A Novel Mouse Model for MPO‐ANCA‐Associated Glomerulonephritis

Abstract

It has been shown that myeloperoxidase (MPO) and the MPO-specific anti-neutrophil cytoplasmic auto-antibody (MPO-ANCA) are risk factors for the development of glomerulonephritis (GN). High titers of MPO-ANCA are frequently detected (2,4,5,8) in the sera of patients with microscopic polyangiitis (MPA) or crescentic GN (CrGN). Animal models have been used for understanding the mechanisms for the development of vasculitis, as a basis for establishing new therapeutic strategies. The SCG/Kj mouse is a model of spontaneous CrGN associated with activated neutrophils (6). The MRL lpr/lpr strain, the background for the SCG/Kj mouse, is known to show high levels of MPO-ANCA in association with renal lesions, including GN and vasculitis (3). MPO-deficient model mice for coronary arteritis induced with Candida albicans-derived substances indicate that MPO is a major antigen for MPO-ANCA production (7). The importance of MPO-ANCA for the development of vasculitis has been demonstrated, using immune-deficient mice with the Rag2 knockout (19). Such a mouse model for renaldamage CrGN with MPO-ANCA production is needed, since understanding the pathogenetic roles of MPO-ANCA and neutrophils in GN and vasculitis remains important for the development of new therapies. Bovine serum albumin (BSA)-induced nephritis was reported in rat (12). Recently, CrGN has been connected with MPO-ANCA production prior to the development of renal lesion. We were interested in knowing whether the development of CrGN induced by BSA administration is related to an increase in MPO-ANCA.In the present study, we established induction model mice for CrGN with vasculitis by serial injection of BSA. The mice showed three phases of renal damage: Abstract: We established a novel model mouse for myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis with crescentic formation, which was induced by administering bovine serum albumin (BSA). Neutrophil infiltration into the renal glomeruli began at 8 weeks and crescent formation was observed from 10 weeks after the first BSA injection. Platelet and neutrophil counts significantly increased, and proteinuria was observed from 5 weeks. MPO-ANCA increased slightly at 4 and markedly at 9 weeks, and the TNF-␣ level increased at 11 weeks. Glomerular neutrophil infiltration was correlated with MPO-ANCA levels. In addition, proteinuria also significantly correlated with MPO-ANCA levels. Finally, renal crescent formation was associated with an increase of MPO-ANCA levels and neutrophil infiltration into glomeruli. The glomerular immune deposition of IgG and C3 was observed. These findings indicate that BSA induces neutrophil activation of peripheral blood followed by the elevation of MPO-ANCA, resulting in the development of crescentic glomerulonephritis in mice. Editor-Communicated Paper A Novel Mouse Model for MPO-ANCA-Associated Glomerulonephritis

Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis

“…The model which we performed was a classical immunecomplex-mediated glomerulonephritis rather than AAV models, but the generation of MPO-ANCA and neutrophil-mediated glomerular inflammation in this model have been demonstrated. 28 Our in vivo findings support that the loss of membrane-bound SEMA4D is crucially involved in the development of neutrophil-mediated vascular inflammation.…”

“… 13 26 27 Consistent with this, we confirmed that soluble SEMA4D promoted the permeability (see online supplementary figure S3A ) and interleukin (IL)-8 secretion of endothelial cells (see online supplementary figure S3B ), without affecting the expression of endothelial adhesion molecules (see online supplementary figure S3C ). To further assess the significance of SEMA4D in AAV pathogenesis, we next studied an in vivo neutrophil-mediated vasculitis model, 28 using wild-type (WT) and SEMA4D-deficient ( SEMA4D −/− ) mice. Contrary to expectations, SEMA4D −/− mice exhibited enhanced phenotypes in comparison with WT mice (see online supplementary figure S4A-E ).…”

A Comparison of the Clinical Features of ANCA-Positive and ANCA-Negative Idiopathic Pulmonary Fibrosis Patients

“…In 10 patients (37%), pulmonary lesions appeared first, in 11 patients (40.7%) the lesions developed simultaneously, and in only 5 patients (8.5%) did the renal lesions appear first. Yumura et al [30] have reported that histological features of lung damage appeared before glomerular changes in a mouse model for MPO-ANCA-associated glomerulonephritis. This suggests the possibility that some kinds of lung damage precede the onset of renal lesions.…”

Endogenous Myeloperoxidase Promotes Neutrophil-Mediated Renal Injury, but Attenuates T Cell Immunity Inducing Crescentic Glomerulonephritis

“…It is possible that these assessments are complicated by WT mice developing injurious autoimmune responses to mMPO, which would not be expected to occur in MPO Ϫ/Ϫ mice (because of genetic deletion of the potential endogenous autoantigen). Some patients with anti-GBM GN develop circulating autoantibodies (ANCA) against MPO (41), and several murine models of MPO-ANCA-associated crescentic GN have been recently described (21,36,42,43 Humoral responses to sheep globulin were also enhanced in the absence of MPO. Consistent with the cytokine data, the IgG3:IgG1 (Th1:Th2) ratio was enhanced in MPO Ϫ/Ϫ mice.…”