RESUMO
Objectives: Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Methods: Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 ( Stim1/2 Foxp3 ), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells from Stim1/2 Foxp3 mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. Results: Stim1/2 Foxp3 mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation in Stim1/2 Foxp3 mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells from Stim1/2 Foxp3 mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4 + T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. Conclusions: We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.
RESUMO
The surrounding surcharge has an adverse impact on the service performance of buildings and bridges, and it can endanger their structural safety, especially in soft soil areas. As one case study, the inclination accident of an expressway ramp bridge and its rectification are investigated in this study. Through the three-dimensional (3D) finite element (FE) analysis of the overall structures composed of the bridge span, the pier, and the pile foundation, the whole process of the inclination by the adjacent dumped earth, partial recovery by the unloading, and the lateral pushing rectification of the bridge structure were simulated. The results show that the surcharge load leads to soil displacement near the bridge pile, and the pile-soil interaction leads to the pile deformation, which further causes the inclination of the pier, and the movement of the bridge span. The severity of the accident can be measured by the inclination of the piers and the opening widths of the bridge expansion joints. Due to the plastic deformation and drainage consolidation of the soft clay foundation under the surcharge load, the inclination of the piles and piers cannot be fully recovered after unloading. In order to capture these processes, the FE simulation was divided into three steps. First, the drainage consolidation of the soil foundation were identified by FE simulation and the field measurement of the recovery of the structure after unloading. Second, the effects of soil properties, the surcharge time and surcharge strength on the bridge inclination and the recovery capacity after unloading are discussed. Finally, the rectification of the bridge by lateral pushing was simulated, and the deformation and stress in the pier and pile were calculated to evaluate the safety of the structures. These analyses provided understanding towards the prevention of the bridge inclination under surcharge load, prediction of the recovery by the unloading, and the methods to reduce the residual deformation to meet the specifications.