Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis

Aleeza J Roth, Joshua Ooi, Jacob J Hess, Mirjan M van Timmeren, Elisabeth A Berg, Caroline E Poulton, JulieAnne McGregor, Madelyn Burkart, Susan L Hogan, Yichun Hu, Witold Winnik, Patrick H Nachman, Coen A Stegeman, John Niles, Peter Heeringa, Arthur Richard Kitching, Stephen Roger Holdsworth, J Charles Jennette, Gloria A Preston, Ronald J Falk

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 ANCA-negative 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.
Original languageEnglish
Pages (from-to)1773 - 1783
Number of pages11
JournalJournal of Clinical Investigation
Volume123
Issue number4
DOIs
Publication statusPublished - 2013

Cite this

Roth, A. J., Ooi, J., Hess, J. J., van Timmeren, M. M., Berg, E. A., Poulton, C. E., ... Falk, R. J. (2013). Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. Journal of Clinical Investigation, 123(4), 1773 - 1783. https://doi.org/10.1172/JCI65292
Roth, Aleeza J ; Ooi, Joshua ; Hess, Jacob J ; van Timmeren, Mirjan M ; Berg, Elisabeth A ; Poulton, Caroline E ; McGregor, JulieAnne ; Burkart, Madelyn ; Hogan, Susan L ; Hu, Yichun ; Winnik, Witold ; Nachman, Patrick H ; Stegeman, Coen A ; Niles, John ; Heeringa, Peter ; Kitching, Arthur Richard ; Holdsworth, Stephen Roger ; Jennette, J Charles ; Preston, Gloria A ; Falk, Ronald J. / Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 4. pp. 1773 - 1783.
@article{810643f8d5c24aec9d52750d54a75dd8,
title = "Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis",
abstract = "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 ANCA-negative 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.",
author = "Roth, {Aleeza J} and Joshua Ooi and Hess, {Jacob J} and {van Timmeren}, {Mirjan M} and Berg, {Elisabeth A} and Poulton, {Caroline E} and JulieAnne McGregor and Madelyn Burkart and Hogan, {Susan L} and Yichun Hu and Witold Winnik and Nachman, {Patrick H} and Stegeman, {Coen A} and John Niles and Peter Heeringa and Kitching, {Arthur Richard} and Holdsworth, {Stephen Roger} and Jennette, {J Charles} and Preston, {Gloria A} and Falk, {Ronald J}",
year = "2013",
doi = "10.1172/JCI65292",
language = "English",
volume = "123",
pages = "1773 -- 1783",
journal = "Journal of Clinical Investigation",
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Roth, AJ, Ooi, J, Hess, JJ, van Timmeren, MM, Berg, EA, Poulton, CE, McGregor, J, Burkart, M, Hogan, SL, Hu, Y, Winnik, W, Nachman, PH, Stegeman, CA, Niles, J, Heeringa, P, Kitching, AR, Holdsworth, SR, Jennette, JC, Preston, GA & Falk, RJ 2013, 'Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis' Journal of Clinical Investigation, vol. 123, no. 4, pp. 1773 - 1783. https://doi.org/10.1172/JCI65292

Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. / Roth, Aleeza J; Ooi, Joshua; Hess, Jacob J; van Timmeren, Mirjan M; Berg, Elisabeth A; Poulton, Caroline E; McGregor, JulieAnne; Burkart, Madelyn; Hogan, Susan L; Hu, Yichun; Winnik, Witold; Nachman, Patrick H; Stegeman, Coen A; Niles, John; Heeringa, Peter; Kitching, Arthur Richard; Holdsworth, Stephen Roger; Jennette, J Charles; Preston, Gloria A; Falk, Ronald J.

In: Journal of Clinical Investigation, Vol. 123, No. 4, 2013, p. 1773 - 1783.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis

AU - Roth, Aleeza J

AU - Ooi, Joshua

AU - Hess, Jacob J

AU - van Timmeren, Mirjan M

AU - Berg, Elisabeth A

AU - Poulton, Caroline E

AU - McGregor, JulieAnne

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, Arthur Richard

AU - Holdsworth, Stephen Roger

AU - Jennette, J Charles

AU - Preston, Gloria A

AU - Falk, Ronald J

PY - 2013

Y1 - 2013

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 ANCA-negative 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 ANCA-negative 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

VL - 123

SP - 1773

EP - 1783

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

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