CD8+ T cells effect glomerular injury in experimental anti-myeloperoxidase GN

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Abstract

Observations in patients with ANCA-associated vasculitis suggest that CD8+ T cells participate in disease, but there is no experimental functional evidence of pathologic involvement for these cells. Myeloperoxidase (MPO) is a well defined autoantigen in ANCA-associated vasculitis. Studies in experimental models of anti-MPO GN suggest that, after ANCA-induced neutrophil localization, deposited MPO within glomeruli is recognized by autoreactive T cells that contribute to injury. We tested the hypothesis that CD8+ T cells mediate disease in experimental ANCA- associated vasculitis. CD8+ T cell depletion in the effector phase of disease attenuated injury in murine anti-MPO GN. This protection associated with decreased levels of intrarenal IFN-g, TNF, and inflammatory chemokines and fewer glomerular macrophages. Moreover, we identified a pathogenic CD8+ T cell MPO epitope (MPO431-439) and found that cotransfer of MPO431-439-specific CD8+ T cell clones exacerbated disease mediated byMPO-specific CD4+ cells in Rag1-/- mice. Transfer ofMPO431-439-specificCD8+ cellswithout CD4+ cellsmediated glomerular injury whenMPOwas planted in glomeruli. These results show a pathogenic role forMPO- specific CD8+ T cells, provide evidence that CD8+ cells are a therapeutic target in ANCA-associated vasculitis, and suggest that a molecular hotspot within the MPO molecule contains important CD8+, CD4+, and B cell epitopes.

Original languageEnglish
Pages (from-to)47-55
Number of pages9
JournalJournal of the American Society of Nephrology
Volume28
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Cite this

@article{b3b0975cafd149498e1c315338024e41,
title = "CD8+ T cells effect glomerular injury in experimental anti-myeloperoxidase GN",
abstract = "Observations in patients with ANCA-associated vasculitis suggest that CD8+ T cells participate in disease, but there is no experimental functional evidence of pathologic involvement for these cells. Myeloperoxidase (MPO) is a well defined autoantigen in ANCA-associated vasculitis. Studies in experimental models of anti-MPO GN suggest that, after ANCA-induced neutrophil localization, deposited MPO within glomeruli is recognized by autoreactive T cells that contribute to injury. We tested the hypothesis that CD8+ T cells mediate disease in experimental ANCA- associated vasculitis. CD8+ T cell depletion in the effector phase of disease attenuated injury in murine anti-MPO GN. This protection associated with decreased levels of intrarenal IFN-g, TNF, and inflammatory chemokines and fewer glomerular macrophages. Moreover, we identified a pathogenic CD8+ T cell MPO epitope (MPO431-439) and found that cotransfer of MPO431-439-specific CD8+ T cell clones exacerbated disease mediated byMPO-specific CD4+ cells in Rag1-/- mice. Transfer ofMPO431-439-specificCD8+ cellswithout CD4+ cellsmediated glomerular injury whenMPOwas planted in glomeruli. These results show a pathogenic role forMPO- specific CD8+ T cells, provide evidence that CD8+ cells are a therapeutic target in ANCA-associated vasculitis, and suggest that a molecular hotspot within the MPO molecule contains important CD8+, CD4+, and B cell epitopes.",
author = "Janet Chang and Peter Eggenhuizen and O'Sullivan, {Kim M.} and Alikhan, {Maliha A.} and Holdsworth, {Stephen R.} and Ooi, {Joshua D.} and Kitching, {A. Richard}",
year = "2017",
month = "1",
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language = "English",
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pages = "47--55",
journal = "Journal of the American Society of Nephrology",
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T1 - CD8+ T cells effect glomerular injury in experimental anti-myeloperoxidase GN

AU - Chang, Janet

AU - Eggenhuizen, Peter

AU - O'Sullivan, Kim M.

AU - Alikhan, Maliha A.

AU - Holdsworth, Stephen R.

AU - Ooi, Joshua D.

AU - Kitching, A. Richard

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Observations in patients with ANCA-associated vasculitis suggest that CD8+ T cells participate in disease, but there is no experimental functional evidence of pathologic involvement for these cells. Myeloperoxidase (MPO) is a well defined autoantigen in ANCA-associated vasculitis. Studies in experimental models of anti-MPO GN suggest that, after ANCA-induced neutrophil localization, deposited MPO within glomeruli is recognized by autoreactive T cells that contribute to injury. We tested the hypothesis that CD8+ T cells mediate disease in experimental ANCA- associated vasculitis. CD8+ T cell depletion in the effector phase of disease attenuated injury in murine anti-MPO GN. This protection associated with decreased levels of intrarenal IFN-g, TNF, and inflammatory chemokines and fewer glomerular macrophages. Moreover, we identified a pathogenic CD8+ T cell MPO epitope (MPO431-439) and found that cotransfer of MPO431-439-specific CD8+ T cell clones exacerbated disease mediated byMPO-specific CD4+ cells in Rag1-/- mice. Transfer ofMPO431-439-specificCD8+ cellswithout CD4+ cellsmediated glomerular injury whenMPOwas planted in glomeruli. These results show a pathogenic role forMPO- specific CD8+ T cells, provide evidence that CD8+ cells are a therapeutic target in ANCA-associated vasculitis, and suggest that a molecular hotspot within the MPO molecule contains important CD8+, CD4+, and B cell epitopes.

AB - Observations in patients with ANCA-associated vasculitis suggest that CD8+ T cells participate in disease, but there is no experimental functional evidence of pathologic involvement for these cells. Myeloperoxidase (MPO) is a well defined autoantigen in ANCA-associated vasculitis. Studies in experimental models of anti-MPO GN suggest that, after ANCA-induced neutrophil localization, deposited MPO within glomeruli is recognized by autoreactive T cells that contribute to injury. We tested the hypothesis that CD8+ T cells mediate disease in experimental ANCA- associated vasculitis. CD8+ T cell depletion in the effector phase of disease attenuated injury in murine anti-MPO GN. This protection associated with decreased levels of intrarenal IFN-g, TNF, and inflammatory chemokines and fewer glomerular macrophages. Moreover, we identified a pathogenic CD8+ T cell MPO epitope (MPO431-439) and found that cotransfer of MPO431-439-specific CD8+ T cell clones exacerbated disease mediated byMPO-specific CD4+ cells in Rag1-/- mice. Transfer ofMPO431-439-specificCD8+ cellswithout CD4+ cellsmediated glomerular injury whenMPOwas planted in glomeruli. These results show a pathogenic role forMPO- specific CD8+ T cells, provide evidence that CD8+ cells are a therapeutic target in ANCA-associated vasculitis, and suggest that a molecular hotspot within the MPO molecule contains important CD8+, CD4+, and B cell epitopes.

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