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Updated: Jun 14, 2026
In Vitro Differentiation of Naive CD4+ T Cells into Pathogenic Th17 Cells in Mouse
Published on: October 25, 2024
Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis
Poh-Yi Gan1, Oliver M Steinmetz, Diana S Y Tan
1Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia.
Abstract:
A major target autoantigen in anti-neutrophil cytoplasmic antibody-associated vasculitis is myeloperoxidase (MPO). Although MPO-specific CD4+ Th cells seem to orchestrate renal injury, the role of the Th17 subset is unknown. We hypothesized that Th17 cells direct injurious anti-MPO autoimmunity in experimental murine anti-MPO-induced glomerulonephritis (GN). We immunized mice with MPO to establish autoimmunity, resulting in systemic IL-17A production with MPO-specific dermal delayed-type hypersensitivity. We triggered disease using antibodies to the glomerular basement membrane to induce glomerular deposition of MPO by neutrophils. Wild-type mice developed necrotizing GN with an influx of glomerular leukocytes and albuminuria. In contrast, mice deficient in the key Th17 effector cytokine IL-17A were nearly completely protected. The protective effects resulted partly from reduced neutrophil recruitment, which led to less disposition of glomerular MPO. To test whether IL-17A also drives autoimmune delayed-type hypersensitivity in the kidney, we injected MPO into the kidneys of MPO-sensitized mice. IL-17A deficiency reduced accumulation of renal macrophages and renal CCL5 mRNA expression. In conclusion, IL-17A contributes to the pathophysiology of autoimmune anti-MPO GN, suggesting that it may be a viable therapeutic target for this disease.
Insights
Interleukin-17A (IL-17A) drives autoimmune kidney damage in anti-myeloperoxidase (MPO) vasculitis. Blocking IL-17A protected mice, suggesting it
Area of Science:
- Immunology
- Nephrology
- Autoimmunity
Background:
- Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) involves autoantibodies against myeloperoxidase (MPO).
- The role of T helper 17 (Th17) cells and their effector cytokine, IL-17A, in MPO-specific autoimmunity and kidney injury remains unclear.
Purpose of the Study:
- To investigate the hypothesis that Th17 cells mediate injurious anti-MPO autoimmunity in experimental anti-MPO glomerulonephritis (GN).
Main Methods:
- Mice were immunized with MPO to induce autoimmunity and systemic IL-17A production.
- Disease was triggered by anti-glomerular basement membrane antibodies, leading to glomerular MPO deposition.
- Mice deficient in IL-17A were compared to wild-type controls.
- Direct MPO injection into kidneys of MPO-sensitized mice assessed IL-17A's role in renal delayed-type hypersensitivity.
Main Results:
- Wild-type mice developed necrotizing GN with leukocyte influx and albuminuria.
- Mice deficient in IL-17A were significantly protected from GN.
- IL-17A deficiency reduced neutrophil recruitment and glomerular MPO deposition.
- In the kidney, IL-17A deficiency decreased macrophage accumulation and CCL5 mRNA expression.
Conclusions:
- IL-17A plays a significant role in the pathophysiology of autoimmune anti-MPO GN.
- IL-17A contributes to neutrophil recruitment and MPO deposition in the kidneys.
- IL-17A may represent a potential therapeutic target for anti-MPO AAV.
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