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Factors involved in the pathogenesis of neutrophilic vasculitis in MRL/Mp-lpr/lpr mice: a model for human microscopic
J M Harper1, D G Healey, S Thiru
1Departmnent of Pathology, University of Cambridge, UK.
Abstract:
Anti-neutrophil cytoplasm antibodies (ANCA) directed against myeloperoxidase (MPO) are detected in patients with microscopic angiitis. Human MPO autoantibodies stimulate neutrophil degranulation in vitro and are thought to be pathogenic. We have previously shown that MRL-lpr mice with MPO autoantibodies have a higher incidence of vasculitis than their seronegative littermates. The aim of the present study is to determine the relationship between MPO autoantibodies and microscopic angiitis. The neutrophil binding properties of anti-MPO monoclonal antibodies (mAbs) from MRL-lpr mice were tested using murine heterophils (neutrophils) present in blood and induced peritoneal exudates. MRL anti-MPO mAbs selectively bind activated neutrophils which express MPO in vitro. The pathogenicity of an IgG2b anti-MPO mAb, C6, was investigated in vivo. Anti-MPO mAb, C6 was administered to young MRL mice which had been primed with exogenous TNF alpha to induce neutrophil activation and expression of MPO. Neutrophilic vasculitis similar to microscopic angiitis occurred in 33% of MRL mice which had been treated with anti-MPO mAb. The lesions were mainly restricted to sites of previous endothelial insult which suggests an active role for injured endothelium in this pathology.
Insights
Autoantibodies against myeloperoxidase (MPO) are linked to microscopic angiitis. In MRL mice, anti-MPO monoclonal antibodies induced vasculitis, suggesting a pathogenic role in this autoimmune disease.
Area of Science:
- Immunology
- Pathology
- Rheumatology
Background:
- Anti-neutrophil cytoplasm antibodies (ANCA) targeting myeloperoxidase (MPO) are associated with microscopic angiitis.
- Human MPO autoantibodies can stimulate neutrophil degranulation and are suspected of being pathogenic.
- Previous studies indicated a higher vasculitis incidence in MRL-lpr mice with MPO autoantibodies.
Purpose of the Study:
- To investigate the direct relationship between MPO autoantibodies and the development of microscopic angiitis.
- To determine if anti-MPO monoclonal antibodies can induce vasculitis in a murine model.
Main Methods:
- Testing the neutrophil binding properties of anti-MPO monoclonal antibodies (mAbs) from MRL-lpr mice using murine neutrophils.
- Investigating the in vivo pathogenicity of a specific anti-MPO mAb (IgG2b, C6) in MRL mice.
- Priming mice with TNF-alpha to activate neutrophils and induce MPO expression before mAb administration.
Main Results:
- MRL anti-MPO mAbs demonstrated selective binding to activated neutrophils expressing MPO in vitro.
- Administration of anti-MPO mAb C6 to primed MRL mice resulted in neutrophilic vasculitis in 33% of subjects.
- Lesions were predominantly observed at sites of prior endothelial injury, indicating a potential role for endothelial insult.
Conclusions:
- Anti-MPO autoantibodies can play a pathogenic role in the development of vasculitis.
- Neutrophil activation and MPO expression are critical for anti-MPO mAb-induced pathology.
- Injured endothelium may be a key factor in the localization and development of anti-MPO-mediated vasculitis.