Tissue‐Specific Expansion of Age‐Associated B Cells via IFN‐γ and IL‐21 Within Salivary Glands in Sjögren Disease

Sjögren disease (SjD) is an autoimmune disorder that predominantly affects the exocrine glands, and advancing age is recognized as an important risk factor for its development. However, the mechanisms linking age and disease progression remain poorly understood. Age-associated B cells (ABCs), a subset of B cells that increase with age, have been implicated in autoimmune responses, but their role in SjD pathogenesis has not been fully clarified. In this study, we examined labial salivary glands (LSGs) from 44 SjD patients and 11 non-SjD sicca controls. T-bet⁺ CD20⁺ ABCs were detected infiltrating the glands in SjD patients, especially in individuals in their 40s-60s, but were rare in non-SjD sicca controls. To investigate the underlying mechanisms, we used a SjD mouse model at various ages. ABCs (CD11b⁺ CD95⁺ CD19⁺) began locally accumulating in the SGs from the mature-adult stage, earlier than in age-matched controls, while remaining low in cervical lymph nodes (cLNs). To explore the drivers of ABC expansion, we examined the factors involved in ABC differentiation, focusing on interleukin-21 (IL-21) and interferon-gamma (IFN-γ). This combination of IL-21 and IFN-γ upregulated T-bet expression on B cells in SjD model mice. In situ hybridization (ISH) and flow cytometric analysis revealed that CD4⁺ T cells, especially follicular helper T (Tfh)-like cells were a major source of IL-21 in the SGs of mature-adult-SjD mice. Additionally, ABCs themselves showed elevated expression of IFN-γ compared to other immune cells, indicating an autocrine mechanism promoting their expansion. Our findings suggest that ABCs accumulate in the SGs of SjD patients and model mice through IL-21 signaling from CD4⁺ T cells and autocrine IFN-γ activity. This localized expansion may contribute to autoimmune tissue damage. These results provide new insights into how aging-associated immune changes may drive the development and progression of SjD, offering potential targets for therapeutic intervention.