Systems serology identifies FcR-related autoantibody signatures and functions for Sjögren's syndrome

Sjögren's Syndrome (SjS) has historically been associated with classical anti-Ro60/SSA, Ro52/SSA and La/SSB, however they are lacking in one third of the patients, which induces delays in diagnosis, and their disease-contributing role is debated. Here we have applied a SjS-tailored Systems Serology approach to a cohort of 58 SjS and 16 non-SjS sicca syndrome patients, and 40 healthy individuals, involving a multiplex assay measuring antibody isotype, subclass, Fc Receptor and complement engagement to 14 SjS-related autoantigens, an antibody-glycosylation profiling assay and a phagocytosis cell-based assay. Via a machine learning approach, we have identified unique autoantibody signatures, including classical and non-classical autoantigens-related features especially involving autoantigen-specific Fc Receptor binding, with apparent functional consequences. These findings provide interesting insights into the autoantibody responses in SjS, possibly paving the way for improved diagnostics, especially in difficult-to-diagnose patients (e.g., seronegative SjS and non-SjS sicca syndrome patients), and novel therapeutic options targeting autoantibody-specific Fc/Fc Receptor-related effector functions.