Shigefumi Matsuzawa, Aya Ushio, Kunihiro Otsuka, Ruka Nagao, Takaaki Tsunematsu, Masafumi Moriyama and Naozumi Ishimaru : Neonatal Thymic Dynamics Influence Autoimmune Pathology by Shaping the Suppressive Potential of Regulatory T Cells, The American Journal of Pathology, 196, 4, 920-933, 2026.
(要約)
Neonatal thymectomy (TX) has been known to induce experimental autoimmune disease models in mice for over half a century. The thymic microenvironment, including thymic epithelial cells (TECs), plays a crucial role in establishing self-tolerance in T cells. However, the extent to which the dynamic changes in the neonatal thymic environment contribute to the onset of autoimmunity remains incompletely understood. In this study, the detailed alterations in the neonatal thymus and peripheral lymphoid organs were analyzed using a mouse model of primary Sjögren disease. Mice treated with TX at 3 days after birth (day 3-TX) exhibited significantly more severe autoimmune pathology than those treated with TX at 7 days after birth. Around day 3, T-cell differentiation and the expansion of TECs, particularly medullary TECs, were markedly accelerated in the neonatal thymus. Furthermore, in day 3-TX mice, the expansion of peripherally induced regulatory T (Treg) cells was impaired, along with the loss of thymic-derived Treg cell output that typically undergoes robust expansion around day 3 after birth. The suppressive activity of Treg cells from day 3-TX mice was significantly impaired compared with that of control Treg cells. These findings suggest that the neonatal thymic environment plays a critical role in regulating peripheral immune tolerance and may influence the pathogenesis of autoimmune diseases.
Mari Nishida, Kunihiro Otsuka, Ruka Nagao, Shigefumi Matsuzawa, Aya Ushio, Takaaki Tsunematsu, Keiko Aota and Naozumi Ishimaru : Tissue-Specific Expansion of Age-Associated B Cells via IFN-γ and IL-21 Within Salivary Glands in Sjögren Disease., Journal of Immunology Research, 2026, 1, 2026.
(要約)
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.