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

Area of Science:

• Immunology
• Autoimmunity
• Proteomics

Background:

• Anti-hinge antibodies (AHAs) target neoepitopes on IgG after proteolytic cleavage.
• Understanding AHA diversity and specificity is crucial for their application as biomarkers.

Purpose of the Study:

• To explore the diversity of protease- and IgG subclass-restricted AHAs.
• To evaluate AHAs as potential immunological markers in healthy donors (HDs), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) patients.

Main Methods:

• Determined AHA reactivity against F(ab')2 fragments of all four human IgG subclasses generated by IdeS or pepsin.
• Utilized inhibition experiments with F(ab')2 fragments and hinge peptides to confirm specificity.

Main Results:

• 68-81% of individuals exhibited AHA reactivity against at least one target.
• Reactivity was dependent on IgG subclass and protease; pepsin-generated fragments better discriminated RA from HDs/SLE.
• Anti-hinge reactivity against pepsin-cleaved IgG4 was significantly higher in RA patients (35% prevalence) compared to HDs/SLE.

Conclusions:

• AHAs specifically recognize IgG subclass- and protease-restricted hinge neoepitopes.
• Protease-restricted specificity suggests distinct AHA responses related to inflammatory or infectious conditions.
• AHAs may serve as markers for and participants in disease processes.