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Anti-Hinge Antibodies Recognize IgG Subclass– and Protease-Restricted Neoepitopes

DOI

30

Citations

33

References

2016

Year

Willem J.J. Falkenburg, Dirkjan van Schaardenburg, Pleuni Ooijevaar‐de Heer, Michel Tsang-A-Sjoe, Irene E. M. Bultink, Alexandre E. Voskuyl, Arthur E. H. Bentlage, Gestur Vidarsson, Gertjan Wolbink, Theo Rispens
The Journal of Immunology

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')<sub>2</sub> fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab')<sub>2</sub> 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')<sub>2</sub> targets, as confirmed by inhibition experiments with F(ab')<sub>2</sub> fragments and hinge peptides. Reactivity against IdeS-generated F(ab')<sub>2</sub> targets was found most frequently, whereas reactivity against pepsin-generated F(ab')<sub>2</sub> 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')<sub>2</sub>s 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')<sub>2</sub>s generated from different IgG subclasses was only observed for subclasses having homologous F(ab')<sub>2</sub> 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.

References

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