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关键词： IMQ   dendritic cells   T helper cells   NF-kappa B pathway   T cell polarization  

摘要： Although imiquimod (IMQ) is widely used to induce psoriasis-like inflammation in mouse models, its direct effects on dendritic cells (DCs) and their capacity to drive T cell polarization remain poorly defined. The systemic complexity of in vivo models hinders the ability to delineate the direct, cell-intrinsic effects of IMQ. To address this gap, an in vitro DC-CD4+ T cell co-culture system was established using bone marrow-derived DCs and na & iuml;ve CD4+ T cells isolated from OT-II mice, enabling precise evaluation of the direct immunomodulatory effects of IMQ. IMQ treatment markedly upregulated maturation markers (CD40, CD80, CD86 and major histocompatibility complex class II), and increased IL-12 and IL-6 secretion in a dose-dependent manner. These effects were significantly attenuated by NF-kappa B inhibitors (caffeic acid phenethyl ester and Bay 11-7082), indicating a critical role for NF-kappa B signaling in DC activation. When co-cultured with na & iuml;ve CD4+ T cells, IMQ-treated DCs promoted robust differentiation toward T helper (Th)1 and Th17 subsets. Neutralization of IL-12 and IL-6 in the co-culture system significantly reduced the frequencies of Th1 and Th17 cells and their cytokine output, confirming that these responses were mediated by DC-derived cytokines. Collectively, the present findings demonstrated that IMQ directly activated DCs via NF-kappa B signaling and induced pathogenic Th cell responses through IL-12 and IL-6 production. By eliminating confounding in vivo factors, the present study provided evidence for the DC-intrinsic effects of IMQ and offered mechanistic insights into the cellular pathways linking innate immune sensing to adaptive T cell responses in psoriasis.

关键词： autoimmune disease   high endothelial venules   interleuikin-17A   pemphigus vegetans   rituximab   tissue-resident memory T cell  

摘要： A 49-year-old man with pemphigus vegetans (PVeg) relapsed several times due to cessation of therapy. At the age of 66, vegetative plaques developed at the left oral commissure following mechanical plucking of approximately 500 beard hairs. Treatment with prednisolone (20 mg/day) was continued but yielded no clinical improvement. Subsequently, rituximab (1000 mg twice, 2 weeks apart) led to a rapid decline of anti-desmoglein 3 (Dsg3) autoantibody and clinical improvement. The lesion resolved after 18 months, and prednisolone was tapered without recurrence. Based on the site-specific recurrence and chronicity, we hypothesized that tissue-resident memory T (TRM) cells and high endothelial venules (HEV)-like vessels contributed to disease persistence. Immunohistochemical analysis revealed a substantial presence of IL-17A-producing CD69 ++ CD103 ++ TRM cells in the dermis. In addition, PNAd++ HEV-like vessels were increased, accompanied by infiltrates of B cells and plasma cells. Notably, Dsg3-specific B cells were also detected, indicating that rituximab-mediated B cell depletion likely contributed to lesion resolution in this case.

关键词： oxidative stress   TNFR2   TNF   Treg   tumor microenvironment  

摘要： TNF is a pleiotropic cytokine with immunomodulatory functions mediated by its interaction with the receptor TNFR2, highly expressed by Tregs. However, Tregs can also produce TNF, and an autocrine TNF-TNFR2 loop has been proposed. Here, we describe that both human and mouse Tregs produce TNF in physiological conditions, in several mouse organs, and in mouse models of chronic inflammation and cancer. However, TNF production and TNFR2 expression are differentially distributed: indeed, TNFR2(+) and TNFR2(-) Treg subsets are, respectively, poor and strong TNF producers. The two subsets of TNFR2(+) and TNFR2(-) Tregs partially maintain their different ability to produce TNF when separately stimulated ex vivo. However, when cocultured, the TNFR2(+) cells greatly outnumber the TNFR2(-) counterpart and induce in TNFR2(-) cells the upregulation of Foxp3 and TNFR2, in association with the transfer of cytoplasmic material. Functionally, TNFR2(+) Tregs display superior suppressive activity and survival in vitro, both related to an improved resistance to oxidative stress. Overall, our data indicate that Tregs exist in two states, respectively committed to TNF production or TNF sensing through TNFR2, which cooperate in promoting the suppressive function of the whole Treg pool.

关键词： allergic rhinitis   circulating inflammatory proteins   cytokine   differential gene expression   immunotherapeutic targets   mendelian randomization  

摘要： Background Inflammatory proteins play a significant role in the pathogenesis of allergic rhinitis (AR), but the causal relationships remain unclear. We aimed to identify potential causal circulating inflammatory proteins contributing to the development of AR. Methods We employed Mendelian randomization (MR) analysis to determine the causal relationship between 91 circulating inflammatory proteins and AR. Inverse variance weighted (IVW) was the main analytic pipeline, followed by sensitivity analysis. The genome-wide association study (GWAS) summary datasets for AR and circulating inflammatory proteins were used for the analysis. The AR dataset comprised 12,240 cases and 392,069 controls, while the summary datasets for 91 plasma proteins contained 14,824 participants. Subsequent to the MR analysis, bioinformatic analysis was employed to probe differences in specific gene expression levels and to construct a network of associated proteins. Results The results of the MR analysis indicated that four inflammatory proteins had a causal effect on AR, including interleukin-4 (IL-4), interleukin-6 (IL-6), Chemokine (C-C motif) ligand 19 (CCL19), and Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER). Through differential gene expression analysis, IL4 mRNA expression was significantly elevated in AR patients compared to healthy controls. Protein-protein interaction (PPI) analysis via the STRING database revealed that IL-6, IL-4, and CCL19 constituted a densely connected network. Conclusion Our study supports the involvement of four circulating inflammatory proteins (IL-4, IL-6, CCL19, and DNER), especially IL-4, in susceptibility to AR. These findings highlight IL-4, IL-6, CCL19, and DNER as promising immunotherapeutic targets, providing mechanistic insights for developing novel diagnostics and biologic therapies for AR management.

关键词： HLA   Desensitization   Antibodies   Waitlist   Infectious complications  

摘要： HLA antibodies remain a barrier to lung transplantation due to the risk of antibody-mediated rejection (AMR). Desensitization is an option to lower antibody levels and increase access to transplant by reducing risk of AMR. However, concerns remain regarding the efficacy, durability, and risks of administering this treatment while waiting for deceased donor offers. We performed longitudinal antibody assessments for 15 highly sensitized lung candidates undergoing desensitization with plasmapheresis-based treatment protocols. Of the 14 patients transplanted, a significant decrease in overall antibody level was observed in the 2 of 4 patients transplanted within 15 days of the end of their first treatment. Conversely, of the 10 who were transplanted more than 15 days after first treatment, 7 patients rebounded to pre-treatment levels or higher within 3-4 weeks. For the 3 patients in this group who showed a durable decrease, this effect did not manifest until months following treatment. When comparing outcomes for the desensitization cohort against a control group that received treatment post-transplant, no significant differences in survival or acute rejection were observed. These results demonstrate that while plasmapheresis-based waitlist desensitization can effectively remove or reduce the level of HLA antibodies, rebound limits its effectiveness for most patients. To promote successful outcomes, pre-transplant therapy should be targeted to candidates with high lung composite allocation scores likely to be transplanted within the first week after treatment, while aggressive post-transplant immunosuppression may be a safer approach for most highly sensitized patients.