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关键词： 黄芩苷   Th1细胞   T淋巴细胞   调节性   细胞分化   体外研究  

摘要： 目的 探讨黄芩素对Naïve CD4+T细胞向Th1和Treg细胞分化的影响.方法 从6～8周龄的BALB/c雄性小鼠脾脏中分选出Naïve CD4+T细胞,并将其分为A～F组.A组细胞接种在包被有抗小鼠CD3抗体的孔板中,在含抗小鼠CD28抗体的培养基中培养72 h;B组细胞在A组基础上再加入白细胞介素-2(IL-2)、IL-12和抗小鼠IL-4抗体;C组细胞在B组的基础上再加入黄芩素.D组细胞的培养体系与 A组相同;E组细胞在D组的基础上再加入IL-2和转化生长因子-β(TGF-β);F组细胞在E组的基础上再加入黄芩素.通过流式细胞术检测A～C组中Th1细胞的比例和D～F组中Treg细胞的比例;通过RT-qPCR检测A～C组细胞中T盒子转录因子(T-bet)、干扰素-γ(IFN-γ)、肿瘤坏死因子-α(TNF-α)的相对表达水平和D～F组中叉头框蛋白P3(Foxp3)和IL-10的相对表达水平;通过免疫荧光染色检测A～C组中Th1细胞阳性率和D～F组中Treg细胞阳性率.结果 流式细胞术检测结果显示,C组Th1细胞比例显著低于B组(F=46.91,q=7.95,P＜0.05),F组Treg细胞比例显著高于 E 组(F=145.20,q=8.64,P＜0.05).RT-qPCR 检测结果显示,C 组细胞中 T-bet、IFN-γ、TNF-α 的相对表达水平显著低于B组(F=15.77～862.50,q=7.05～26.34,P＜0.05),F组细胞中Foxp3和IL-10的相对表达水平显著高于 E组(F=38.25、49.24,q=4.65、7.64,P＜0.05).免疫荧光结果显示,C组Th1细胞阳性率显著低于B组(F=11.64,q=4.50,P＜0.05),F 组 Treg 细胞阳性率显著高于 E 组(F=20.31,q=4.64,P＜0.05).结论 黄芩素对Naïve CD4+T细胞向Th1细胞分化具有抑制作用,对Naïve CD4+T细胞向Treg细胞分化具有促进作用.

关键词： Multiple sclerosis   Haplotypes   Sensory perception   Brainstem   Medical risk factors   Major histocompatibility complex   Autoimmune diseases   Central nervous system  

摘要： Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS). The pathogenesis of MS is characterized by neuronal axonal degeneration and demyelination. Among the genes that raises MS risk are the HLA-class II genes. The goals of this study were to investigate the role of the HLA-DRB1 and HLA-DQB1 genes (for the first time) in Jordanian MS patients and their association with MS disease. The association of these genes with other clinical features, such as optic neuritis, sensory impairment, and brainstem symptoms in MS patients was investigated as well using PCR-SSP techniques. Our findings indicated an association between HLA-DRB1 * 03:01 (Pc = 0.01) and HLA-DRB1 * 04:01 (Pc = 0.004) alleles with Jordanian MS patients. In addition, a significant linkage between HLA-DRB1 * 15:01 and HLA-DQB1 * 06:01 alleles (Pc <= 0.001 and Pc = 0.012, respectively) were presented among Jordanian MS patients with optic neuritis compared to Jordanian MS patients without optic neuritis. Moreover, HLA-DQB1 * 05:01 and HLA-DQB1 * 06:02 alleles (Pc <= 0.001 and Pc = 0.006, respectively) was found to be related with sensory impairment in MS patients. Additionally, HLA-DRB1 * 07:01 allele indicates a positive correlation in MS patients with brainstem symptoms (Pc < 0.001). Moreover, our results indicated that there is no association on the HLA-DRB1 similar to HLA-DQB1 haplotype level and MS disease. Knowing the genes that are linked to MS, they may facilitate MS diagnosis, prevention, and treatment at earlier stage. Also, these results may serve in the development of more potent therapeutic regimens for MS and its related complications, such as optic neuritis, sensory impairment, and brainstem symptoms.

关键词： atopic dermatitis   autoinflammatory syndrome   basiliximab   IL-2R inhibitors   monoclonal antibody   precision medicine  

摘要： Options for pediatric patients with severe atopic dermatitis who do not respond to biologics remain limited. We report the case of a 10-year-old boy with severe, recalcitrant atopic dermatitis associated with episodic fever, joint pains, and elevated serum IL-2R, which responded to basiliximab. To our knowledge, this is the first reported use of basiliximab for atopic dermatitis in a pediatric patient. This case highlights the potential for basiliximab as a therapy for severe cases of atopic dermatitis and the potential for precision medicine in dermatology.

关键词： maternal-fetal immune tolerance   endometrial receptivity   embryonic development   eomesodermin   methionine   methylation   transcription   IL-5  

摘要： Endometrial receptivity and maternal-fetal immune tolerance are two crucial processes for a successful pregnancy. However, the molecular mechanisms of nutrition involved are largely unexplored. Here, we showed that maternal methionine supply significantly improved pregnancy outcomes, which was closely related to interleukin-5 (IL-5) concentration. Mechanistically, methionine induced embryonic IL-5 secretion, which enhanced the conversion of CD4+ T cells to IL-5+ Th2 cells in the uterus, thereby improving maternal-fetal immune tolerance. Meanwhile, methionine-mediated IL-5 secretion activated the nuclear factor kB (NF-kB) pathway and enhanced integrin avb3 expression in endometrial cells, which improved endometrial receptivity. Further, methionine strongly influenced the DNA methylation and transcription levels of the transcription factor eomesodermin (Eomes), which bound directly to the IL-5 promoter region and inhibited IL-5 transcription. Methionine modulated IL-5 transcription, maternal-fetal immune tolerance, and endometrial receptivity via its effects on Eomes. This study reveals the crucial functions of methionine and IL-5 and offers a potential nutritional strategy for successful pregnancy.

关键词： Andrographolide   Inflammation   TNF-alpha   IL-6   Molecular docking  

摘要： Benzylidene derivatives of 14-deoxyandrographolide (14-DAG) have been synthesised in good to excellent yield. All the synthesised compounds were screened for anti-inflammatory activity. The results of the cell viability assay suggested that most of the compounds were non-toxic and were further selected for investigation of NO inhibition potential. The selected compounds were investigated for their NO inhibition potential in comparison to andrographolide using LPS induced RAW 264.7 cells. The results demonstrated significant NO inhibitory activity of compound 4e in comparison to andrographolide. Based on these results, compound 4e was further investigated for inhibition of pro-inflammatory cytokines, including cytokines TNF-alpha and IL-6 in LPS-induced murine macrophages. Inhibitory effects of compound 4e, on pro-inflammatory cytokines TNF-alpha and IL-6 were compared to the parent compound, andrographolide, wherein the results demonstrated that compound 4e exhibited an IC50 (TNF- alpha) of 8.07 mu M in comparison to andrographolide which exhibited an IC50 of 15.86 mu M. Further molecular docking studies of the most potent compound 4e was also performed, which showed that the chemical forms substantial hydrogen and alkyl bonds with TNF-alpha, demonstrating a greater binding affinity than IL-6. The overall findings of compound 4e suggested that it can possibly be a promising structural lead for the development of new anti-inflammatory agents.

关键词： Autoimmunity   Immunotherapy   Interleukin-18   Interleukin-1β   MAS825   Macrophage activation syndrome   Still's disease   Systemic juvenile idiopathic arthritis  

摘要： Graphical abstract

关键词： dendritic cells   GRASP55   antigen presentation   MHC transport   phagosomes  

摘要： Dendritic cells (DCs) present exogenous antigens via major histocompatibility complex class I (MHC-I) and MHC class II (MHC-II) molecules, activating CD8+ and CD4+ T cells. A critical but poorly understood step in this process is the trafficking of peptide-loaded MHC molecules from the endocytic system to the cell surface. In this study, we demonstrate that the Golgi reassembly-stacking protein of 55 kDa (GRASP55), which has been shown to have no role in stacking, is essential for antigen presentation. Using soluble, bead-coated, and bacterial-bound antigens, we found significantly impaired exogenous antigen presentation in GRASP55deficient bone-marrow-derived DCs (BMDCs). Notably, GRASP55 was recruited to late phagosomes, and our data suggest that it is crucial for sorting MHC-I and MHC-II molecules, facilitating their trafficking to the plasma membrane. Our findings highlight the vital role of GRASP55 in the intracellular transport of MHC molecules bound to their respective peptides during exogenous antigen presentation.

关键词： celiac disease   HLA   diagnosis   potential CeD   pediatric  

摘要： Objectives Diagnosis of celiac disease (CeD), an immune-mediated disorder, is based on clinical presentation, a panel of serological markers, and the histopathological findings in duodenal biopsies. Commonly, pediatric CeD patients fulfill these criteria for diagnosis. However, lack of correlation between serology tests and histology, or no accessible biopsies because of clinical conditions or during the COVID pandemic, are conditions that led to inconclusive diagnoses. Since the majority of CeD patients carry HLA-DQ2 and/or DQ8 alleles, HLA testing is used as a complementary tool in diagnosis though is costly and not broadly available for gastroenterology *** We performed a retrospective study to assess the performance of HLA testing when applied to selected groups of patients who could not be definitely diagnosed following the common algorithm. Eighty patients underwent testing for CeD-related HLA-DQ2 and DQ8 *** HLA typing contributed to diagnosis in 34 patients with positive serology but normal mucosa or those who presented negative serology or slightly positive serology (less than 3 times ULN) and duodenal histopathological changes. In patients with normal histology and negative or slightly positive serology, or those who did not undergo intestinal biopsy (39 in total), HLA typing contributed to CeD diagnosis in 23 cases, only 16 patients were admitted for a clinical follow-up *** HLA-DQ typing supported the diagnosis in 57 of 80 children (71.2%) with previously inconclusive results, providing a beneficial approach for diagnosing celiac disease (CeD) in selected cases.

关键词： RV   resistance   pathogenesis   receptor   tropism   Atoh1   Muc2   secretory cell   MHC II  

摘要： Enteric pathogen rotavirus (RV) primarily infects mature enterocytes at the tips of the intestinal villi;however, the role of secretory Paneth and goblet cells in RV pathogenesis remains unappreciated. Atoh1 knockout mice (Atoh1cKO) were used to conditionally delete Paneth, goblet, and enteroendocrine cells in the epithelium to investigate the role of secretory cells in RV infection. Unexpectedly, the number of infected enterocytes and the amount of RV shedding in the stool were greatly decreased following secretory cell deletion. Resistance to RV infection persisted for 7 days after virus inoculation, and Atoh1 knockout mice co-housed with infected wild-type mice were uninfected, based on lack of shedding virus, despite the highly infectious nature of RV. This response was directly proportional to the extent of secretory cell deletion, with infection predominantly occurring in areas containing intact secretory cells. RV infection of Muc2 knockout mice recapitulated the secretory cell deletion phenotype, indicating that goblet cell loss is responsible for attenuated infection. Transcriptome analysis of Atoh1cKO intestine via single-cell RNA sequencing revealed downregulation of MHC II molecules specifically in tip enterocytes, and MHC II-/- mice were likewise resistant to RV infection. These data suggest a previously unknown role for both MUC2 and MHC II expression in susceptibility to RV infection.