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 language | English |
|---|---|
| Pages (from-to) | 47-55 |
| Number of pages | 9 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 28 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Jan 2017 |
Cite this
}
CD8+ T cells effect glomerular injury in experimental anti-myeloperoxidase GN. / Chang, Janet; Eggenhuizen, Peter; O'Sullivan, Kim M.; Alikhan, Maliha A.; Holdsworth, Stephen R.; Ooi, Joshua D.; Kitching, A. Richard.
In: Journal of the American Society of Nephrology, Vol. 28, No. 1, 01.01.2017, p. 47-55.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85020553906&partnerID=8YFLogxK
U2 - 10.1681/ASN.2015121356
DO - 10.1681/ASN.2015121356
M3 - Article
VL - 28
SP - 47
EP - 55
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 1
ER -