“…6). In vivo support for the pathogenicity of ANCA is provided by studies in which injection of anti-MPO antibodies causes focal necrotizing crescentic glomerulonephritis in mice in a neutrophildependent manner (7,8). However, the effects of ANCA on MPO-and PR3-expressing monocytes have received far less attention.…”

Role of serine proteases in inflammation: Bowman–Birk protease inhibitor (BBI) as a potential therapy for autoimmune diseases

“…In another study, neutrophil elastase-deficient mice were not susceptible to an antibody-mediated autoimmune dermatosis called bullous pemphigoid disease (Liu et al, 2000). Serine proteases also contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis by releasing IL-1β (Coughlan et al, 2012).…”