Experimental models of vasculitis and glomerulonephritis induced by antineutrophil cytoplasmic autoantibodies

Abstract

Antineutrophil cytoplasmic autoantibodies (ANCA) are closely associated with systemic small vessel vasculitis characterized by segmental vessel wall necrotizing inflammation and a paucity of immunoglobulin deposition. Clinically, in vitro and experimental animal model observations indicate a direct pathogenic role for ANCA. This review focuses on the results of experiments utilizing a mouse model of ANCA disease induced by transfer of mouse anti-MPO IgG or anti-MPO lymphocytes into recipient mice, which causes small vessel vasculitis and glomerulonephritis that closely mimics human disease. Evidence for the following conclusion about this model, and by implication about human ANCA disease, will be summarized as follows: (1) anti-MPO IgG is sufficient even in the absence of functional T cells to cause disease and anti-MPO T lymphocytes are not sufficient to cause acute injury; (2) neutrophils are required; (3) ANCA antigens in bone marrow-derived cells are sufficient targets; (4) increased circulating pro-inflammatory cytokines and microbial products exacerbate disease, and concurrent viral infection exacerbates and modulates the phenotype of disease; (5) Fcγ receptor engagement is required for disease induction, and Fcγ receptor repertoire modulates the phenotype of disease, especially pulmonary disease; (6) activation of the alternative pathway of complement is required, complement is activated by factors released by neutrophils stimulated by ANCA IgG and engagement of C5a receptors is a primary event in complement-mediated amplification; and (7) genetic background has a marked influence on the severity and outcome of disease, and modified gene expression in bone marrow-derived cells is the primary basis for genetically determined differences in disease susceptibility. Investigations using this animal model of ANCA disease have provided important insights into the cellular, molecular and genetic factors involved in the pathogenesis of ANCA disease which are likely to lead to the identification of improved markers of disease activity and response to therapy, as well as more effective and less toxic therapies.

Fig. 1

Vasculitic lesions in WT B6 mice 6 days after they received anti-MPO IgG. a Glomerulus with segmental fibrinoid neurosis (periodic acid Schiff stain). b Glomerulus with segmental fibrinoid necrosis and crescent formation (periodic acid Schiff stain). c Glomerulus with segmental fibrinoid necrosis and crescent formation (H&E stain). d Immunofluorescence microscopy for fibrin showing prominent staining corresponding to segmental necrosis and crescent formation. e Necrotizing arteritis with leukocytoclasia in the dermis of the ear (H&E stain). f Pulmonary alveolar capillaritis on the left and more normal lung on the right. Reproduced with permission from [16].

Fig. 2

Depiction of a hypothesis for the pathogenic events in ANCA vasculitis and glomerulonephritis. Beginning in the upper left, cytokines or other priming factors, such as TNF-α and C5a, induce neutrophils to express more ANCA antigens at the cell surface where they are available for binding to ANCA. ANCA engagement of antigen activates neutrophils by both Fc receptor engagement and direct Fab′2 binding to antigen. Activated neutrophils release toxic factors that cause apoptosis and necrosis of endothelial cells and other vessel wall components. Neutrophils that have been activated by ANCA also release factors that trigger the alternative complement pathway, which generates mediators such as C5a and C3a that amplify the intensity of ANCA-induced inflammation, in part by additional priming additional neutrophils for interaction with ANCA. Modified with permission from [26].