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J Immunol. 2017 Jan 1;198(1):82-93. Epub 2016 Nov 18.

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

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Amsterdam Rheumatology and Immunology Center, Reade, 1056 AB Amsterdam, the Netherlands;
Department of Immunopathology, Sanquin Research, 1006 AN Amsterdam, the Netherlands.
Amsterdam Rheumatology and Immunology Center, Reade, 1056 AB Amsterdam, the Netherlands.
Amsterdam Rheumatology and Immunology Center, Academic Medical Center, 1100 DD Amsterdam, the Netherlands.
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands.
Amsterdam Rheumatology and Immunology Center, VU University Medical Center, 1007 MB Amsterdam, the Netherlands; and.
Department of Experimental Immunohematology, Sanquin Research, 1006 AN Amsterdam, the Netherlands.


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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