Pathogenesis of Vascular Inflammation by Anti-Neutrophil Cytoplasmic Antibodies

Abstract

The reports of a newborn who developed glomerulonephritis and pulmonary hemorrhage after transplacental transfer of anti-neutrophil cytoplasmic antibody (ANCA) IgG with specificity for myeloperoxidase (MPO) is compelling clinical evidence that ANCA are pathogenic. In vitro studies indicate that ANCA activate cytokine-primed neutrophils and monocytes through both direct Fab2 binding and Fc receptor engagement. Neutrophils that have been activated by ANCA release oxygen radicals, lytic enzymes, and inflammatory cytokines and adhere to and kill endothelial cells. A murine model caused by passive administration of mouse anti-mouse MPO IgG provides convincing evidence that ANCA IgG alone in the absence of antigen-specific T cells can cause necrotizing glomerulonephritis and vasculitis. This pathogenic process is enhanced by synergistic inflammatory factors, probably through priming of neutrophils. Immunization of rats with human MPO induces antibodies that cross-react with rat MPO and cause glomerulonephritis and vasculitis. These ANCA act in concert with chemokines to cause adherence of leukocytes to the walls of small vessels with subsequent injury. To date, animal models of disease that is induced by anti-proteinase 3 are less robust. Clinical and experimental data suggest but do not prove that the ANCA autoimmune response is initiated by an immune response to an antisense peptide of the ANCA antigen or its mimic that may be introduced into the body by an infectious pathogen. This antibody response elicits anti-idiotypic antibodies that cross-react with ANCA antigens. The pathogenesis of ANCA disease is multifactorial, with genetic and environmental factors influencing onset of the autoimmune response, the mediation of acute injury, and the induction of the chronic response to injury.

Membranous Glomerulonephritis with ANCA-Associated Necrotizing and Crescentic Glomerulonephritis

“…On the basis of these studies and the poor outcomes in our cohort, patients with MGN and ANCA-associated NCGN are likely to have heavier proteinuria and a worse prognosis than patients with ANCA-associated NCGN alone. Of note, the presence of immune deposits has also been shown to augment glomerular injury induced by ANCA in mice (31,32).…”

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

“…GPA is associated with anti-neutrophil cytoplasmic autoantibodies (ANCAs) directed against proteinase 3 (PR3) (2).…”

Anti-Neutrophil Cytoplasmic Antibodies Stimulate Release of Neutrophil Microparticles

“…3,4 ANCAs directed against neutrophil antigens, typically proteinase 3 (PR3-ANCA) in WG or myeloperoxidase (MPO-ANCA) in MPA, are found in the sera of most affected patients. 5 Data from in vitro studies, 6,7 animal models, 8,9 and clinical observations in humans [10][11][12] indicate that ANCAs are directly involved in the pathogenesis of vasculitis. One proposed paradigm of ANCA pathogenesis is that neutrophils, after cytokine priming, are fully activated by ANCAs either in the blood or within lesional tissue and firmly adhere to the vascular endothelium.…”