Anti-hinge antibodies recognize IgG subclass- and protease-restricted neoepitopes

Willem J.J. Falkenburg, Dirkjan Van Schaardenburg, Pleuni Ooijevaar-De Heer, Michel W.P. Tsang-A-Sjoe, Irene E.M. Bultink, Alexandre E. Voskuyl, Arthur E.H. Bentlage, Gestur Vidarsson, Gertjan Wolbink, Theo Rispens

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease- and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)- or pepsin-generated F(ab′)2 fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab′)2 targets was found in 68% (68 of 100) of HDs, 69% (68 of 99) of SLE patients, and 81% (79 of 97) of RA patients. Specific recognition of hinge epitopes was dependent on IgG subclass and protease used to create the F(ab′)2 targets, as confirmed by inhibition experiments with F(ab′)2 fragments and hinge peptides. Reactivity against IdeS-generated F(ab′)2 targets was found most frequently, whereas reactivity against pepsin-generated F(ab′)2 targets better discriminated between RA and HDs or SLE, with significantly higher AHA levels against IgG1/3/4. In contrast, AHA levels against pepsin-cleaved IgG2 were comparable. No reactivity against IdeS-generated IgG2-F(ab′)2s was detected. The most discriminatory AHA reactivity in RA was against pepsin-cleaved IgG4, with a 35% prevalence, ≥5.8-fold higher than in HDs/SLE, and significantly higher levels (p < 0.0001). Cross-reactivity for F(ab′)2s generated from different IgG subclasses was only observed for subclasses having homologous F(ab′)2 C termini (IgG1/3/4). For IgG2, two pepsin cleavage sites were identified; anti-hinge reactivity was restricted to only one of these. In conclusion, AHAs specifically recognize IgG subclass- and protease-restricted hinge neoepitopes. Their protease-restricted specificity suggests that different AHA responses developed under distinct inflammatory or infectious conditions and may be markers of, and participants in, such processes.

Original languageEnglish
Pages (from-to)82-93
Number of pages12
JournalJournal of Immunology
Volume198
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Cite this

Falkenburg, Willem J.J. ; Van Schaardenburg, Dirkjan ; Ooijevaar-De Heer, Pleuni ; Tsang-A-Sjoe, Michel W.P. ; Bultink, Irene E.M. ; Voskuyl, Alexandre E. ; Bentlage, Arthur E.H. ; Vidarsson, Gestur ; Wolbink, Gertjan ; Rispens, Theo. / Anti-hinge antibodies recognize IgG subclass- and protease-restricted neoepitopes. In: Journal of Immunology. 2017 ; Vol. 198, No. 1. pp. 82-93.
@article{2eaecaf6a504457f876f7928791516ea,
title = "Anti-hinge antibodies recognize IgG subclass- and protease-restricted neoepitopes",
abstract = "Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease- and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)- or pepsin-generated F(ab′)2 fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab′)2 targets was found in 68{\%} (68 of 100) of HDs, 69{\%} (68 of 99) of SLE patients, and 81{\%} (79 of 97) of RA patients. Specific recognition of hinge epitopes was dependent on IgG subclass and protease used to create the F(ab′)2 targets, as confirmed by inhibition experiments with F(ab′)2 fragments and hinge peptides. Reactivity against IdeS-generated F(ab′)2 targets was found most frequently, whereas reactivity against pepsin-generated F(ab′)2 targets better discriminated between RA and HDs or SLE, with significantly higher AHA levels against IgG1/3/4. In contrast, AHA levels against pepsin-cleaved IgG2 were comparable. No reactivity against IdeS-generated IgG2-F(ab′)2s was detected. The most discriminatory AHA reactivity in RA was against pepsin-cleaved IgG4, with a 35{\%} prevalence, ≥5.8-fold higher than in HDs/SLE, and significantly higher levels (p < 0.0001). Cross-reactivity for F(ab′)2s generated from different IgG subclasses was only observed for subclasses having homologous F(ab′)2 C termini (IgG1/3/4). For IgG2, two pepsin cleavage sites were identified; anti-hinge reactivity was restricted to only one of these. In conclusion, AHAs specifically recognize IgG subclass- and protease-restricted hinge neoepitopes. Their protease-restricted specificity suggests that different AHA responses developed under distinct inflammatory or infectious conditions and may be markers of, and participants in, such processes.",
author = "Falkenburg, {Willem J.J.} and {Van Schaardenburg}, Dirkjan and {Ooijevaar-De Heer}, Pleuni and Tsang-A-Sjoe, {Michel W.P.} and Bultink, {Irene E.M.} and Voskuyl, {Alexandre E.} and Bentlage, {Arthur E.H.} and Gestur Vidarsson and Gertjan Wolbink and Theo Rispens",
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Anti-hinge antibodies recognize IgG subclass- and protease-restricted neoepitopes. / Falkenburg, Willem J.J.; Van Schaardenburg, Dirkjan; Ooijevaar-De Heer, Pleuni; Tsang-A-Sjoe, Michel W.P.; Bultink, Irene E.M.; Voskuyl, Alexandre E.; Bentlage, Arthur E.H.; Vidarsson, Gestur; Wolbink, Gertjan; Rispens, Theo.

In: Journal of Immunology, Vol. 198, No. 1, 01.01.2017, p. 82-93.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Anti-hinge antibodies recognize IgG subclass- and protease-restricted neoepitopes

AU - Falkenburg, Willem J.J.

AU - Van Schaardenburg, Dirkjan

AU - Ooijevaar-De Heer, Pleuni

AU - Tsang-A-Sjoe, Michel W.P.

AU - Bultink, Irene E.M.

AU - Voskuyl, Alexandre E.

AU - Bentlage, Arthur E.H.

AU - Vidarsson, Gestur

AU - Wolbink, Gertjan

AU - Rispens, Theo

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease- and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)- or pepsin-generated F(ab′)2 fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab′)2 targets was found in 68% (68 of 100) of HDs, 69% (68 of 99) of SLE patients, and 81% (79 of 97) of RA patients. Specific recognition of hinge epitopes was dependent on IgG subclass and protease used to create the F(ab′)2 targets, as confirmed by inhibition experiments with F(ab′)2 fragments and hinge peptides. Reactivity against IdeS-generated F(ab′)2 targets was found most frequently, whereas reactivity against pepsin-generated F(ab′)2 targets better discriminated between RA and HDs or SLE, with significantly higher AHA levels against IgG1/3/4. In contrast, AHA levels against pepsin-cleaved IgG2 were comparable. No reactivity against IdeS-generated IgG2-F(ab′)2s was detected. The most discriminatory AHA reactivity in RA was against pepsin-cleaved IgG4, with a 35% prevalence, ≥5.8-fold higher than in HDs/SLE, and significantly higher levels (p < 0.0001). Cross-reactivity for F(ab′)2s generated from different IgG subclasses was only observed for subclasses having homologous F(ab′)2 C termini (IgG1/3/4). For IgG2, two pepsin cleavage sites were identified; anti-hinge reactivity was restricted to only one of these. In conclusion, AHAs specifically recognize IgG subclass- and protease-restricted hinge neoepitopes. Their protease-restricted specificity suggests that different AHA responses developed under distinct inflammatory or infectious conditions and may be markers of, and participants in, such processes.

AB - Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease- and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)- or pepsin-generated F(ab′)2 fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab′)2 targets was found in 68% (68 of 100) of HDs, 69% (68 of 99) of SLE patients, and 81% (79 of 97) of RA patients. Specific recognition of hinge epitopes was dependent on IgG subclass and protease used to create the F(ab′)2 targets, as confirmed by inhibition experiments with F(ab′)2 fragments and hinge peptides. Reactivity against IdeS-generated F(ab′)2 targets was found most frequently, whereas reactivity against pepsin-generated F(ab′)2 targets better discriminated between RA and HDs or SLE, with significantly higher AHA levels against IgG1/3/4. In contrast, AHA levels against pepsin-cleaved IgG2 were comparable. No reactivity against IdeS-generated IgG2-F(ab′)2s was detected. The most discriminatory AHA reactivity in RA was against pepsin-cleaved IgG4, with a 35% prevalence, ≥5.8-fold higher than in HDs/SLE, and significantly higher levels (p < 0.0001). Cross-reactivity for F(ab′)2s generated from different IgG subclasses was only observed for subclasses having homologous F(ab′)2 C termini (IgG1/3/4). For IgG2, two pepsin cleavage sites were identified; anti-hinge reactivity was restricted to only one of these. In conclusion, AHAs specifically recognize IgG subclass- and protease-restricted hinge neoepitopes. Their protease-restricted specificity suggests that different AHA responses developed under distinct inflammatory or infectious conditions and may be markers of, and participants in, such processes.

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