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Trafficking of QD-conjugated MPO-ANCA in murine systemic vasculitis and glomerulonephritis model mice
Akiyoshi Hoshino1, Tomokazu Nagao, Toshiko Ito-Ihara
1Department of Bioactive Molecules, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
Abstract:
In systemic vasculitis, the serum level of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA) is significantly elevated with the progression of disease. We have established a model of murine systemic vasculitis by administration of MPO-ANCA and fungal mannoprotein to C57BL/6 mice. We examined the role of MPO and MPO-ANCA in the pathogenesis of glomerulonephritis and systemic vasculitis in this model using quantum dots (QDs). We demonstrated that QD-conjugated MPO-ANCA (ANCA-QD) visualized the translocation of MPO on the neutrophil membrane surface after stimulation with proinflammatory cytokines. We also observed that MPO translocation on neutrophils in both patients with rapid progressive glomerulonephritis and these model mice without any stimulation, suggesting that MPO translocation is certain to contribute to the development of glomerular lesion. In addition, blood flow on the kidney surface vessel was significantly decelerated in both SCG/Kj mice and this model, suggesting that ANCA induces the damage of blood vessel. These results indicate that MPO-ANCA and surface-translocated MPO on the activated neutrophils coordinately plays essential roles in the initial steps of the glomerulonephritis.
Insights
Myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA) drive glomerulonephritis and vasculitis. MPO-ANCA triggers MPO translocation on neutrophils, initiating kidney damage and blood vessel issues.
Area of Science:
- Immunology
- Nephrology
- Pathology
Background:
- Serum levels of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA) increase with systemic vasculitis progression.
- MPO-ANCA is a key biomarker in systemic vasculitis and glomerulonephritis.
Purpose of the Study:
- To investigate the role of MPO and MPO-ANCA in the pathogenesis of glomerulonephritis and systemic vasculitis.
- To visualize MPO translocation on neutrophils using quantum dots (QDs).
Main Methods:
- Established a murine model of systemic vasculitis by administering MPO-ANCA and fungal mannoprotein.
- Utilized QD-conjugated MPO-ANCA (ANCA-QD) to visualize MPO translocation.
- Observed neutrophil MPO translocation in patients with rapid progressive glomerulonephritis and in the model mice.
- Assessed kidney surface blood flow in model mice.
Main Results:
- ANCA-QD visualized MPO translocation on neutrophil membranes upon stimulation with proinflammatory cytokines.
- MPO translocation was observed on neutrophils in patients and model mice even without stimulation, indicating its role in glomerular lesions.
- Significant deceleration of kidney surface blood flow was noted in model mice, suggesting ANCA-induced blood vessel damage.
- MPO-ANCA and surface-translocated MPO are crucial in the initial stages of glomerulonephritis.
Conclusions:
- MPO-ANCA and surface-translocated MPO play coordinated roles in the initiation of glomerulonephritis.
- MPO translocation on neutrophils is a critical event in the development of glomerular lesions.
- ANCA contributes to blood vessel damage in the kidneys, exacerbating vasculitis.
