Animal Models of ANCA Associated Vasculitis

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and severe autoimmune multisystemic disease. Its pathogenesis involves multiple arms of the immune system, as well as complex interactions between immune cells and target organs. Experimental animal models of disease can provide the crucial link from human disease to translational research into new therapies. This is particularly true in AAV, due to low disease incidence and substantial disease heterogeneity. Animal models allow for controlled environments in which disease mechanisms can be defined, without the clinical confounders of environmental and lifestyle factors. To date, multiple animal models have been developed, each of which shed light on different disease pathways. Results from animal studies of AAV have played a crucial role in enhancing our understanding of disease mechanisms, and have provided direction toward newer targeted therapies. This review will summarize our understanding of AAV pathogenesis as has been gleaned from currently available animal models, as well as address their strengths and limitations. We will also discuss the potential for current and new animal models to further our understanding of this important condition.

Keywords: animal models; antineutrophil cytoplasmic; autoantibodies; autoimmunity; glomerulonephritis; myeloperoxidase; proteinase 3; translational medical research.

Figure 1

Features of central and peripheral mechanisms of tolerance to MPO as defined by animal models. (A) Central tolerance in the thymus is regulated by the transcription factor autoimmune regulator (AIRE) within the nucleus of thymic epithelial cells. This regulates autoantigen presentation to T cells on human leukocyte antigen (HLA) class II molecules, with subsequent T cell selection. (B) Peripherally, tolerance to MPO is maintained through MPO presentation on HLA class II by unlicensed dendritic cells to naïve T cells under the influence of IL-10 producing mast cells, promoting the development of regulatory T cells. (C) In certain situations, tolerance to MPO is lost, prompting expansion of T cells, and subsequent help for B cells to produce ANCA.

Figure 2

Features of neutrophil priming and activation by ANCA as defined by animal models. (A) Pro-inflammatory stimuli (including lipopolysaccharide and complement factor C5a) cause neutrophil priming, with increased expression of ANCA antigens on the neutrophil surface. (B) Mediated by regulatory Fcγ receptors, ANCA have the capacity to activate neutrophils. Neutrophil activation causes release of C5a, with subsequent complement pathway activation as well as further neutrophil priming.

Figure 3

Features of neutrophil migration and adhesion, and endothelial damage as defined by animal models. (A) Activated neutrophils migrate to vulnerable vascular beds, including the glomerulus. The presence of TNF is associated with TLR4 upregulation on glomerular endothelial cells, which contributes to neutrophil migration through production of chemoattractants CXCL1 and CXCL2. After activation by ANCA, neutrophils express β2-integrins (LFA-1 and MAC-1), which enhance neutrophil adhesion to the glomerular endothelium. Neutrophil retention within the glomerular capillaries is moderated by the C5a receptor. (B) MPO is planted onto the glomerular endothelium, allowing local recognition by MPO-specific effector T cells and subsequent injury. Circulating monocytes have been shown experimentally to present antigens within glomeruli; however, microvascular endothelial cells and dendritic cells may also be involved in antigen recognition by effector T cells. Release of interleukin-17A (IL-17A) by T cells further encourages neutrophil migration. After localization to vulnerable vascular beds, neutrophils undergo necroptosis, and form neutrophil extracellular traps (NETs). This process promotes complement activation, and subsequent endothelial damage. Furthermore, NETs facilitate MPO presentation and propagation of the autoimmune response.