TY - JOUR
T1 - Epitope specificity determines pathogenicity and detectability in anca-associated vasculitis
AU - Roth, Aleeza J.
AU - Ooi, Joshua D.
AU - Hess, Jacob J.
AU - Van Timmeren, Mirjan M.
AU - Berg, Elisabeth A.
AU - Poulton, Caroline E.
AU - McGregor, Julie Anne
AU - Burkart, Madelyn
AU - Hogan, Susan L.
AU - Hu, Yichun
AU - Winnik, Witold
AU - Nachman, Patrick H.
AU - Stegeman, Coen A.
AU - Niles, John
AU - Heeringa, Peter
AU - Kitching, A. Richard
AU - Holdsworth, Stephen
AU - Jennette, J. Charles
AU - Preston, Gloria A.
AU - Falk, Ronald J.
PY - 2013/4/1
Y1 - 2013/4/1
N2 - Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCAnegative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.
AB - Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCAnegative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.
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U2 - 10.1172/JCI65292
DO - 10.1172/JCI65292
M3 - Article
C2 - 23549081
AN - SCOPUS:84875827100
SN - 0021-9738
VL - 123
SP - 1773
EP - 1783
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -