Interferon-α-Driven Stratification of B Cells Reveals Metabolic Reprogramming of Double-Negative, Naïve, and Transitional Cell Subsets and Refines Molecular Classification in Sjögren's Disease.

Sjögren's disease (SjD) is a chronic autoimmune condition marked by lymphocytic infiltration of exocrine glands and production of autoantibodies such as anti-SSA/Ro, anti-SSB/La, and rheumatoid factor. B lymphocytes play a central role in disease pathogenesis, driving autoantibody production and glandular damage, and contributing to lymphomagenesis. Despite promising therapies, no effective treatment is currently available, partly due to the biological and clinical heterogeneity of the disease. While interferon (IFN) signatures and B cell-related markers are used for patient stratification, their integration remains unexplored. This study analyzed B cell transcriptional and metabolic profiles using bulk transcriptomic, clinical, and flow cytometry data from the PRECISESADS consortium, alongside public single-cell RNA-sequencing datasets. A B cell-specific IFN-α signature was established to stratify patients into IFN-positive and IFN-negative groups. Both showed reduced oxidative phosphorylation (OXPHOS) and translation in B cell subsets, suggesting a shared early metabolic reprogramming state. IFN-positive patients, however, displayed additional features, including enhanced glycolysis, amino acid and lipid metabolism, autophagy, and NF-κB signaling. They also showed an expansion of IFN-activated-naïve (naive IFN), Transitional, and double-negative (DN) B cells, particularly DN2 and DN2_CXCR3 subsets, which have been linked in the literature to autoreactivity and lymphoma development. The IFN-signature in naïve B cells and DN2 correlated with elevated anti-SSA/Ro and anti-SSB/La titers, while only naïve B cells showed an association with increased histological focus scores. These findings support B cell-specific IFN signature relevance in stratifying SjD patients and suggest new metabolic and transcriptional targets for disease monitoring and therapeutic development.