Abstract
The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides are autoimmune diseases associated with significant morbidity and mortality. They often affect the kidney causing rapidly progressive glomerulonephritis. While signalling by complement anaphylatoxin C5a though the C5a receptor is important in this disease, the role of the anaphylatoxin C3a signalling via the C3a receptor (C3aR) is not known. Using two different murine models of anti-myeloperoxidase (MPO) glomerulonephritis, one mediated by passive transfer of anti-MPO antibodies, the other by cell-mediated immunity, we found that the C3aR did not alter histological disease severity. However, it promoted macrophage recruitment to the inflamed glomerulus and inhibited the generation of MPO-ANCA whilst not influencing T cell autoimmunity. Thus, whilst the C3aR modulates some elements of disease pathogenesis, overall it is not critical in effector responses and glomerular injury caused by autoimmunity to MPO.
Highlights
The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) are diseases in which autoimmunity to the neutrophil granule proteins myeloperoxidase (MPO) or proteinase-3 (Pr3) can cause multi-organ injury, including rapidly progressive glomerulonephritis
Endogenous C3a does not exacerbate glomerular injury induced by passive transfer of anti-MPO IgG but promotes glomerular macrophage recruitment
Fewer glomerular macrophages were observed in C3ar-/- mice with glomerulonephritis (Fig 1D–1F)
Summary
The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) are diseases in which autoimmunity to the neutrophil granule proteins myeloperoxidase (MPO) or proteinase-3 (Pr3) can cause multi-organ injury, including rapidly progressive glomerulonephritis. T and B cell tolerance to MPO or Pr3 is lost, resulting in the secretion of autoantibodies (ANCA). ANCA can bind to their cognate autoantigen on primed neutrophils, inducing them to activate[1] and lodge in the glomerulus. These intraglomerular neutrophils degranulate, producing reactive oxygen species and causing direct glomerular injury. Degranulation results in extensive glomerular deposits of non-leukocyte associated MPO in patients with AAV [2]. Murine models suggest that MPO-specific effector T cells recognize MPO deposited in glomeruli and contribute to glomerular injury [3,4]
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