CD8+ T Cells Effect Glomerular Injury in Experimental Anti-Myeloperoxidase GN.
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-γ, 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 by MPO-specific CD4+cells in Rag1-/-mice. Transfer of MPO431-439-specific CD8+cells without CD4+cells mediated glomerular injury when MPO was planted in glomeruli. These results show a pathogenic role for MPO-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.
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and.
Janet
J
Chang
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and.
Peter
P
Eggenhuizen
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and.
Kim M
KM
O'Sullivan
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and.
Maliha A
MA
Alikhan
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and.|Departments of Nephrology and.
Stephen R
SR
Holdsworth
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and Joshua.Ooi@monash.edu.
Joshua D
JD
Ooi
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and.|Departments of Nephrology and.|Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia.
A Richard
AR
Kitching
D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000201:enzymology* / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D005921:Glomerulonephritis / Q000201:enzymology* / Q000276:immunology*; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000276:immunology*
D001324:Autoantigens; D009195:Peroxidase
ANCA; glomerulonephritis; immunology; vasculitis