Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase

Abstract

SUMMARY Anti‐neutrophil cytoplasmic antibodies (ANCA), including anti‐myeloperoxidase (MPO) antibodies, are associated with pauci‐immune necrotizing small vessel vasculitis or glomerulonephritis, 1n order to substantiate a pathogenic role for ANCA, an animal model of pauci‐immune ANCA‐induced glomerulonephritis or vasculitis is required. Brouwer et al. reported pauci‐immune glomerulonephritis in rats immunized with human MPO followed by perfusion of kidneys with lysosomal enzyme extract combined with H2O2, and suggested that this could serve as a model of ANCA‐induced disease. We repeated these studies in spontaneously hypertensive rats (SHR) and Brown Norway rats (BNR). We immunized rats with human MPO, When circulating anti‐MPO antibodies were detectable by indirect immunofluorescence microscopy and ELISA, blood pressure was measured, then perfusion of the left kidney of each rat was done via the renal artery in a closed, blood‐free circuit with either MPO + H2O;, MPO, H2O2 alone or MPO + H2O2 neutral protease. Rats were killed on day 4 or day 10 after perfusion, and specimens were examined by light and immunofluorescence microscopy. Pathological lesions and deposits of IgG. C3, and MPO were found in immunized rats perfused with MPO + H2O2 with or without neutral protease, or MPO alone, in both rat strains and on both day 4 and day 10, The degree of histologic injury was proportional in intensity to the amount of IgG immune deposits. Spontaneously hypertensive rats sustained more damage and higher blood pressure than Brown Norway rats. No lesion was observed in immunized rats perfused with H2O2 or in the non‐perfused right kidneys. Some of the non‐immunized rats perfused with MPO + H2O2 developed pathological lesions. In conclusion, these rat models are examples of immune complex‐mediated glomerulonephritis, and therefore are not similar to human ANCA‐associated disease.

Detection of myeloperoxidase in membranous nephropathy-like deposits in patients with anti-neutrophil cytoplasmic antibody–associated glomerulonephritis

“…This model might explain the paucity of the immune deposits in ANCA-associated glomerulonephritis [2,16]. Other studies however suggested that this model might represent immune complex-mediated glomerulonephritis, dissimilar to human crescentic glomerulonephritis [17]. Although an immune complex-mediated process in ANCA-induced inflammation may be speculated, it may differ from classic immune complex-mediated vasculitis, which requires gross accumulation of the immune complexes and typically does not result in severe necrotizing injury [1].…”

Mechanisms of Vasculitis: How Pauci-Immune Is ANCA-Associated Renal Vasculitis?

“…Most interestingly, ICX deposits were observed in the kidney shortly after perfusion, but these ICX appeared to have dissolved already at the time that renal damage was at its peak. Using a similar approach, Yang et al [24] observed that the degree of histological injury correlated with the amount of glomerular IgG immune deposits and concluded that this perfusion rat model is an example of ICX-mediated glomerulonephritis.…”

ANCA—pathophysiology revisited

“…Yang et al [21] recently could not reproduce the pauciimmune character of the lesions in this model, although they mentioned that some glomeruli had proliferative lesions without immune deposits. Nevertheless, they observed a correlation between the severity of the histologie lesions and the amount of IgG deposition.…”