Details

Autor(en) / Beteiligte

• Ooi, Joshua D
• Chang, Janet
• Hickey, Michael J
• Borza, Dorin-Bogdan
• Fugger, Lars
• Holdsworth, Stephen R
• Kitching, A. Richard

Titel

immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2012-09, Vol.109 (39), p.E2615-E2624

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Microscopic polyangiitis is an autoimmune small-vessel vasculitis that often manifests as focal and necrotizing glomerulonephritis and renal failure. Antineutrophil cytoplasmic Abs (ANCAs) specific for myeloperoxidase (MPO) play a role in this disease, but the role of autoreactive MPO-specific CD4 ⁺ T cells is uncertain. By screening overlapping peptides of 20 amino acids spanning the MPO molecule, we identified an immunodominant MPO CD4 ⁺ T-cell epitope (MPO ₄₀₉–₄₂₈). Immunizing C57BL/6 mice with MPO ₄₀₉–₄₂₈ induced focal necrotizing glomerulonephritis similar to that seen after whole MPO immunization, when MPO was deposited in glomeruli. Transfer of an MPO ₄₀₉–₄₂₈-specific CD4 ⁺ T-cell clone to Rag 1 ⁻/⁻ mice induced focal necrotizing glomerulonephritis when glomerular MPO deposition was induced either by passive transfer of MPO-ANCA and LPS or by planting MPO ₄₀₉–₄₂₈ conjugated to a murine antiglomerular basement membrane mAb. MPO ₄₀₉–₄₂₈ also induced biologically active anti-MPO Abs in mice. The MPO ₄₀₉–₄₂₈ epitope has a minimum immunogenic core region of 11 amino acids, MPO ₄₁₅–₄₂₆, with several critical residues. ANCA-activated neutrophils not only induce injury but lodged the autoantigen MPO in glomeruli, allowing autoreactive anti-MPO CD4 ⁺ cells to induce delayed type hypersensitivity-like necrotizing glomerular lesions. These studies identify an immunodominant MPO T-cell epitope and redefine how effector responses can induce injury in MPO-ANCA–associated microscopic polyangiitis.